Journal articles: 'Circulating tumour cell clusters'

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Kulasinghe, Arutha, Jian Zhou, Liz Kenny, Ian Papautsky, and Chamindie Punyadeera. "Capture of Circulating Tumour Cell Clusters Using Straight Microfluidic Chips." Cancers 11, no. 1 (January 14, 2019): 89. http://dx.doi.org/10.3390/cancers11010089.

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Circulating tumour cells (CTCs) are the metastatic precursors to distant disease in head and neck cancers (HNCs). Whilst the prognostic and predictive value of single CTCs have been well documented, the role of CTC clusters, which potentially have a higher metastatic capacity are limited. In this study, the authors used a novel straight microfluidic chip to focus and capture CTCs. The chip offers high cell recoveries with clinically relevant numbers (10–500 cells/mL) without the need for further purification. Single CTCs were identified in 10/21 patient samples (range 2–24 CTCs/mL), CTC clusters in 9/21 patient samples (range 1–6 CTC clusters/mL) and circulating tumour microemboli (CTM) in 2/21 samples. This study demonstrated that CTC clusters contain EGFR amplified single CTCs within the cluster volume. This novel microfluidic chip demonstrates the efficient sorting and preservation of single CTCs, CTC clusters and CTMs. The authors intend to expand this study to a larger cohort to determine the clinical implication of the CTC subsets in HNC.

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Herath, Sayuri, Sajad Razavi Bazaz, James Monkman, Majid Ebrahimi Warkiani, Derek Richard, Ken O’Byrne, and Arutha Kulasinghe. "Circulating tumor cell clusters: Insights into tumour dissemination and metastasis." Expert Review of Molecular Diagnostics 20, no. 11 (November 1, 2020): 1139–47. http://dx.doi.org/10.1080/14737159.2020.1846523.

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Krol, Ilona, Francesc Castro-Giner, Martina Maurer, Sofia Gkountela, Barbara Maria Szczerba, Ramona Scherrer, Niamh Coleman, et al. "Detection of circulating tumour cell clusters in human glioblastoma." British Journal of Cancer 119, no. 4 (August 2018): 487–91. http://dx.doi.org/10.1038/s41416-018-0186-7.

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Molnar, B., A. Ladanyi, J. Bocsi, L. Floro, L. Sreter, and Z. Tulassay. "Multifluorescent labelling of immunomagnetic enriched circulating colon tumour cells and cell clusters." European Journal of Cancer 37 (April 2001): S124. http://dx.doi.org/10.1016/s0959-8049(01)80945-x.

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Schikora, Detlef. "In vivo detection of circulating tumour cell clusters by photodiagnostic spectroscopy." Photodiagnosis and Photodynamic Therapy 30 (June 2020): 101755. http://dx.doi.org/10.1016/j.pdpdt.2020.101755.

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Krol, Ilona, Fabienne D. Schwab, Roberta Carbone, Mathilde Ritter, Sabrina Picocci, Marzia L. De Marni, Grazyna Stepien, et al. "Detection of clustered circulating tumour cells in early breast cancer." British Journal of Cancer 125, no. 1 (March 24, 2021): 23–27. http://dx.doi.org/10.1038/s41416-021-01327-8.

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AbstractCirculating tumour cell (CTC) clusters have been proposed to be major players in the metastatic spread of breast cancer, particularly during advanced disease stages. Yet, it is unclear whether or not they manifest in early breast cancer, as their occurrence in patients with metastasis-free primary disease has not been thoroughly evaluated. In this study, exploiting nanostructured titanium oxide-coated slides for shear-free CTC identification, we detect clustered CTCs in the curative setting of multiple patients with early breast cancer prior to surgical treatment, highlighting their presence already at early disease stages. These results spotlight an important aspect of metastasis biology and the possibility to intervene with anti-cluster therapeutics already during the early manifestation of breast cancer.

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Ahmed, Zafarali, and Simon Gravel. "Intratumor Heterogeneity and Circulating Tumor Cell Clusters." Molecular Biology and Evolution 35, no. 9 (June 12, 2017): 2135–44. http://dx.doi.org/10.1093/molbev/msy115.

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Yu, Min. "Metastasis Stemming from Circulating Tumor Cell Clusters." Trends in Cell Biology 29, no. 4 (April 2019): 275–76. http://dx.doi.org/10.1016/j.tcb.2019.02.001.

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Au, Sam H., Brian D. Storey, John C. Moore, Qin Tang, Yeng-Long Chen, Sarah Javaid, A. Fatih Sarioglu, et al. "Clusters of circulating tumor cells traverse capillary-sized vessels." Proceedings of the National Academy of Sciences 113, no. 18 (April 18, 2016): 4947–52. http://dx.doi.org/10.1073/pnas.1524448113.

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Multicellular aggregates of circulating tumor cells (CTC clusters) are potent initiators of distant organ metastasis. However, it is currently assumed that CTC clusters are too large to pass through narrow vessels to reach these organs. Here, we present evidence that challenges this assumption through the use of microfluidic devices designed to mimic human capillary constrictions and CTC clusters obtained from patient and cancer cell origins. Over 90% of clusters containing up to 20 cells successfully traversed 5- to 10-μm constrictions even in whole blood. Clusters rapidly and reversibly reorganized into single-file chain-like geometries that substantially reduced their hydrodynamic resistances. Xenotransplantation of human CTC clusters into zebrafish showed similar reorganization and transit through capillary-sized vessels in vivo. Preliminary experiments demonstrated that clusters could be disrupted during transit using drugs that affected cellular interaction energies. These findings suggest that CTC clusters may contribute a greater role to tumor dissemination than previously believed and may point to strategies for combating CTC cluster-initiated metastasis.

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Cima, Igor, Say Li Kong, Debarka Sengupta, Iain B. Tan, Wai Min Phyo, Daniel Lee, Min Hu, et al. "Tumor-derived circulating endothelial cell clusters in colorectal cancer." Science Translational Medicine 8, no. 345 (June 29, 2016): 345ra89. http://dx.doi.org/10.1126/scitranslmed.aad7369.

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Clusters of tumor cells are often observed in the blood of cancer patients. These structures have been described as malignant entities for more than 50 years, although their comprehensive characterization is lacking. Contrary to current consensus, we demonstrate that a discrete population of circulating cell clusters isolated from the blood of colorectal cancer patients are not cancerous but consist of tumor-derived endothelial cells. These clusters express both epithelial and mesenchymal markers, consistent with previous reports on circulating tumor cell (CTC) phenotyping. However, unlike CTCs, they do not mirror the genetic variations of matched tumors. Transcriptomic analysis of single clusters revealed that these structures exhibit an endothelial phenotype and can be traced back to the tumor endothelium. Further results show that tumor-derived endothelial clusters do not form by coagulation or by outgrowth of single circulating endothelial cells, supporting a direct release of clusters from the tumor vasculature. The isolation and enumeration of these benign clusters distinguished healthy volunteers from treatment-naïve as well as pathological early-stage (≤IIA) colorectal cancer patients with high accuracy, suggesting that tumor-derived circulating endothelial cell clusters could be used as a means of noninvasive screening for colorectal cancer. In contrast to CTCs, tumor-derived endothelial cell clusters may also provide important information about the underlying tumor vasculature at the time of diagnosis, during treatment, and throughout the course of the disease.

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Amintas, Samuel, Aurélie Bedel, François Moreau-Gaudry, Julian Boutin, Louis Buscail, Jean-Philippe Merlio, Véronique Vendrely, Sandrine Dabernat, and Etienne Buscail. "Circulating Tumor Cell Clusters: United We Stand Divided We Fall." International Journal of Molecular Sciences 21, no. 7 (April 10, 2020): 2653. http://dx.doi.org/10.3390/ijms21072653.

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The presence of circulating tumor cells (CTCs) and CTC clusters, also known as tumor microemboli, in biological fluids has long been described. Intensive research on single CTCs has made a significant contribution in understanding tumor invasion, metastasis tropism, and intra-tumor heterogeneity. Moreover, their being minimally invasive biomarkers has positioned them for diagnosis, prognosis, and recurrence monitoring tools. Initially, CTC clusters were out of focus, but major recent advances in the knowledge of their biogenesis and dissemination reposition them as critical actors in the pathophysiology of cancer, especially metastasis. Increasing evidence suggests that “united” CTCs, organized in clusters, resist better and carry stronger metastatic capacities than “divided” single CTCs. This review gathers recent insight on CTC cluster origin and dissemination. We will focus on their distinct molecular package necessary to resist multiple cell deaths that all circulating cells normally face. We will describe the molecular basis of their increased metastatic potential as compared to single CTCs. We will consider their clinical relevance as prognostic biomarkers. Finally, we will propose future directions for research and clinical applications in this promising topic in cancer.

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Reduzzi, Carolina, Serena Di Cosimo, Lorenzo Gerratana, Rosita Motta, Antonia Martinetti, Andrea Vingiani, Paolo D’Amico, et al. "Circulating Tumor Cell Clusters Are Frequently Detected in Women with Early-Stage Breast Cancer." Cancers 13, no. 10 (May 13, 2021): 2356. http://dx.doi.org/10.3390/cancers13102356.

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The clinical relevance of circulating tumor cell clusters (CTC-clusters) in breast cancer (BC) has been mostly studied using the CellSearch®, a marker-dependent method detecting only epithelial-enriched clusters. However, due to epithelial-to-mesenchymal transition, resorting to marker-independent approaches can improve CTC-cluster detection. Blood samples collected from healthy donors and spiked-in with tumor mammospheres, or from BC patients, were processed for CTC-cluster detection with 3 technologies: CellSearch®, CellSieve™ filters, and ScreenCell® filters. In spiked-in samples, the 3 technologies showed similar recovery capability, whereas, in 19 clinical samples processed in parallel with CellSearch® and CellSieve™ filters, filtration allowed us to detect more CTC-clusters than CellSearch® (median number = 7 versus 1, p = 0.0038). Next, samples from 37 early BC (EBC) and 23 metastatic BC (MBC) patients were processed using ScreenCell® filters for attaining both unbiased enrichment and marker-independent identification (based on cytomorphological criteria). At baseline, CTC-clusters were detected in 70% of EBC cases and in 20% of MBC patients (median number = 2, range 0–20, versus 0, range 0–15, p = 0.0015). Marker-independent approaches for CTC-cluster assessment improve detection and show that CTC-clusters are more frequent in EBC than in MBC patients, a novel finding suggesting that dissemination of CTC-clusters is an early event in BC natural history.

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Pang, Kai, Dan Wei, Pengfei Hai, Zhangru Yang, Xiaofu Weng, and Xunbin Wei. "Algorithm to identify circulating tumor cell clusters using in vivo flow cytometer." Journal of Innovative Optical Health Sciences 11, no. 05 (September 2018): 1850024. http://dx.doi.org/10.1142/s1793545818500244.

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Recent studies in oncology have addressed the importance of detecting circulating tumor cell clusters because circulating tumor cell clusters might survive and metastasize more easily than single circulating tumor cells. Signals with larger peak widths detected by in vivo flow cytometer (IVFC) have been used to identify cell clusters in previous studies. However, the accuracy of this criterion might be greatly degraded by variance in blood flow and the rolling behaviors of circulating tumor cells. Here, we propose a criterion and algorithm to distinguish cell clusters from single cells. In this work, we first used area-based and volume-based models for single fluorescent cells. Simulating each model, we analyzed the corresponding morphology of IVFC signals from cell clusters. According to the Rayleigh criterion, the valley between two adjacent peak signals from two distinguishable cells should be lower than 73.5% of the peak values. A novel signal processing algorithm for IVFC was developed based on this criterion. The results showed that cell clusters can be reliably identified using our proposed algorithm. Intravital imaging was also performed to further support our algorithm. With enhanced accuracy, IVFC is a powerful tool to study circulating cell clusters.

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Charles Jacob, Harrys, John Charles Richard, Rossana Signorelli, Tyler Kashuv, Shweta Lavania, Utpreksha Vaish, Ranjitha Boopathy, et al. "Modulation of Early Neutrophil Granulation: The Circulating Tumor Cell-Extravesicular Connection in Pancreatic Ductal Adenocarcinoma." Cancers 13, no. 11 (May 31, 2021): 2727. http://dx.doi.org/10.3390/cancers13112727.

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Tumor cells dissociate from the primary site and enter into systemic circulation (circulating tumor cells, CTCs) either alone or as tumor microemboli (clusters); the latter having an increased predisposition towards forming distal metastases than single CTCs. The formation of clusters is, in part, created by contacts between cell–cell junction proteins and/or cytokine receptor pairs with other cells such as neutrophils, platelets, fibroblasts, etc. In the present study, we provide evidence for an extravesicular (EV) mode of communication between pancreatic cancer CTCs and neutrophils. Our results suggest that the EV proteome of CTCs contain signaling proteins that can modulate degranulation and granule mobilization in neutrophils and, also, contain tissue plasminogen activator and other proteins that can regulate cluster formation. By exposing naïve neutrophils to EVs isolated from CTCs, we further show how these changes are modulated in a dynamic fashion indicating evidence for a deeper EV based remodulatory effect on companion cells in clusters.

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Vasantharajan, Sai Shyam, Edward Barnett, Elin S. Gray, John L. McCall, Euan J. Rodger, Michael R. Eccles, Fran Munro, Sharon Pattison, and Aniruddha Chatterjee. "Assessment of a Size-Based Method for Enriching Circulating Tumour Cells in Colorectal Cancer." Cancers 14, no. 14 (July 15, 2022): 3446. http://dx.doi.org/10.3390/cancers14143446.

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Circulating tumour cells (CTC) from solid tumours are a prerequisite for metastasis. Isolating CTCs and understanding their biology is essential for developing new clinical tests and precision oncology. Currently, CellSearch is the only FDA (U.S. Food and Drug Administration)-approved method for CTC enrichment but possesses several drawbacks owing to a reliance on the epithelial cell adhesion molecule (EpCAM) and a resource-intensive nature. Addressing these shortcomings, we optimised an existing size-based method, MetaCell, to enrich CTCs from blood of colorectal cancer (CRC) patients. We evaluated the ability of MetaCell to enrich CTCs by spiking blood with CRC cell lines and assessing the cell recovery rates and WBC depletion via immunostaining and gene expression. We then applied MetaCell to samples from 17 CRC patients and seven controls. Recovery rates were >85% in cell lines, with >95% depletion in WBCs. MetaCell yielded CTCs and CTC clusters in 52.9% and 23.5% of the patients, respectively, without false positives in control patients. CTCs and cluster detection did not correlate with histopathological parameters. Overall, we demonstrated that the MetaCell platform enriched CRC cells with high recovery rates and high purity. Our pilot study also demonstrated the ability of MetaCell to detect CTCs in CRC patients.

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Lo, Hin Ching, Zhan Xu, Ik Sun Kim, Aaron Muscarella, Jun Liu, Sarah Hein, Hai Wang, et al. "Circulating tumor cell clusters exhibit enhanced immune evasion from natural killer cells." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 88.18. http://dx.doi.org/10.4049/jimmunol.204.supp.88.18.

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Abstract During cancer metastasis, the ability to evade immunosurveillance is key to the survival of circulating tumor cells (CTCs). Recent studies have found that in addition to single CTCs, multicellular clusters of CTCs can be detected in patient blood. Strikingly, CTC clusters show higher metastatic potential than single CTCs, but the molecular mechanism is unclear. We hypothesize that CTC clusters adopt immune evasive strategies, which enhance their metastatic ability. In mouse models of breast cancer, CTC clusters show enhanced metastatic growth over single cells in immunocompetent mice, but this difference is abrogated in immunodeficient mice lacking NK cells or mice treated with NK cell-depleting antibodies. Adoptive transfer of NK cells into NK cell-deficient hosts selectively suppresses metastatic growth by single CTCs, suggesting that single CTCs are more sensitive to NK cells than clusters. Analysis of cell line and patient RNA-seq data reveal that CTC clusters have elevated expression of cell-cell adhesion and epithelial genes as compared to single cells, which is in turn associated with decreased expression of NK cell-activating NKG2D ligands. Furthermore, modulation of tumor cell epithelial status alters NK ligand expression and sensitivity to NK cell killing, but this effect is attenuated by the addition of an NKG2D-blocking antibody. Taken together, we propose a model in which the epithelial characteristics of CTC clusters promotes their resistance to NK cell attack and thus their overall metastatic success. These findings reveal that NK cells play an important role in determining the fate of CTCs of different epithelial/mesenchymal states, and illuminate our understanding of immune evasion mechanisms by CTCs.

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Floro, L., B. Molnar, K. Horvat-Karajz, L. Sreter, and Z. Tulassay. "Immunomagnetic detection and characterisation of circulating tumour cells and cell clusters in patients with colorectal cancer." European Journal of Cancer 37 (April 2001): S124—S125. http://dx.doi.org/10.1016/s0959-8049(01)80947-3.

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Hayashi, Masanori, Peixuan Zhu, Gregory McCarty, Christian F. Meyer, Christine A. Pratilas, Adam Levin, Carol D. Morris, et al. "Size-based detection of sarcoma circulating tumor cells and cell clusters." Oncotarget 8, no. 45 (August 24, 2017): 78965–77. http://dx.doi.org/10.18632/oncotarget.20697.

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Bocci, Federico, Mohit K. Jolly, Satyendra C. Tripathi, Mitzi Aguilar, Samir M. Hanash, Herbert Levine, and José N. Onuchic. "Numb prevents a complete epithelial–mesenchymal transition by modulating Notch signalling." Journal of The Royal Society Interface 14, no. 136 (November 2017): 20170512. http://dx.doi.org/10.1098/rsif.2017.0512.

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Epithelial–mesenchymal transition (EMT) plays key roles during embryonic development, wound healing and cancer metastasis. Cells in a partial EMT or hybrid epithelial/mesenchymal (E/M) phenotype exhibit collective cell migration, forming clusters of circulating tumour cells—the primary drivers of metastasis. Activation of cell–cell signalling pathways such as Notch fosters a partial or complete EMT, yet the mechanisms enabling cluster formation remain poorly understood. Using an integrated computational–experimental approach, we examine the role of Numb—an inhibitor of Notch intercellular signalling—in mediating EMT and clusters formation. We show via an mathematical model that Numb inhibits a full EMT by stabilizing a hybrid E/M phenotype. Consistent with this observation, knockdown of Numb in stable hybrid E/M cells H1975 results in a full EMT, thereby showing that Numb acts as a brake for a full EMT and thus behaves as a ‘phenotypic stability factor' by modulating Notch-driven EMT. By generalizing the mathematical model to a multi-cell level, Numb is predicted to alter the balance of hybrid E/M versus mesenchymal cells in clusters, potentially resulting in a higher tumour-initiation ability. Finally, Numb correlates with a worse survival in multiple independent lung and ovarian cancer datasets, hence confirming its relationship with increased cancer aggressiveness.

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Prasanna, Biderahalli Kruthika, Ajay Balakrishnan, and Prashant Kumar. "Circulating tumor cell clusters and circulating tumor cell-derived explant models as a tool for treatment response." BioTechniques 69, no. 1 (July 2020): 4–5. http://dx.doi.org/10.2144/btn-2020-0029.

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Boareto, Marcelo, Mohit Kumar Jolly, Aaron Goldman, Mika Pietilä, Sendurai A. Mani, Shiladitya Sengupta, Eshel Ben-Jacob, Herbert Levine, and Jose’ N. Onuchic. "Notch-Jagged signalling can give rise to clusters of cells exhibiting a hybrid epithelial/mesenchymal phenotype." Journal of The Royal Society Interface 13, no. 118 (May 2016): 20151106. http://dx.doi.org/10.1098/rsif.2015.1106.

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Metastasis can involve repeated cycles of epithelial-to-mesenchymal transition (EMT) and its reverse mesenchymal-to-epithelial transition. Cells can also undergo partial transitions to attain a hybrid epithelial/mesenchymal (E/M) phenotype that allows the migration of adhering cells to form a cluster of circulating tumour cells. These clusters can be apoptosis-resistant and possess an increased metastatic propensity as compared to the cells that undergo a complete EMT (mesenchymal cells). Hence, identifying the key players that can regulate the formation and maintenance of such clusters may inform anti-metastasis strategies. Here, we devise a mechanism-based theoretical model that links cell–cell communication via Notch-Delta-Jagged signalling with the regulation of EMT. We demonstrate that while both Notch-Delta and Notch-Jagged signalling can induce EMT in a population of cells, only Jagged-dominated Notch signalling, but not Delta-dominated signalling, can lead to the formation of clusters containing hybrid E/M cells. Our results offer possible mechanistic insights into the role of Jagged in tumour progression, and offer a framework to investigate the effects of other microenvironmental signals during metastasis.

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Hassan, Sara, Tony Blick, Erik W. Thompson, and Elizabeth D. Williams. "Diversity of Epithelial-Mesenchymal Phenotypes in Circulating Tumour Cells from Prostate Cancer Patient-Derived Xenograft Models." Cancers 13, no. 11 (June 1, 2021): 2750. http://dx.doi.org/10.3390/cancers13112750.

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Metastasis is the leading cause of cancer-related deaths worldwide. The epithelial-mesenchymal plasticity (EMP) status of primary tumours has relevance to metastatic potential and therapy resistance. Circulating tumour cells (CTCs) provide a window into the metastatic process, and molecular characterisation of CTCs in comparison to their primary tumours could lead to a better understanding of the mechanisms involved in the metastatic cascade. In this study, paired blood and tumour samples were collected from four prostate cancer patient-derived xenograft (PDX) models (BM18, LuCaP70, LuCaP96, LuCaP105) and assessed using an EMP-focused, 42 gene human-specific, nested quantitative RT-PCR assay. CTC burden varied amongst the various xenograft models with LuCaP96 having the highest number of CTCs per mouse (mean: 704; median: 31) followed by BM18 (mean: 101; median: 21), LuCaP70 (mean: 73; median: 16) and LuCaP105 (mean: 57; median: 6). A significant relationship was observed between tumour size and CTC number (p = 0.0058). Decreased levels of kallikrein-related peptidase 3 (KLK3) mRNA (which encodes prostate-specific antigen; PSA) were observed in CTC samples from all four models compared to their primary tumours. Both epithelial- and mesenchymal-associated genes were commonly expressed at higher levels in CTCs compared to the bulk primary tumour, although some common EMT-associated genes (CDH1, VIM, EGFR, EPCAM) remained unchanged. Immunofluorescence co-staining for pan-cytokeratin (KRT) and vimentin (VIM) indicated variable proportions of CTCs across the full EMP axis, even in the same model. EMP hybrids predominated in the BM18 and LuCaP96 models, but were not detected in the LuCaP105 model, and variable numbers of KRT+ and human VIM+ cells were observed in each model. SERPINE1, which encodes plasminogen activator inhibitor-1 (PAI-1), was enriched at the RNA level in CTCs compared to primary tumours and was the most commonly expressed mesenchymal gene in the CTCs. Co-staining for SERPINE1 and KRT revealed SERPINE1+ cells in 7/11 samples, six of which had SERPINE+KRT+ CTCs. Cell size variation was observed in CTCs. The majority of samples (8/11) contained larger CTCs ranging from 15.3 to 37.8 µm, whilst smaller cells (10.7 ± 4.1 µm, similar in size to peripheral blood mononuclear cells (PBMCs)) were identified in 6 of 11 samples. CTC clusters were also identified in 9/11 samples, containing 2–100 CTCs per cluster. Where CTC heterogeneity was observed in the clusters, epithelial-like cells (KRT+VIM−) were located on the periphery of the cluster, forming a layer around hybrid (KRT+VIM+) or mesenchymal-like (KRT−VIM+) cells. The CTC heterogeneity observed in these models emphasises the complexity in CTC isolation and classification and supports the increasingly recognised importance of the epithelial-mesenchymal hybrid state in cancer progression and metastasis.

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Martínez-Pena, Inés, Pablo Hurtado, Nuria Carmona-Ule, Carmen Abuín, Ana Belén Dávila-Ibáñez, Laura Sánchez, Miguel Abal, et al. "Dissecting Breast Cancer Circulating Tumor Cells Competence via Modelling Metastasis in Zebrafish." International Journal of Molecular Sciences 22, no. 17 (August 27, 2021): 9279. http://dx.doi.org/10.3390/ijms22179279.

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Background: Cancer metastasis is a deathly process, and a better understanding of the different steps is needed. The shedding of circulating tumor cells (CTCs) and CTC-cluster from the primary tumor, its survival in circulation, and homing are key events of the metastasis cascade. In vitro models of CTCs and in vivo models of metastasis represent an excellent opportunity to delve into the behavior of metastatic cells, to gain understanding on how secondary tumors appear. Methods: Using the zebrafish embryo, in combination with the mouse and in vitro assays, as an in vivo model of the spatiotemporal development of metastases, we study the metastatic competency of breast cancer CTCs and CTC-clusters and the molecular mechanisms. Results: CTC-clusters disseminated at a lower frequency than single CTCs in the zebrafish and showed a reduced capacity to invade. A temporal follow-up of the behavior of disseminated CTCs showed a higher survival and proliferation capacity of CTC-clusters, supported by their increased resistance to fluid shear stress. These data were corroborated in mouse studies. In addition, a differential gene signature was observed, with CTC-clusters upregulating cell cycle and stemness related genes. Conclusions: The zebrafish embryo is a valuable model system to understand the biology of breast cancer CTCs and CTC-clusters.

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Hamid, Faysal Bin, Vinod Gopalan, Marco Matos, Cu-Tai Lu, and Alfred King-yin Lam. "Genetic Heterogeneity of Single Circulating Tumour Cells in Colorectal Carcinoma." International Journal of Molecular Sciences 21, no. 20 (October 20, 2020): 7766. http://dx.doi.org/10.3390/ijms21207766.

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The aim of the present study was to isolate and investigate the genetic heterogeneities in single circulating tumour cells (CTCs) from patients with colorectal carcinoma (CRC). Twenty-eight single CTCs were collected from eight patients with CRC using a negative immunomagnetic enrichment method. After validation with glyceraldehyde 3-phosphate dehydrogenase (GAPDH) gene expression in 3 colon cancer cell lines, a panel of 19 genes were used to analyse the single CTCs (n = 28), primary colorectal carcinoma tissues (n = 8) and colon carcinoma cells (n = 6) using real-time qPCR. Genetic heterogeneities were assessed by comparing gene expression profiles of single CTCs from the different patients and in the same patient, respectively. Genetic profiling of the single CTCs showed extensive heterogeneities of the selected genes among the CTCs. Hierarchical clustering analyses exhibited two clusters of CTCs with differentially expressed genes, which highlighted different modifications from the primary carcinomas. Further, the genetic heterogeneities were observed between different patients or in the same patient. Finally, AKT1 expression was significantly (p = 0.0129) higher in single CTCs from CRC of advanced pathological stages (III or IV) CRC than in CTCs from CRC of early stages (I or II). Our findings suggest that single-cell genetic analysis can monitor the genetic heterogeneities and guide the personalised therapeutic targets in clinical sectors.

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Payne, Karl, Jill Brooks, Rachel Spruce, Nikolaos Batis, Graham Taylor, Paul Nankivell, and Hisham Mehanna. "Circulating Tumour Cell Biomarkers in Head and Neck Cancer: Current Progress and Future Prospects." Cancers 11, no. 8 (August 5, 2019): 1115. http://dx.doi.org/10.3390/cancers11081115.

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Head and neck cancer (HNC) continues to carry a significant burden of disease both for patients and health services. Facilitating biomarker-led treatment decisions is critical to improve outcomes in this group and deliver therapy tailored to the individual tumour biological profile. One solution to develop such biomarkers is a liquid biopsy analysing circulating tumour cells (CTCs)—providing a non-invasive and dynamic assessment of tumour specific alterations in ‘real-time’. A major obstacle to implementing such a test is the standardisation of CTC isolation methods and subsequent down-stream analysis. Several options are available, with a recent shift in vogue from positive-selection marker-dependent isolation systems to marker-independent negative-selection techniques. HNC single-CTC characterisation, including single-cell sequencing, to identify actionable mutations and gene-expression signatures has the potential to both guide the understanding of patient tumour heterogeneity and support the adoption of personalised medicine strategies. Microfluidic approaches for isolating CTCs and cell clusters are emerging as novel technologies which can be incorporated with computational platforms to complement current diagnostic and prognostic strategies. We review the current literature to assess progress regarding CTC biomarkers in HNC and potential avenues for future translational research and clinical implementation.

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Rostami, Peyman, Navid Kashaninejad, Khashayar Moshksayan, Mohammad Said Saidi, Bahar Firoozabadi, and Nam-Trung Nguyen. "Novel approaches in cancer management with circulating tumor cell clusters." Journal of Science: Advanced Materials and Devices 4, no. 1 (March 2019): 1–18. http://dx.doi.org/10.1016/j.jsamd.2019.01.006.

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Suo, Yuanzhen, Chengying Xie, Xi Zhu, Zhichao Fan, Zhangru Yang, Hao He, and Xunbin Wei. "Proportion of circulating tumor cell clusters increases during cancer metastasis." Cytometry Part A 91, no. 3 (December 23, 2016): 250–53. http://dx.doi.org/10.1002/cyto.a.23037.

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Aceto, Nicola. "Abstract IA009: Biology and vulnerabilities of circulating tumor cell clusters." Cancer Research 83, no. 2_Supplement_2 (January 15, 2023): IA009. http://dx.doi.org/10.1158/1538-7445.metastasis22-ia009.

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Abstract The metastatic spread of cancer occurs through the generation and hematogenous dissemination of circulating tumor cells (CTCs). Among these, CTC clusters have recently emerged as key players in the metastatic process. With a combination of microfluidic technologies and single cell-resolution molecular analysis applied to cancer patients and mouse models, we gained fundamental insights into the biology, vulnerabilities, and clinical implications of CTC clusters. For instance, we found that their physical features enable molecular changes that promote stemness and metastasis, allowing us to define new treatment concepts aimed at suppressing their metastatic potential. Further, we investigated CTC heterogeneity at the single cell level, revealing fundamental interactions that occur between CTCs and immune cells and that accelerate metastasis formation, as well as microenvironment signals that impact on CTC generation. More recently, we also gained important insights into CTC generation dynamics and signals that trigger intravasation. Together, our findings support a model whereby upon defined microenvironmental cues, CTCs form multicellular aggregates to expand their metastatic ability, providing a new rationale for targeting these interactions in cancer. Citation Format: Nicola Aceto. Biology and vulnerabilities of circulating tumor cell clusters [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr IA009.

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Wang, Chun, Zhenchao Zhang, Weelic Chong, Rui Luo, Ronald E. Myers, Jian Gu, Jianqing Lin, et al. "Improved Prognostic Stratification Using Circulating Tumor Cell Clusters in Patients with Metastatic Castration-Resistant Prostate Cancer." Cancers 13, no. 2 (January 13, 2021): 268. http://dx.doi.org/10.3390/cancers13020268.

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Liquid biopsy-based biomarkers have advantages in monitoring the dynamics of metastatic castration-resistant prostate cancer (mCRPC), a bone-predominant metastatic disease. Previous studies have demonstrated associations between circulating tumor cells (CTCs) and clinical outcomes of mCRPC patients, but little is known about the prognostic value of CTC-clusters. In 227 longitudinally collected blood samples from 64 mCRPC patients, CTCs and CTC-clusters were enumerated using the CellSearch platform. The associations of CTC and CTC-cluster counts with progression-free survival (PFS) and overall survival (OS), individually and jointly, were evaluated by Cox models. CTCs and CTC-clusters were detected in 24 (37.5%) and 8 (12.5%) of 64 baseline samples, and in 119 (52.4%) and 27 (11.9%) of 227 longitudinal samples, respectively. CTC counts were associated with both PFS and OS, but CTC-clusters were only independently associated with an increased risk of death. Among patients with unfavorable CTCs (≥5), the presence of CTC-clusters signified a worse survival (log-rank p = 0.0185). mCRPC patients with both unfavorable CTCs and CTC-clusters had the highest risk for death (adjusted hazard ratio 19.84, p = 0.0072), as compared to those with <5 CTCs. Analyses using longitudinal data yielded similar results. In conclusion, CTC-clusters provided additional prognostic information for further stratifying death risk among patients with unfavorable CTCs.

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Lim, Minji, Suhyun Park, Hyoung-Oh Jeong, Sung Hee Park, Sumit Kumar, Aelee Jang, Semin Lee, Dong Uk Kim, and Yoon-Kyoung Cho. "Circulating Tumor Cell Clusters Are Cloaked with Platelets and Correlate with Poor Prognosis in Unresectable Pancreatic Cancer." Cancers 13, no. 21 (October 20, 2021): 5272. http://dx.doi.org/10.3390/cancers13215272.

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Circulating tumor cells (CTCs) are known to be heterogeneous and clustered with tumor-associated cells, such as macrophages, neutrophils, fibroblasts, and platelets. However, their molecular profile and clinical significance remain largely unknown. Thus, we aimed to perform a comprehensive gene expression analysis of single CTCs and CTC clusters in patients with pancreatic cancer and to identify their potential clinical relevance to provide personalized medicine. Epitope-independent, rapid (>3 mL of whole blood/min) isolation of single CTCs and CTC clusters was achieved from a prospective cohort of 16 patients with unresectable pancreatic cancer using a centrifugal microfluidic device. Forty-eight mRNA expressions of individual CTCs and CTC clusters were analyzed to identify pancreatic CTC phenotype. CTC clusters had a larger proportion of mesenchymal expression than single CTCs (p = 0.0004). The presence of CTC clusters positively correlated with poor prognosis (progression-free survival, p = 0.0159; overall survival, p = 0.0186). Furthermore, we found that most CTCs in these patients (90.7%) were cloaked with platelets and found the presence of a positive correlation between the increase in CTC clusters and rapid disease progression during follow-ups. Efficient CTC cluster isolation and analysis techniques will enhance the understanding of complex tumor metastasis processes and can facilitate personalized disease management.

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Kulasinghe, Arutha, Joanna Kapeleris, Carolina Cooper, Majid Ebrahimi Warkiani, Kenneth O’Byrne, and Chamindie Punyadeera. "Phenotypic Characterization of Circulating Lung Cancer Cells for Clinically Actionable Targets." Cancers 11, no. 3 (March 18, 2019): 380. http://dx.doi.org/10.3390/cancers11030380.

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Objectives: In non-small cell lung cancers (NSCLC), tumour biopsy can often be an invasive procedure. The development of a non-invasive methodology to study genetic changes via circulating tumour cells (CTCs) is an appealing concept. Whilst CTCs typically remain as rare cells, improvements in epitope-independent CTC isolation techniques has given rise to a greater capture of CTCs. In this cross sectional study, we demonstrate the capture and characterization of NSCLC CTCs for the clinically actionable markers epidermal growth factor receptor (EGFR) alterations, anaplastic lymphoma kinase (ALK) rearrangements and programmed death ligand-1 (PD-L1) expression. The study identified CTCs/CTC clusters in 26/35 Stage IV NSCLC patients, and subsequently characterized the CTCs for EGFR mutation, ALK status and PD-L1 status. This pilot study demonstrates the potential of a non-invasive fluid biopsy to determine clinically relevant biomarkers in NSCLC.

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Cheung, Kevin J., Veena Padmanaban, Vanesa Silvestri, Koen Schipper, Joshua D. Cohen, Amanda N. Fairchild, Michael A. Gorin, et al. "Polyclonal breast cancer metastases arise from collective dissemination of keratin 14-expressing tumor cell clusters." Proceedings of the National Academy of Sciences 113, no. 7 (February 1, 2016): E854—E863. http://dx.doi.org/10.1073/pnas.1508541113.

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Recent genomic studies challenge the conventional model that each metastasis must arise from a single tumor cell and instead reveal that metastases can be composed of multiple genetically distinct clones. These intriguing observations raise the question: How do polyclonal metastases emerge from the primary tumor? In this study, we used multicolor lineage tracing to demonstrate that polyclonal seeding by cell clusters is a frequent mechanism in a common mouse model of breast cancer, accounting for >90% of metastases. We directly observed multicolored tumor cell clusters across major stages of metastasis, including collective invasion, local dissemination, intravascular emboli, circulating tumor cell clusters, and micrometastases. Experimentally aggregating tumor cells into clusters induced a >15-fold increase in colony formation ex vivo and a >100-fold increase in metastasis formation in vivo. Intriguingly, locally disseminated clusters, circulating tumor cell clusters, and lung micrometastases frequently expressed the epithelial cytoskeletal protein, keratin 14 (K14). RNA-seq analysis revealed that K14+ cells were enriched for desmosome and hemidesmosome adhesion complex genes, and were depleted for MHC class II genes. Depletion of K14 expression abrogated distant metastases and disrupted expression of multiple metastasis effectors, including Tenascin C (Tnc), Jagged1 (Jag1), and Epiregulin (Ereg). Taken together, our findings reveal K14 as a key regulator of metastasis and establish the concept that K14+ epithelial tumor cell clusters disseminate collectively to colonize distant organs.

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Khoo, Bee Luan, Gianluca Grenci, Tengyang Jing, Ying Bena Lim, Soo Chin Lee, Jean Paul Thiery, Jongyoon Han, and Chwee Teck Lim. "Liquid biopsy and therapeutic response: Circulating tumor cell cultures for evaluation of anticancer treatment." Science Advances 2, no. 7 (July 2016): e1600274. http://dx.doi.org/10.1126/sciadv.1600274.

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The lack of a robust anticancer drug screening system to monitor patients during treatment delays realization of personalized treatment. We demonstrate an efficient approach to evaluate drug response using patient-derived circulating tumor cell (CTC) cultures obtained from liquid biopsy. Custom microfabricated tapered microwells were integrated with microfluidics to allow robust formation of CTC clusters without pre-enrichment and subsequent drug screening in situ. Rapid feedback after 2 weeks promotes immediate intervention upon detection of drug resistance or tolerance. The procedure was clinically validated with blood samples (n = 73) from 55 patients with early-stage, newly diagnosed, locally advanced, or refractory metastatic breast cancer. Twenty-four of these samples were used for drug evaluation. Cluster formation potential correlated inversely with increased drug concentration and therapeutic treatment. This new and robust liquid biopsy technique can potentially evaluate patient prognosis with CTC clusters during treatment and provide a noninvasive and inexpensive assessment that can guide drug discovery development or therapeutic choices for personalized treatment.

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Smietanka, Urszula, Małgorzata Szostakowska-Rodzos, Sylwia Tabor, Anna Fabisiewicz, and Ewa A. Grzybowska. "Clusters, Assemblies and Aggregates of Tumor Cells in the Blood of Breast Cancer Patients; Composition, Mode of Action, Detection and Impact on Metastasis and Survival." International Journal of Translational Medicine 1, no. 1 (June 4, 2021): 55–68. http://dx.doi.org/10.3390/ijtm1010005.

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Circulating tumor cells (CTCs) are gaining momentum as a diagnostic tool and therapeutic target. CTC clusters are more metastatic, but harder to study and characterize, because they are rare and the methods of isolation are mostly focused on single CTCs. This review highlights the recent advances to our understanding of tumor cell clusters with the emphasis on their composition, origin, biology, methods of detection, and impact on metastasis and survival. New approaches to therapy, based on cluster characteristics are also described.

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Lu, Lingeng, Hongmei Zeng, Xinsheng Gu, and Wenxue Ma. "Circulating tumor cell clusters-associated gene plakoglobin and breast cancer survival." Breast Cancer Research and Treatment 151, no. 3 (May 10, 2015): 491–500. http://dx.doi.org/10.1007/s10549-015-3416-1.

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Aceto, Nicola, Aditya Bardia, David T. Miyamoto, Maria C. Donaldson, Ben S. Wittner, Joel A. Spencer, Min Yu, et al. "Circulating Tumor Cell Clusters Are Oligoclonal Precursors of Breast Cancer Metastasis." Cell 158, no. 5 (August 2014): 1110–22. http://dx.doi.org/10.1016/j.cell.2014.07.013.

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Hurtado, Pablo, Inés Martínez-Pena, and Roberto Piñeiro. "Dangerous Liaisons: Circulating Tumor Cells (CTCs) and Cancer-Associated Fibroblasts (CAFs)." Cancers 12, no. 10 (October 5, 2020): 2861. http://dx.doi.org/10.3390/cancers12102861.

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The crosstalk between cancer cells and the tumor microenvironment (TME) is a key determinant of cancer metastasis. Cancer-associated fibroblasts (CAFs), one of the main cellular components of TME, promote cancer cell invasion and dissemination through mechanisms including cell-cell interactions and the paracrine secretion of growth factors, cytokines and chemokines. During metastasis, circulating tumor cells (CTCs) are shed from the primary tumor to the bloodstream, where they can be detected as single cells or clusters. The current knowledge about the biology of CTC clusters positions them as key actors in metastasis formation. It also indicates that CTCs do not act alone and that they may be aided by stromal and immune cells, which seem to shape their metastatic potential. Among these cells, CAFs are found associated with CTCs in heterotypic CTC clusters, and their presence seems to increase their metastatic efficiency. In this review, we summarize the current knowledge on the role that CAFs play on metastasis and we discuss their implication on the biogenesis, metastasis-initiating capacity of CTC clusters, and clinical implications. Moreover, we speculate about possible therapeutic strategies aimed to limit the metastatic potential of CTC clusters involving the targeting of CAFs as well as their difficulties and limitations.

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Hou, Jian-Mei, Matthew G. Krebs, Lee Lancashire, Robert Sloane, Alison Backen, Rajeeb K. Swain, Lynsey J. C. Priest, et al. "Clinical Significance and Molecular Characteristics of Circulating Tumor Cells and Circulating Tumor Microemboli in Patients With Small-Cell Lung Cancer." Journal of Clinical Oncology 30, no. 5 (February 10, 2012): 525–32. http://dx.doi.org/10.1200/jco.2010.33.3716.

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Purpose Circulating tumor cells (CTCs) may have utility as surrogate biomarkers and “virtual” biopsies. We report the clinical significance and molecular characteristics of CTCs and CTC clusters, termed circulating tumor microemboli (CTM), detected in patients with small-cell lung cancer (SCLC) undergoing standard treatment. Patients and Methods Serial blood samples from 97 patients receiving chemotherapy were analyzed using EpCam-based immunomagnetic detection and a filtration-based technique. Proliferation status (Ki67) and apoptotic morphology were examined. Associations of CTC and CTM number with clinical factors and prognosis were determined. Results CTCs were present in 85% of patients (77 of 97 patients) and were abundant (mean ± standard deviation = 1,589 ± 5,565). CTM and apoptotic CTCs were correlated with total CTC number and were detected in 32% and 57% of patients, respectively. Pretreatment CTCs, change in CTC number after one cycle of chemotherapy, CTM, and apoptotic CTCs were independent prognostic factors. Overall survival was 5.4 months for patients with ≥ 50 CTCs/7.5 mL of blood and 11.5 months (P < .0001) for patients with less than 50 CTCs/7.5 mL of blood before chemotherapy (hazard ratio = 2.45; 95% CI, 1.39 to 4.30; P = .002). Subpopulations of apoptotic and of proliferating solitary CTCs were detected, whereas neither were observed within cell clusters (CTM), implicating both protection from anoikis and relative resistance to cytotoxic drugs for cells within CTM. Conclusion Both baseline CTC number and change in CTC number after one cycle of chemotherapy are independent prognostic factors for SCLC. Molecular comparison of CTCs to cells in CTM may provide novel insights into SCLC biology.

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Schnoor, Brian, and Anne-Laure Papa. "Abstract A007: Development of a fibrinolytic platelet system to dissociate circulating tumor cell clusters." Cancer Research 83, no. 2_Supplement_2 (January 15, 2023): A007. http://dx.doi.org/10.1158/1538-7445.metastasis22-a007.

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Abstract Circulating tumor cell (CTC) clusters play a significant role in cancer metastasis. During metastasis, CTCs can travel in the bloodstream as individual cells or as clusters associated with fibrin and platelets (Palumbo et al., Blood 2000; Karpatkin and Pearlstein, Annals of Internal Medicine, 1981). The CTC clusters have a higher metastatic potential than individual tumor cells (Aceto, Cell 2014) due to the increased viability of tumor cells in clusters, the increased chance of large clusters arresting in small vessels, and the increased ability of clusters to form a metastatic niche at a distal location. As such, there is a need to develop methods to disperse CTC clusters. Previous work with urokinase-type plasminogen activator has shown initial success in reducing metastasis by dissociating cancer cell clusters (Choi et al., Cancer Res. 2015). However, there is another key component of this metastatic challenge, the interaction of CTCs with platelets. Platelets bind to the CTC surface which protects the CTC clusters from shear stress and immune detection, increasing their metastatic potential (Morris, Schnoor, and Papa, Biochim. Biophys. Acta BBA - Rev. Cancer 2022). However, these interactions also provide an approach to target CTC clusters. As such, the objective of this project is to develop a fibrinolytic platelet system to dissociate CTC clusters while also disrupting CTC-platelet interactions. For this approach, TPA was loaded onto two modified platelet systems: platelet decoys (Papa et al., Sci. Transl. Med. 2019) and lyophilized platelets (Schnoor and Papa, Front. Bioeng. Biotechnol. 2022). Each system was assessed to determine the surface receptor characteristics, drug loading, and interaction with tumor cells in vitro. The fibrinolytic activity of the systems was also characterized using a FRET based assay and the angiogenic effects of the systems were measured using a HUVEC tube formation assay. Furthermore, the ability of the system to dissociate cancer cell clusters in vitro was assessed for the first time using light transmission aggregometry. The results demonstrate that the TPA was successfully loaded onto both platelet decoys and lyophilized platelets while maintaining the fibrinolytic activity of the platelets. Furthermore, a high percentage of cancer cells interacted with the TPA-loaded carriers, which corresponds to the maintenance of key surface receptors such as GP IIb/IIIa. The data also demonstrates that the fibrinolytic platelet systems can successfully dissociate cancer cells in vitro. Currently, the effectiveness of these fibrinolytic platelet systems for preventing cancer cell metastasis is being assessed in vivo. Based on these results, this fibrinolytic platelet approach is a promising method to leverage platelet-CTC interactions to disperse CTC clusters and reduce metastasis. Citation Format: Brian Schnoor, Anne-Laure Papa. Development of a fibrinolytic platelet system to dissociate circulating tumor cell clusters [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr A007.

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Campenni, Marco, Alexander N. May, Amy Boddy, Valerie Harris, and Aurora M. Nedelcu. "Agent‐based modelling reveals strategies to reduce the fitness and metastatic potential of circulating tumour cell clusters." Evolutionary Applications 13, no. 7 (March 18, 2020): 1635–50. http://dx.doi.org/10.1111/eva.12943.

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Costa, Clotilde, Laura Muinelo-Romay, Victor Cebey-López, Thais Pereira-Veiga, Inés Martínez-Pena, Manuel Abreu, Alicia Abalo, et al. "Analysis of a Real-World Cohort of Metastatic Breast Cancer Patients Shows Circulating Tumor Cell Clusters (CTC-clusters) as Predictors of Patient Outcomes." Cancers 12, no. 5 (April 29, 2020): 1111. http://dx.doi.org/10.3390/cancers12051111.

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Circulating tumor cell (CTC) enumeration has emerged as a powerful biomarker for the assessment of prognosis and the response to treatment in metastatic breast cancer (MBC). Moreover, clinical evidences show that CTC-cluster counts add prognostic information to CTC enumeration, however, their significance is not well understood, and more clinical evidences are needed. We aim to evaluate the prognostic value of longitudinally collected single CTCs and CTC-clusters in a heterogeneous real-world cohort of 54 MBC patients. Blood samples were longitudinally collected at baseline and follow up. CTC and CTC-cluster enumeration was performed using the CellSearch® system. Associations with progression-free survival (PFS) and overall survival (OS) were evaluated using Cox proportional hazards modelling. Elevated CTC counts and CTC-clusters at baseline were significantly associated with a shorter survival time. In joint analysis, patients with high CTC counts and CTC-cluster at baseline were at a higher risk of progression and death, and longitudinal analysis showed that patients with CTC-clusters had significantly shorter survival compared to patients without clusters. Moreover, patients with CTC-cluster of a larger size were at a higher risk of death. A longitudinal analysis of a real-world cohort of MBC patients indicates that CTC-clusters analysis provides additional prognostic value to single CTC enumeration, and that CTC-cluster size correlates with patient outcome.

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Li, Chuan, Yee Peng Phoon, Keaton Karlinsey, Ye Tian, Samjhana Thapaliya, Lili Qu, Mark Cameron, et al. "P853 Single cell transcriptome analysis identifies unique features in circulating CD8+ T cells that can predict immunotherapy response in melanoma patients." Journal for ImmunoTherapy of Cancer 8, Suppl 1 (April 2020): A5.1—A5. http://dx.doi.org/10.1136/lba2019.7.

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BackgroundImmune checkpoint blockade (ICB) has greatly advanced the treatment of melanoma. A key component of ICB is the stimulation of CD8+ T cells in the tumor. However, ICB therapy only benefits a subset of patients and a reliable prediction method that does not require invasive biopsies is still a major challenge in the field.MethodsWe conducted a set of comprehensive single-cell transcriptomic analyses of CD8+ T cells in the peripheral blood (mPBL) and tumors (mTIL) from 8 patients with metastatic melanoma.ResultsCompared to circulating CD8+ T cells from healthy donors (hPBL), mPBLs contained subsets resembling certain features of mTIL. More importantly, three clusters (2, 6 and 15) were represented in both mPBL and mTIL. Cluster 2 was the major subset of the majority of hPBL, which phenocopied hallmark parameters of resting T cells. Cluster 6 and 15 were uniquely presented in melanoma patients. Cluster 15 had the highest PD-1 levels, with elevated markers of both activation and dysfunction/exhaustion; while Cluster 6 was enriched for ‘dormant’ cells with overall toned-down transcriptional activity except PPAR signaling, a known suppressor for T cell activation. Interestingly, unlike other mTIL clusters that would classically be defined as exhausted, Cluster 15 exhibited the highest metabolic activity (oxidative-phosphorylation and glycolysis). We further analyzed total sc-transcriptomics using cell trajectory algorithms and identified that these three clusters were the most distinct subtypes of CD8 T cells from each other, representing: resting (cluster 2), metabolically active-dysfunctional (cluster 15), and dormant phenotypes (cluster 6). Further, three unique intracellular programs in melanoma drive the transition of resting CD8+ T cells (cluster 2) to both metabolic/dysfunctional (cluster 15) and dormant states (cluster 6) that are unique to tumor bearing conditions. Based on these high-resolution analyses, we developed original algorithms to build a novel ICB response predictive model using immune-blockade co-expression gene patterns. The model was trained and tested using previously published GEO datasets containing CD8 T cells from anti-PD-1 treated patients and presented an AUC of 0.82, with 92% and 89% accuracy of ICB response in the two datasets.ConclusionsWe identified and analyzed unique populations of CD8+ T cells in circulation and tumor using high-resolution single-cell transcriptomics to define the landscape of CD8+ T cell states, revealing critical subsets with shared features in PBLs and TILs. Most importantly, we established an innovative model for ICB response prediction by using peripheral blood lymphocytes.Ethics ApprovalThis study was performed under an IRB approved protocol.

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He, Yongpeng, Hai Huang, Haixia Wang, Lin Yi, Yichao Chen, Haiwei Zhang, Jing Ran, Hesong Shen, Qingming Jiang, and Weiqi Nian. "Small cell carcinoma of the endometrium: A case report with circulating tumor cell clusters." Frontiers in Laboratory Medicine 1, no. 4 (December 2017): 179–81. http://dx.doi.org/10.1016/j.flm.2017.11.004.

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Park, Junhyun, Sunyoung Park, Kyung A. Hyun, and Hyo-Il Jung. "Microfluidic recapitulation of circulating tumor cell–neutrophil clusters via double spiral channel-induced deterministic encapsulation." Lab on a Chip 21, no. 18 (2021): 3483–97. http://dx.doi.org/10.1039/d1lc00433f.

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Banovetz, Joseph T., Min Li, Darshna Pagariya, Sungu Kim, Baskar Ganapathysubramanian, and Robbyn K. Anand. "Defining Cell Cluster Size by Dielectrophoretic Capture at an Array of Wireless Electrodes of Several Distinct Lengths." Micromachines 10, no. 4 (April 23, 2019): 271. http://dx.doi.org/10.3390/mi10040271.

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Clusters of biological cells play an important role in normal and disease states, such as in the release of insulin from pancreatic islets and in the enhanced spread of cancer by clusters of circulating tumor cells. We report a method to pattern cells into clusters having sizes correlated to the dimensions of each electrode in an array of wireless bipolar electrodes (BPEs). The cells are captured by dielectrophoresis (DEP), which confers selectivity, and patterns cells without the need for physical barriers or adhesive interactions that can alter cell function. Our findings demonstrate that this approach readily achieves fine control of cell cluster size over a broader range set by other experimental parameters. These parameters include the magnitude of the voltage applied externally to drive capture at the BPE array, the rate of fluid flow, and the time allowed for DEP-based cell capture. Therefore, the reported method is anticipated to allow the influence of cluster size on cell function to be more fully investigated.

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Lyons, Joe, Michael Polmear, Nora D. Mineva, Mathilde Romagnoli, Gail E. Sonenshein, and Irene Georgakoudi. "Endogenous light scattering as an optical signature of circulating tumor cell clusters." Biomedical Optics Express 7, no. 3 (February 25, 2016): 1042. http://dx.doi.org/10.1364/boe.7.001042.

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Hong, Yupeng, Francia Fang, and Qi Zhang. "Circulating tumor cell clusters: What we know and what we expect (Review)." International Journal of Oncology 49, no. 6 (October 24, 2016): 2206–16. http://dx.doi.org/10.3892/ijo.2016.3747.

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Zeinali, Mina, Maggie Lee, Arthi Nadhan, Anvya Mathur, Casey Hedman, Eric Lin, Ramdane Harouaka, et al. "High-Throughput Label-Free Isolation of Heterogeneous Circulating Tumor Cells and CTC Clusters from Non-Small-Cell Lung Cancer Patients." Cancers 12, no. 1 (January 3, 2020): 127. http://dx.doi.org/10.3390/cancers12010127.

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(1) Background: Circulating tumor cell (CTC) clusters are emerging as clinically significant harbingers of metastases in solid organ cancers. Prior to engaging these CTC clusters in animal models of metastases, it is imperative for technology to identify them with high sensitivity. These clusters often present heterogeneous surface markers and current methods for isolation of clusters may fall short. (2) Methods: We applied an inertial microfluidic Labyrinth device for high-throughput, biomarker-independent, size-based isolation of CTCs/CTC clusters from patients with metastatic non-small-cell lung cancer (NSCLC). (3) Results: Using Labyrinth, CTCs (PanCK+/DAPI+/CD45−) were isolated from patients (n = 25). Heterogeneous CTC populations, including CTCs expressing epithelial (EpCAM), mesenchymal (Vimentin) or both markers were detected. CTCs were isolated from 100% of patients (417 ± 1023 CTCs/mL). EpCAM− CTCs were significantly greater than EpCAM+ CTCs. Cell clusters of ≥2 CTCs were observed in 96% of patients—of which, 75% were EpCAM−. CTCs revealed identical genetic aberrations as the primary tumor for RET, ROS1, and ALK genes using fluorescence in situ hybridization (FISH) analysis. (4) Conclusions: The Labyrinth device recovered heterogeneous CTCs in 100% and CTC clusters in 96% of patients with metastatic NSCLC. The majority of recovered CTCs/clusters were EpCAM−, suggesting that these would have been missed using traditional antibody-based capture methods.

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Nelson-Taylor, Sarah K., Avery Bodlack, Andrew Goodspeed, Amy Treece, Nathan Donaldson, Carrye Cost, Tim Garrington, et al. "Abstract 1681: Single cell RNA sequencing of primary Ewing sarcoma tumors and identification of circulating tumor cells in patient-matched peripheral blood samples." Cancer Research 82, no. 12_Supplement (June 15, 2022): 1681. http://dx.doi.org/10.1158/1538-7445.am2022-1681.

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Abstract Ewing sarcoma (ES) is the second most common bone cancer in children, accounting for 2% of pediatric cancer diagnoses. Patients who present with metastatic disease at the time of diagnosis have a dismal prognosis, compared to the >70% 5-year survival of those with localized disease. Here, we utilized single-cell RNA sequencing (scRNA-seq) to characterize the transcriptional landscape of primary ES tumors, and to identify circulating tumor cells (CTCs) in peripheral blood at the time of diagnosis in order to further understand ES transcriptional heterogeneity and factors that drive metastasis. Methods: Viably frozen primary tumor and peripheral blood samples were obtained from 7 ES patients at the time of diagnosis and prior to the initiation of treatment. Tumors were dissociated into a single cell suspension and sorted for viability using FACS (fluorescence activated cell sorting) whereas peripheral blood samples were subjected to a size-based selection with the CellSieve microfiltration system. ScRNA-seq was performed using the 10xChromium platform and count matrices were generated using 10x Genomics Cell Ranger software. Quality control, integration, and cluster analysis was performed with Seurat. Results: Cluster analysis of integrated, primary tumor samples demonstrated that candidate ES cell clusters express FLI1 and ES marker NKX2-2 and cluster separately from immune cell populations. Additionally, using inferCNV, ES clusters were demonstrated to harbor chromosomal copy number alterations known to be associated with ES and that were previously identified clinically on preliminary pathology reports for each patient; further GSEA analysis showed significant overlap between published ES gene sets and genes upregulated in ES clusters. Further analysis of ES cells demonstrated that cell-cycle phase determined a cluster enriched in pro-proliferation gene signatures, and overall heterogeneity of expression of previously known therapeutic targets. Candidate ES CTCs were identified among the peripheral blood samples among clusters which corresponded with distinct immune cell populations. The candidate ES CTCs expressed NKX2-2 and demonstrated enrichment in oncogenic gene signatures. Conclusion: ScRNA-seq of primary ES tumors is feasible and demonstrates that ES tumor cells are largely homogeneous in nature; and candidate ES CTCs can be identified in peripheral blood at the time of diagnosis in ES patient and warrant further investigation as to their utility as a biomarker of metastatic disease. Citation Format: Sarah K. Nelson-Taylor, Avery Bodlack, Andrew Goodspeed, Amy Treece, Nathan Donaldson, Carrye Cost, Tim Garrington, Brian Greffe, Sandra Luna-Fineman, Jenna Sopfe, Masanori Hayashi. Single cell RNA sequencing of primary Ewing sarcoma tumors and identification of circulating tumor cells in patient-matched peripheral blood samples [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1681.

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Bagadia, Ritvi K., Vishal Uchila Shishir Rao, Ajay Balakrishnan, Abhijith George, and Prashant Kumar. "Association between central and peripheral circulating tumor cell (CTC) clusters in oral squamous cell carcinoma (OSCC): A prospective, observational study." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e15548-e15548. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e15548.

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e15548 Background: Around 90% of cancer-related mortalities are caused by tumor metastasis. CTC clusters, which constitute an intermediate stage of metastasis, have not been studied extensively in head & neck cancers. The mortality rate of oral cancers remains alarmingly high, despite multimodality treatment. The aim of the study is to identify the presence of CTC clusters in patients with Oral Squamous Cell Carcinoma (OSCC) and to correlate their presence with clinical and pathological factors. Methods: Fifty patients diagnosed with histologically proven OSCC, treatment naïve, and underwent surgery at HCG Cancer Centre, Bangalore, were consented and enrolled in the study. An IRB-approved protocol allowed for the collection of 10 ml of blood from central (jugular) and peripheral veins intra-operatively, prior to tumor removal. The culturing of CTC clusters was done using ellipsoidal microwell plates maintained at hypoxic conditions, at the Institute of Bioinformatics, Bangalore. After fourteen days of culturing, the cells were fixed and stained for DAPI, Pan-CK and CD45. The CTC clusters were classified into Loose, Tight and very Tight based on the median gray values obtained from DAPI staining on ImageJ software. Clinical data was collected from patient records and subjected to analysis using Descriptive statistics. Results: From the 50 patients included in the study, 22 (44%) patients exhibited tight clusters in central blood, while only 13 (26%) patients exhibited tight clusters in peripheral blood. A higher clinical stage was observed in a greater percentage of patients with tight clusters in central blood (early: 45.5% versus late: 54.5%), but the same findings could not be inferred with pathological staging (early stage: 59.1% versus late stage: 40.1%). No significant correlation with adverse pathological features was noted. Conclusions: This observational study provides an insight into the varying biological behaviours of similarly grouped cancers, which is based on the standard TNM staging. The study forms the basis for the hypothesis of tight clusters in the central and peripheral circulation, correlating with loco-regional and distant metastasis respectively, thus leading to poorer disease-free and overall survival rates.

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Journal articles on the topic 'Circulating tumour cell clusters'

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