Relevant bibliographies by topics / Genetically-engineered mouse (GEM) models

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Academic literature on the topic 'Genetically-engineered mouse (GEM) models'

Author: Grafiati
Published: 4 June 2021
Last updated: 1 February 2022

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Journal articles on the topic "Genetically-engineered mouse (GEM) models"

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Cho, Kyungjoo, Simon Weonsang Ro, Sang Hyun Seo, Youjin Jeon, Hyuk Moon, Do Young Kim, and Seung Up Kim. "Genetically Engineered Mouse Models for Liver Cancer." Cancers 12, no. 1 (December 19, 2019): 14. http://dx.doi.org/10.3390/cancers12010014.

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Liver cancer is the fourth leading cause of cancer-related death globally, accounting for approximately 800,000 deaths annually. Hepatocellular carcinoma (HCC) is the most common type of liver cancer, comprising approximately 80% of cases. Murine models of HCC, such as chemically-induced models, xenograft models, and genetically engineered mouse (GEM) models, are valuable tools to reproduce human HCC biopathology and biochemistry. These models can be used to identify potential biomarkers, evaluate potential novel therapeutic drugs in pre-clinical trials, and develop molecular target therapies. Considering molecular target therapies, a novel approach has been developed to create genetically engineered murine models for HCC, employing hydrodynamics-based transfection (HT). The HT method, coupled with the Sleeping Beauty transposon system or the CRISPR/Cas9 genome editing tool, has been used to rapidly and cost-effectively produce a variety of HCC models containing diverse oncogenes or inactivated tumor suppressor genes. The versatility of these models is expected to broaden our knowledge of the genetic mechanisms underlying human hepatocarcinogenesis, allowing the study of premalignant and malignant liver lesions and the evaluation of new therapeutic strategies. Here, we review recent advances in GEM models of HCC with an emphasis on new technologies.
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Varticovski, L., M. G. Hollingshead, M. R. Anver, A. I. Robles, J. E. Green, K. W. Hunter, G. Merlino, et al. "Preclinical testing using tumors from genetically engineered mouse mammary models." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 10067. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.10067.

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10067 Background: Mouse models have been used extensively in preclinical testing of anticancer drugs. However, few of these models reflect the progression of human disease, and even fewer predict the performance of these drugs in clinical trials. Testing anticancer therapies in genetically engineered mouse (GEM) holds the promise of improving preclinical models and guiding the design of clinical trials. Unfortunately, the use of tumor-bearing GEM is hampered by the difficulty in simultaneously obtaining sufficient numbers of animals with the same stage of tumor development. The additional complexity in testing breast cancer therapies in the mouse is that all 10 mammary glands can develop tumors, frequently at different times. Methods: To circumvent the variable tumor latency and lack of synchrony in GEM, we transplanted tumor fragments or cell suspensions from multiple mammary tumor-bearing GEM into the mammary fat pad or subcutaneously into naïve syngeneic, immunodeficient athymic nude, or scid mice. Results: Tumors transplanted as fragments or cell suspensions derived from anterior mammary gland grew faster than the posterior tumors for serial passages without any significant morphologic differences. Cell suspensions using fresh or frozen cells were equally effective in generating tumors, and increasing the numbers of transplanted cells resulted in faster tumor growth. The transplantation strategy was reproducible in multiple breast cancer mouse models, including MMTV-PyMT, -Her2/neu, -wnt1/p53, BRCA1/p53, and others. Metastatic disease in the lungs was evident after removing the primary tumors at different rates for each mouse model. The transplanted primary tumors and the tumors arising in the original GEM had similar morphologic appearance and sensitivity to several chemotherapeutic and novel molecular targeted agents. Conclusions: We have established transplantable synchronous mammary tumors from GEM which also develop metastatic disease. These valuable mouse models are suitable for studying tumor-host interactions, tumor progression, and preclinical testing in a well-characterized molecular and genetic background. Testing these GEM tumors for conventional and novel molecular targeted therapies will be discussed. No significant financial relationships to disclose.
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Shibata, Maho, and Michael M. Shen. "Stem cells in genetically-engineered mouse models of prostate cancer." Endocrine-Related Cancer 22, no. 6 (September 4, 2015): T199—T208. http://dx.doi.org/10.1530/erc-15-0367.

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The cancer stem cell model proposes that tumors have a hierarchical organization in which tumorigenic cells give rise to non-tumorigenic cells, with only a subset of stem-like cells able to propagate the tumor. In the case of prostate cancer, recent analyses of genetically engineered mouse (GEM) models have provided evidence supporting the existence of cancer stem cells in vivo. These studies suggest that cancer stem cells capable of tumor propagation exist at various stages of tumor progression from prostatic intraepithelial neoplasia (PIN) to advanced metastatic and castration-resistant disease. However, studies of stem cells in prostate cancer have been limited by available approaches for evaluating their functional properties in cell culture and transplantation assays. Given the role of the tumor microenvironment and the putative cancer stem cell niche, future studies using GEM models to analyze cancer stem cells in their native tissue microenvironment are likely to be highly informative.
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Szabova, Ludmila, Baktiar Karim, Melanie Gordon, Lucy Lu, Nathan Pate, and Zoe Weaver Ohler. "A Transplantable Syngeneic Allograft Mouse Model for Nongestational Choriocarcinoma of the Ovary." Veterinary Pathology 56, no. 3 (January 13, 2019): 399–403. http://dx.doi.org/10.1177/0300985818823669.

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Nongestational choriocarcinoma is a rare malignancy in humans with poor prognosis. Naturally occurring choriocarcinoma is also rare in laboratory mice, and no genetic mouse model accurately recapitulates the features of this cancer. Here we report development of a genetically engineered mouse (GEM) model with alterations in Brca2, Trp53, and RB that develops ovarian tumors. Most of the ovarian tumors displayed histological characteristics of nongestational choriocarcinoma of the ovary (NGCO) (47%) with abundant syncytiotrophoblasts and cytotrophoblasts, positive immunolabeling for human chorionic gonadotropin, and positive periodic acid–Schiff reaction. The rest of the ovarian tumors were serous epithelial ovarian carcinoma (SEOC) (26%) or mixed tumors consisting of NGCO and SEOC (26%). We further established syngeneic orthotopic mouse models for NGCO by in vivo passaging of GEM tumors. These metastatic models provide a platform for evaluating new treatment strategies in preclinical studies aimed at improving outcomes in choriocarcinoma patients.
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Garcia, Patrick L., Aubrey L. Miller, and Karina J. Yoon. "Patient-Derived Xenograft Models of Pancreatic Cancer: Overview and Comparison with Other Types of Models." Cancers 12, no. 5 (May 22, 2020): 1327. http://dx.doi.org/10.3390/cancers12051327.

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Pancreatic cancer (PC) is anticipated to be second only to lung cancer as the leading cause of cancer-related deaths in the United States by 2030. Surgery remains the only potentially curative treatment for patients with pancreatic ductal adenocarcinoma (PDAC), the most common form of PC. Multiple recent preclinical studies focus on identifying effective treatments for PDAC, but the models available for these studies often fail to reproduce the heterogeneity of this tumor type. Data generated with such models are of unknown clinical relevance. Patient-derived xenograft (PDX) models offer several advantages over human cell line-based in vitro and in vivo models and models of non-human origin. PDX models retain genetic characteristics of the human tumor specimens from which they were derived, have intact stromal components, and are more predictive of patient response than traditional models. This review briefly describes the advantages and disadvantages of 2D cultures, organoids and genetically engineered mouse (GEM) models of PDAC, and focuses on the applications, characteristics, advantages, limitations, and the future potential of PDX models for improving the management of PDAC.
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Ferri-Borgogno, Sammy, Sugata Barui, Amberly M. McGee, Tamara Griffiths, Pankaj K. Singh, Cortt G. Piett, Bidyut Ghosh, et al. "Paradoxical Role of AT-rich Interactive Domain 1A in Restraining Pancreatic Carcinogenesis." Cancers 12, no. 9 (September 21, 2020): 2695. http://dx.doi.org/10.3390/cancers12092695.

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Background & Aims: ARID1A is postulated to be a tumor suppressor gene owing to loss-of-function mutations in human pancreatic ductal adenocarcinomas (PDAC). However, its role in pancreatic pathogenesis is not clear despite recent studies using genetically engineered mouse (GEM) models. We aimed at further understanding of its direct functional role in PDAC, using a combination of GEM model and PDAC cell lines. Methods: Pancreas-specific mutant Arid1a-driven GEM model (Ptf1a-Cre; KrasG12D; Arid1af/f or “KAC”) was generated by crossing Ptf1a-Cre; KrasG12D (“KC”) mice with Arid1af/f mice and characterized histologically with timed necropsies. Arid1a was also deleted using CRISPR-Cas9 system in established human and murine PDAC cell lines to study the immediate effects of Arid1a loss in isogenic models. Cell lines with or without Arid1a expression were developed from respective autochthonous PDAC GEM models, compared functionally using various culture assays, and subjected to RNA-sequencing for comparative gene expression analysis. DNA damage repair was analyzed in cultured cells using immunofluorescence and COMET assay. Results: Retention of Arid1a is critical for early progression of mutant Kras-driven pre-malignant lesions into PDAC, as evident by lower Ki-67 and higher apoptosis staining in “KAC” as compared to “KC” mice. Enforced deletion of Arid1a in established PDAC cell lines caused suppression of cellular growth and migration, accompanied by compromised DNA damage repair. Despite early development of relatively indolent cystic precursor lesions called intraductal papillary mucinous neoplasms (IPMNs), a subset of “KAC” mice developed aggressive PDAC in later ages. PDAC cells obtained from older autochthonous “KAC” mice revealed various compensatory (“escaper”) mechanisms to overcome the growth suppressive effects of Arid1a loss. Conclusions: Arid1a is an essential survival gene whose loss impairs cellular growth, and thus, its expression is critical during early stages of pancreatic tumorigenesis in mouse models. In tumors that arise in the setting of ARID1A loss, a multitude of “escaper” mechanisms drive progression.
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Donson, Andrew, Kent Riemondy, Sujatha Venkataraman, Ahmed Gilani, Bridget Sanford, Andrea Griesinger, Vladimir Amani, et al. "MBRS-46. CHARTING NEOPLASTIC AND IMMUNE CELL HETEROGENEITY IN HUMAN AND GEM MODELS OF MEDULLOBLASTOMA USING scRNAseq." Neuro-Oncology 22, Supplement_3 (December 1, 2020): iii406. http://dx.doi.org/10.1093/neuonc/noaa222.555.

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Abstract We explored cellular heterogeneity in medulloblastoma using single-cell RNA sequencing (scRNAseq), immunohistochemistry and deconvolution of bulk transcriptomic data. Over 45,000 cells from 31 patients from all main subgroups of medulloblastoma (2 WNT, 10 SHH, 9 GP3, 11 GP4 and 1 GP3/4) were clustered using Harmony alignment to identify conserved subpopulations. Each subgroup contained subpopulations exhibiting mitotic, undifferentiated and neuronal differentiated transcript profiles, corroborating other recent medulloblastoma scRNAseq studies. The magnitude of our present study builds on the findings of existing studies, providing further characterization of conserved neoplastic subpopulations, including identification of a photoreceptor-differentiated subpopulation that was predominantly, but not exclusively, found in GP3 medulloblastoma. Deconvolution of MAGIC transcriptomic cohort data showed that neoplastic subpopulations are associated with major and minor subgroup subdivisions, for example, photoreceptor subpopulation cells are more abundant in GP3-alpha. In both GP3 and GP4, higher proportions of undifferentiated subpopulations is associated with shorter survival and conversely, differentiated subpopulation is associated with longer survival. This scRNAseq dataset also afforded unique insights into the immune landscape of medulloblastoma, and revealed an M2-polarized myeloid subpopulation that was restricted to SHH medulloblastoma. Additionally, we performed scRNAseq on 16,000 cells from genetically engineered mouse (GEM) models of GP3 and SHH medulloblastoma. These models showed a level of fidelity with corresponding human subgroup-specific neoplastic and immune subpopulations. Collectively, our findings advance our understanding of the neoplastic and immune landscape of the main medulloblastoma subgroups in both humans and GEM models.
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Mohammed, Altaf, Naveena B. Janakiram, Venkateshwar Madka, Min Li, Adam S. Asch, and Chinthalapally V. Rao. "Current Challenges and Opportunities for Chemoprevention of Pancreatic Cancer." Current Medicinal Chemistry 25, no. 22 (July 4, 2018): 2535–44. http://dx.doi.org/10.2174/0929867324666170209104453.

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Background: The incidence of pancreatic cancer (PC) is rising in parallel with the deaths caused by this malignant disease largely due to limited improvement in current treatment strategies. In spite of aggressive PC research, for the past three decades, there has been no significant improvement in the five-year survival for this cancer. Like many other cancers, it takes several years for normal pancreatic cells to transform into pancreatic precursor lesions and to further progress into invasive carcinoma. Hence there is a scope for the development of chemo-preventive strategies to inhibit/ delay/prevent progression of this disease into an advanced stage cancer. Objective: Chemoprevention of pancreatic cancer. Method: Review of published literature. OResults and Conclusion: Availability of various genetically engineered mouse (GEM) models of PC has led to accelerated progress in understanding the disease and developing intervention strategies otherwise stalled for a long time. These GEM models spontaneously develop PC in a stepwise manner and mimic the disease etiology in humans. Understanding PC development from initiation to progression to metastasis is very important for early detection and prevention of PC. In this review, we focus on the current situation, the potential challenges, the progress in existing strategies and available opportunities as well as suggest key areas for research within the increasingly important area of pancreatic cancer chemoprevention.
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Park, Jun Won, Hyejin Um, Hanna Yang, Joo Young Cha, Kyoung-June Lee, and Hark K. Kim. "CWP232291, a Wnt/β-catenin inhibitor, to suppress the growth and development of gastrointestinal cancers." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): e15534-e15534. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e15534.

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e15534 Background: CWP232291 (JW Pharmaceutical Corp, Seoul, Korea) is a potent β-catenin inhibitor currently tested in phase I trials for AML and MM. We evaluated the preclinical efficacy of CWP232291 for gastrointestinal cancers using xenograft and genetically-engineered mouse (GEM) models. Methods: For xenograft experiments, we intraperitoneally administered 150 mg/kg of CWP232291 twice a week to 14 heterotopic and 2 orthotopic xenografts of human gastric cancer cell lines formed in NOD/SCID mice. For GEM experiments, we intraperitoneally administered 100 mg/kg of CWP232291 (n = 19) or vehicle (n = 27) twice a week for 17 weeks to 3-week-old Villin-Cre;Smad4 F/F;Trp53F/F GEM mice that spontaneously form intestinal tumors with the β-catenin signaling activation. Results: CWP232291 exhibited in vivo activity in human gastric cancer xenografts. Activity of CWP232291 was more prominent in human gastric cancer cell lines harboring mutations in the β-catenin signaling pathway, such as APC, and in the 5-FU-resistant derivative of SNU-620, than in the other xenografts (P = 0.028, t-test). In the MKN-45 orthotopic xenograft, we noted a decrease in luciferase signal intensity after 4 weeks of CWP232291 treatment. CWP232291 demonstrated synergistic activity with paclitaxel and irinotecan in the SNU-484 heterotopic xenograft. In GEM experiments, CWP232291 treatment significantly suppressed the spontaneous development of intestinal tumors (56.3% vs. 91.3% with vehicle) in Villin-Cre;Smad4 F/F;Trp53F/F mice. Furthermore, CWP232291 treatment significantly reduced the number of mice that develop intestinal adenocarcinomas (37.5% vs. 78.3% with vehicle). Immunohistochemistry revealed CD8 T cell activation within the mouse intestinal tumors. Conclusions: CWP232291 demonstrated significant preclinical efficacy in gastrointestinal tumors, especially in cancers with the β-catenin signaling activation.
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De Velasco, Marco A., and Hirotsugu Uemura. "Preclinical Remodeling of Human Prostate Cancer through the PTEN/AKT Pathway." Advances in Urology 2012 (2012): 1–12. http://dx.doi.org/10.1155/2012/419348.

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Knowledge gained from the identification of genetic and epigenetic alterations that contribute to the progression of prostate cancer in humans is now being implemented in the development of functionally relevant translational models. GEM (genetically modified mouse) models are being developed to incorporate the same molecular defects associated with human prostate cancer. Haploinsufficiency is common in prostate cancer and homozygous loss ofPTENis strongly correlated with advanced disease. In this paper, we discuss the evolution of thePTENknockout mouse and the cooperation betweenPTENand other genetic alterations in tumor development and progression. Additionally, we will outline key points that make these models key players in the development of personalized medicine, as potential tools for target and biomarker development and validation as well as models for drug discovery.
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Dissertations / Theses on the topic "Genetically-engineered mouse (GEM) models"

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Creedon, Helen. "Use of genetically engineered mouse models in preclinical drug development." Thesis, University of Edinburgh, 2015. http://hdl.handle.net/1842/15911.

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The paucity of well validated preclinical models is frequently cited as a contributing factor to the high attrition rates seen in clinical oncological trials. There remains a critical need to develop models which are accurately able to recapitulate the features of human disease. The aims of this study were to use genetically engineered mouse models (GEMMs) to explore the efficacy of novel treatment strategies in HER2 positive breast cancer and to further develop the model to facilitate the study of mechanisms underpinning drug resistance. Using the BLG--HER2KI-PTEN+/- model, we demonstrated that Src plays an important role in the early stages of tumour development. Chemopreventative treatment with dasatinib delayed tumour inititation (p= 0.046, Wilcoxon signed rank test) and prolonged overall survival (OS) (p=0.06, Wilcoxon signed rank test). Dasatinib treatment also induced squamous metaplasia in 66% of drug treated tumours. We used 2 cell lines derived from this model to further explore dasatinib’s mechanism of action and demonstrated reduced proliferation, migration and invasion following in vitro treatment. Due to the prolonged tumour latency and the low metastatic rate seen in this model, further studies were undertaken with the MMTV-NIC model. This model also allowed us to study the impact of PTEN loss on therapeutic response. We validated this model by treating a cohort of MMTV-NIC PTEN+/- mice with paclitaxel and demonstrated prolonged OS (p=0.035, Gehan Breslow Wilcoxon test). AZD8931 is an equipotent signalling inhibitor of HER2, HER3 and EGFR. We observed heterogeneity in tumour response but overall AZD8931 treatment prolonged OS in both MMTV-NIC PTEN FL/+ and MMTV-NIC PTEN+/- models. PTEN loss was associated with reduced sensitivity to AZD8931 and failure to suppress Src activity, suggesting these may be suitable predictive biomarkers of AZD8931 response. To facilitate further studies exploring resistance, we transplanted MMTV-NIC PTEN+/- fragments into syngeneic mice and generated 3 tumours with acquired resistance to AZD8931. These tumours displayed differing resistance strategies; 1 tumour continued to express HER2 whilst the remaining 2 underwent EMT and lost HER2 expression reflecting to a very limited degree some of the heterogeneity of resistance strategies seen in human disease. To further explore resistance to HER2 targeting tyrosine kinase inhibitors, we generated a panel of human cell lines with acquired resistance to AZD8931 and lapatinib. Western blotting demonstrated loss of HER2, HER3 and PTEN in all resistant lines. Acquisition of resistance was associated with a marked change in phenotype and western blotting confirmed all lines had undergone EMT. We used a combination of RPPA and mass spectrometry to further characterise the AZD8931 resistant lines and identified multiple potential novel proteins involved in the resistant phenotype, including several implicated in EMT. In conclusion, when coupled with appropriate in vitro techniques, the MMTV-NIC model is a valuable tool for selection of emerging drugs to carry forward into clinical trials of HER2 positive breast cancer.
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Vallerand, David. "Etude du stroma de tumeurs mammaires humaines xénogreffées et de modèles transgéniques murins." Thesis, Paris 11, 2014. http://www.theses.fr/2014PA11T001.

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La progression tumorale est un processus multi-étapes dépendant notamment des interactions entre les cellules cancéreuses et le stroma environnant. Le développement du cancer du sein implique une communication étroite entre les cellules épithéliales mammaires, les cellules inflammatoires, les myofibroblastes et les cellules endothéliales. Ainsi, le microenvironnement tumoral apparaît comme une cible de choix dans le traitement anti-tumoral. L’utilisation de modèles précliniques est une étape clé dans le développement et la validation de nouvelles thérapies. Néanmoins, peu d’études sont disponibles sur le rôle du stroma péri-tumoral dans ces modèles.Dans le but d’étudier le stroma péri-tumoral des modèles précliniques de cancers du sein, nous avons combiné une analyse par cytométrie en flux à une analyse par immunohistochimie afin d’identifier, puis de quantifier, les différentes populations stromales hématopoïétiques (lymphocytes, monocytes/macrophages, polynucléaires) et non hématopoïétiques (myofibroblastes, cellules endothéliales). Vingt et un modèles de xénogreffe de tumeurs humaines de cancers du sein ainsi que 2 modèles transgéniques (MMTV-PyMT et MMTV-ErbB2), ainsi que leurs allogreffes respectives, furent utilisés lors de ce travail.Les analyses des tumeurs humaines et murines ont montré un infiltrat stromal très hétérogène d’une tumeur à l’autre, avec pour composante majoritaire les macrophages. Un infiltrat important en polynucléaires a également été détecté dans les modèles de PDX, caractéristique d’une inflammation locale importante dans ces modèles. L’analyse phénotypique de macrophages a montré une expression variable de marqueurs M1 et M2 dans les modèles de PDX. Les macrophages issus de tumeurs murines transgéniques, spontanées ou allogreffées, présentaient quant à eux un profil majoritairement M1. L’étude transcriptomique de macrophages triés, a permis à la fois de valider les résultats obtenus au niveau protéique mais a également mis en évidence des différences majeures dans l’expression de nombreux gènes, impliqués dans des voies de signalisation variées telles que la croissance tumorale, l’invasion et la métastase.Cette étude nous a permis de mettre en évidence le rôle de la tumeur sur son microenvironnement. En effet, celle-ci est à la fois capable d’attirer un panel de cellules stromales qui lui et propre et ensuite de l’activer de façon spécifique
Tumor development is a multi-step process influencing by interactions between tumor cells and surrounding stroma. Breast cancer development involves a high level of communication between mammary epithelial cells, inflammatory cells, myofibroblasts and endothelial cells. So, the tumoral microenvironment appears as a prime target for anti-tumoral treatment. The use of preclinical models is a critical step in development and validation processes of new therapies. Nevertheless, the role of stroma in these models is poorly understood.In order to evaluate stromal cell populations in breast cancer preclinical models, we combined flow cytometry analysis and immunohistochemistry to identify, and then quantify, various stromal populations as hematopoietic cells (lymphocytes, monocytes/macrophages, polymorphonuclear leukocytes) and non-hematopoietic cells (myofibroblasts, endothelial cells). Twenty-one breast cancer patient-derived xenografts as well as 2 transgenic mouse models (MMTV-PyMT and MMTV-ErbB2), and their respective allografts, were studied.Analysis of human and murine tumors showed a strong heterogeneity between tumors regarding infiltrating stroma-cells, with a high proportion of macrophages. A significant amount of polymorphonuclear leukocytes was also detected in PDXs, indicating a local inflammation in these models. The phenotypic analysis of macrophages showed a variable expression of M1 and M2 markers in PDXs. Macrophages infiltrating transgenic mouse tumors, spontaneous or allografted, were mainly M1. Transcriptomic analyses of sorted macrophages, allowed us to validate previous results but also highlighted major differences in the expression of numerous genes implicated in various pathways as tumor growth, invasion and metastasis.Finally, this study highlighted the impact of tumor cells on their surrounding stroma. Indeed, we demonstrate that cancer cells are able to attract a specific panel of stromal cells and activate them in a specific way
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Lin, Shyr-Yeu 1962. "Genetically engineered mouse models for the study of follistatin biology." Monash University, Institute of Reproduction and Development, 2003. http://arrow.monash.edu.au/hdl/1959.1/5739.

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Lambert, Laurens J. (Laurens Johannes). "Development and characterization of immunogenic genetically engineered mouse models of pancreatic cancer." Thesis, Massachusetts Institute of Technology, 2020. https://hdl.handle.net/1721.1/129020.

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Thesis: Ph. D., Massachusetts Institute of Technology, Department of Biology, 2020
Cataloged from student-submitted PDF of thesis. Vita. Page 191 blank.
Includes bibliographical references.
Insights into mechanisms of immune escape have fueled the clinical success of immunotherapy in many cancers. However, pancreatic cancer has remained largely refractory to checkpoint immunotherapy. To uncover mechanisms of immune escape, we have characterized two preclinical models of immunogenic pancreatic ductal adenocarcinoma (PDAC). In order to dissect the endogenous antigen-specific T cell response in PDAC, lentivirus encoding the Cre recombinase and a tumor specific antigen (SIINFEKL, OVA[subscript 257-264]) was delivered to Kras[superscript LSL-G12D/+]; Trp[superscript 53flox/flox] (KP) mice. We demonstrate that KP tumors show distinct antigenic outcomes: a subset of PDAC tumors undergoes clearance or editing by a robust antigen-specific CD8+ T cell response, while a fraction undergo immune escape. Subsequently, we have developed an immunogenic pancreatic tumor organoid orthotopic transplant model.
In this model, immunogenic pancreatic tumors manifest divergent tumor phenotypes; 40% of tumor organoids do not form tumors ("non-progressors"), whereas 50% of organoids form aggressive tumors despite maintaining antigen expression and a demonstrable T cell response ("progressors"). Additionally, a subset (10%) of tumors show an intermediate phenotype, possibly reflective of an immune equilibrium state. We have further phenotypically and transcriptionally characterized the CD8+ T cell response to understand immune escape in this model. Our analyses reveal unexpected T cell heterogeneity, and acquisition of T cell dysfunctionality. Therapeutic combinatorial targeting of co-inhibitory receptors identified on dysfunctional antigen-specific CD8+ T cells led to dramatic regression of aggressive pancreatic tumors.
Finally, we demonstrate that human CD8+ T cells isolated from pancreatic tumors co-express co-inhibitory receptors, suggesting that T cell dysfunction may be operational in human disease. This is the first demonstration of immunoediting in an autochthonous and organoid-based model of pancreatic cancer. Further characterization of these preclinical model systems will enable rational design of novel clinical immunotherapeutic strategies for treatment of this devastating disease.
by Laurens J. Lambert.
Ph. D.
Ph.D. Massachusetts Institute of Technology, Department of Biology
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Du, Page Michel Justin Porter. "Investigation of T cell-mediated immune surveillance against tumor-specific antigens in genetically engineered mouse models of cancer." Thesis, Massachusetts Institute of Technology, 2011. http://hdl.handle.net/1721.1/62620.

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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, 2011.
This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.
Cataloged from student-submitted PDF version of thesis. Vita.
Includes bibliographical references.
The association of tumor cells and lymphocytes has led to the hypothesis that our immune system actively inhibits the formation and progression of cancer, a phenomenon called tumor immune surveillance. T cells specific to mutant proteins have been identified in cancer patients and the recent success of cancer immunotherapies provides evidence that the immune system can fight this disease. Yet the frequent occurrence of malignant disease despite T cell recognition presents a significant medical problem. Only after we determine how tumors bypass the immune system can immunotherapeutic approaches be improved. To understand how tumors subvert immune responses, tumor transplantation or transgenic mice expressing tumor-associated antigens have been used to model cancer. To assess the role of anti-tumor T cells in models that more accurately reflect the human disease, I developed new systems to introduce exogenous antigens, to mimic neoantigens, into genetically engineered mouse models of lung cancer and sarcomas. Utilizing the mouse model of lung cancer, I show that endogenous T cells respond to and infiltrate lung tumors, delaying malignant progression. Despite continued antigen expression, T cell infiltration does not persist and tumors ultimately escape immune attack. Transplantation of cell lines derived from lung tumors that express these antigens or prophylactic vaccination against autochthonous tumors, however, results in rapid tumor eradication or selection of tumors that lose antigen expression. These results support clinical data that suggest a role for the immune system in cancer suppression rather than prevention. Tumor immune surveillance and immunoediting have largely been defined using carcinogen-driven models of sarcomagenesis. Using a genetically engineered model of sarcomagenesis, I show that immunoediting requires potent T cell antigens and that lymphocytes drive the evolution of less immunogenic tumors by selecting for antigen loss. Finally, immunotherapies have historically been ineffective in treating cancer patients. I show that vaccination against specific antigens expressed in mouse lung cancers leads to sustained anti-tumor T cell responses that eradicate recently initiated tumors. Vaccination also stimulates anti-tumor T cell responses in an antigen-independent fashion by enhancing the expansion and activity of T cells that recognize antigens only expressed in tumors.
by Michel Justin Porter Du Page.
Ph.D.
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Schmidt, Leah Marie. "Investigating functions of tumor-infiltrating natural killer cells in genetically-engineered mouse models of non-small cell lung cancer." Thesis, Massachusetts Institute of Technology, 2016. http://hdl.handle.net/1721.1/104480.

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Thesis: Ph. D., Massachusetts Institute of Technology, Department of Biology, 2016.
Cataloged from PDF version of thesis. Vita.
Includes bibliographical references.
The immune system has long been hypothesized to play a role in restraining tumor growth, but compelling evidence for this role evaded scientists for the better part of a century. After many years of skepticism, the field of cancer immunology has recently undergone a major revolution. The success of modern immunotherapeutics has transformed the arenas of oncology and drug development. Large efforts are now focused on understanding the factors that dictate patient responses to immunotherapy, for the identification of possible points of intervention to expand the fraction of patients who benefit from therapy. The majority of approved immunotherapeutics directly target adaptive immune effectors. However, emerging evidence suggests that these treatments preferentially benefit patients with pre-existing immune responses against tumors, and patients who fail therapies often harbor tumors that are poorly infiltrated by adaptive immune cells. I have explored the role of an innate immune effector known for its capacity to kill tumor cells and its importance in stimulating and shaping adaptive immune responses, the natural killer (NK) cell. To this end, I developed a new system for assaying NK cell function in the context of established, autochthonous lung cancer, by engineering vectors for producing tumors with inducible NK cell activating ligands. Using this model, I have shown that NK cells in established tumors exhibit dysfunctional phenotypes, but their responses can be boosted by providing activating stimuli. Strikingly, stimulation of NK cells results in the recruitment of adaptive immune cells to tumors. By developing a next-generation model for inducing activating NK cell ligands in tumors engineered to express T cell antigens, I demonstrated that NK cell activation in immunogenic tumors results in effective immune responses that restrain tumor growth, highlighting the potential for cooperation between innate and adaptive arms of the immune system in anti-tumor immunity. Finally, I developed a novel immunotherapeutic molecule for stimulating NK cell responses against cancer cells. Bifunctional molecules are an emerging class of anti-cancer agents, designed to target immune effectors against tumors. I produced and performed initial functional testing on a bifunctional molecule that stimulates NK cell responses against tumors by 'decorating' the surface of cancer cells with activating NK cell ligands. I demonstrated that this bifunctional molecule induces NK cell cytotoxicity against tumor targets. Based on this work, we hypothesize that strategies for stimulating NK cells in tumors may enhance the efficacy of T cell-targeted therapies in the treatment of cancer.
by Leah Marie Schmidt.
Ph. D.
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Lee, Tony. "Investigations into the role of nitric oxide in cardiovascular development and disease, insights gained from genetically engineered mouse models of human disease." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape4/PQDD_0019/MQ54141.pdf.

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Grüner, Barbara Maria [Verfasser], Angelika [Akademischer Betreuer] Schnieke, Michael [Akademischer Betreuer] Schemann, and Jens T. [Akademischer Betreuer] Siveke. "Molecular and proteomic analysis of signaling pathways in pancreatic ductal adenocarcinoma using genetically engineered mouse models / Barbara Maria Grüner. Gutachter: Angelika Schnieke ; Jens T. Siveke ; Michael Schemann. Betreuer: Michael Schemann." München : Universitätsbibliothek der TU München, 2012. http://d-nb.info/1031512365/34.

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Schönhuber, Nina Verfasser], Angelika [Akademischer Betreuer] [Schnieke, Dieter K. M. [Akademischer Betreuer] Saur, and Oliver [Akademischer Betreuer] Krämer. "Next-generation genetically engineered mouse models to study PI3K/3-phosphoinositide-dependent protein kinase 1 (Pdk1) signaling in pancreatic cancer / Nina Schönhuber. Betreuer: Dieter K. M. Saur. Gutachter: Oliver Krämer ; Dieter K. M. Saur ; Angelika Schnieke." München : Universitätsbibliothek der TU München, 2015. http://d-nb.info/1079654976/34.

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Lin, Lu-Hsun, and 林呂勳. "Investigation of the Anti-Carcinogenesis potential of X Genetically Engineered Mouse (GEM) Model." Thesis, 2015. http://ndltd.ncl.edu.tw/handle/fr5cgq.

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Abstract:
碩士
國立陽明大學
生物藥學研究所
103
X gene is a DNA-binding protein mainly consists of an N-terminal transactivation domain and followed by a C-terminal region of DNA-binding domain. To understand the function of A mutation in X gene. We generate an X genetically engineered mice (X GEM). The lower cancer incidence phenotype in X GEM were be observed in our preliminary results. Interestingly, the expression microarray results were also identify important genes associated with carcinogenic. To study X GEM, which is relevant to the cancer incidence, we design an experiment to challenge cancer growth. Used chemical induction of liver cancer model to test the associated with carcinogenic in X GEM. The tumor size, number, phenotype and blood biochemistry were not significant differences between WT and X GEM mice, respectively. These results suggested that the X gene isn’t related to DEN induced HCC.
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Books on the topic "Genetically-engineered mouse (GEM) models"

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D, Hoit Brian, and Walsh Richard A. 1946-, eds. Cardiovascular physiology in the genetically engineered mouse. Norwell, MA: Kluwer Academic Publishers, 1998.

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D, Hoit Brian, and Walsh Richard A. 1946-, eds. Cardiovascular physiology in the genetically engineered mouse. 2nd ed. Boston: Kluwer Academic Publishers, 2002.

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Cardiovascular Physiology in the Genetically Engineered Mouse (Developments in Cardiovascular Medicine). 2nd ed. Springer, 2001.

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Investigations into the role of nitric oxide in cardiovascular development and disease: Insights gained from genetically engineered mouse models of human disease. Ottawa: National Library of Canada, 2000.

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Bates, Gillian P., and Christian Landles. Preclinical Experimental Therapeutics. Oxford University Press, 2014. http://dx.doi.org/10.1093/med/9780199929146.003.0016.

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This chapter begins by reviewing the mammalian models of Huntington’s disease (HD) that have been developed using mice, rats, and a number of large animals, including sheep, pigs, and nonhuman primates. Analysis of these models, together with genetically engineered mice created through specific manipulations of the mouse genome, has provided considerable insights into the molecular pathogenesis of HD. The number of potential therapeutic targets that have been proposed for HD is considerable, and their preclinical evaluation in HD mouse models is being used to select targets that should be pursued in drug development programs. Hence, mouse models have been used extensively to validate therapeutic targets and in the preclinical testing of therapeutic strategies. The limitations of these studies are discussed, and best-practice approaches are highlighted. The chapter concludes with a summary of the gene therapy approaches that are being developed, including strategies to lower the levels of huntingtin.
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Book chapters on the topic "Genetically-engineered mouse (GEM) models"

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Doetschman, Thomas, and L. Philip Sanford. "Overview of Designing Genetically Engineered Mouse (GEM) Models." In Genetically Engineered Mice for Cancer Research, 1–15. New York, NY: Springer New York, 2011. http://dx.doi.org/10.1007/978-0-387-69805-2_1.

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Rosales, Cecilia, and Manel Esteller. "Epigenetic Mouse Models." In Genetically Engineered Mice for Cancer Research, 375–96. New York, NY: Springer New York, 2011. http://dx.doi.org/10.1007/978-0-387-69805-2_18.

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Kucherlapati, Melanie, Ken Hung, Mari Kuraguchi, and Raju Kucherlapati. "Mouse Models for Colorectal Cancer." In Genetically Engineered Mice for Cancer Research, 309–29. New York, NY: Springer New York, 2011. http://dx.doi.org/10.1007/978-0-387-69805-2_15.

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Prescher, Jennifer A., and Christopher H. Contag. "Imaging Mouse Models of Human Cancer." In Genetically Engineered Mice for Cancer Research, 235–60. New York, NY: Springer New York, 2011. http://dx.doi.org/10.1007/978-0-387-69805-2_11.

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Kadmiel, Mahita, Kimberly L. Fritz-Six, and Kathleen M. Caron. "Understanding RAMPs Through Genetically Engineered Mouse Models." In Advances in Experimental Medicine and Biology, 49–60. New York, NY: Springer US, 2012. http://dx.doi.org/10.1007/978-1-4614-2364-5_5.

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Carbajal, Eletha, and Eric C. Holland. "Mouse Models in Preclinical Drug Development: Applications to CNS Models." In Genetically Engineered Mice for Cancer Research, 549–67. New York, NY: Springer New York, 2011. http://dx.doi.org/10.1007/978-0-387-69805-2_26.

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Largaespada, David A. "Insertional Mutagenesis for Generating Mouse Models of Cancer." In Genetically Engineered Mice for Cancer Research, 57–82. New York, NY: Springer New York, 2011. http://dx.doi.org/10.1007/978-0-387-69805-2_4.

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Hezel, Aram F., and Nabeel Bardeesy. "Genetically Engineered Mouse Models of Pancreatic Ductal Adenocarcinoma." In Tumor Models in Cancer Research, 377–95. Totowa, NJ: Humana Press, 2010. http://dx.doi.org/10.1007/978-1-60761-968-0_16.

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Philip, Subha, and Shyam K. Sharan. "Using Recombineering Technology to Create Genetically Engineered Mouse Models." In Genetically Engineered Mice for Cancer Research, 37–56. New York, NY: Springer New York, 2011. http://dx.doi.org/10.1007/978-0-387-69805-2_3.

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Sacca, Rosalba, Sandra J. Engle, Wenning Qin, Jeffrey L. Stock, and John D. McNeish. "Genetically Engineered Mouse Models in Drug Discovery Research." In Methods in Molecular Biology, 37–54. Totowa, NJ: Humana Press, 2009. http://dx.doi.org/10.1007/978-1-60761-058-8_3.

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Conference papers on the topic "Genetically-engineered mouse (GEM) models"

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Yamaguchi, Takashi, Sanae K. Ikehara, Hayao Nakanishi, and Yuzuru Ikehara. "Abstract 822: Genetically engineered mouse models of catastrophic pancreatic ductal adenocarcinoma." In Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA. American Association for Cancer Research, 2015. http://dx.doi.org/10.1158/1538-7445.am2015-822.

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Werr, LH, J. Ackermann, Y. Kahlert, J. Fischer, FT Wunderlich, and M. Fischer. "Investigating the role of activated telomerase in genetically engineered neuroblastoma mouse models." In 33. Jahrestagung der Kind-Philipp-Stiftung für pädiatr. onkolog. Forschung. © Georg Thieme Verlag KG, 2020. http://dx.doi.org/10.1055/s-0040-1709777.

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Gupta, Aayush, Marija Trajkovic-Arsic, Irina Heid, Nicole Teichman, Evdokia Kalederis, Rickmer Braren, and Jens Siveke. "Abstract B141: Predictive value of genetically engineered endogenous mouse models in preclinical therapeutic studies." In Abstracts: AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; November 5-9, 2015; Boston, MA. American Association for Cancer Research, 2015. http://dx.doi.org/10.1158/1535-7163.targ-15-b141.

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Vitucci, Mark, Byron Huff, Ryan E. Bash, Natalie O. Karpinich, Ralf S. Schmid, and C. Ryan Miller. "Abstract 4305: Dissecting the requirements for astrocytoma and invasion using genetically-engineered mouse models." In Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL. American Association for Cancer Research, 2012. http://dx.doi.org/10.1158/1538-7445.am2012-4305.

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Chung, Wei-Jen, Jason Long, Jason Cheng, Chris Tran, Anwesha Dey, Anneleen Daemen, and Melissa Junttila. "Abstract 2987: Next generation sequencing analysis of genetically engineered mouse models of human cancers." In Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA. American Association for Cancer Research, 2015. http://dx.doi.org/10.1158/1538-7445.am2015-2987.

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Scott, Clare L., Gwo Y. Ho, Elizabeth E. Lieschke, Olga Kondrashova, Ronny Drapkin, David Bowtell, and Matthew J. Wakefield. "Abstract 4798: Genetically engineered mouse models of proliferative C5 high grade serous ovarian cancer." In Proceedings: AACR Annual Meeting 2017; April 1-5, 2017; Washington, DC. American Association for Cancer Research, 2017. http://dx.doi.org/10.1158/1538-7445.am2017-4798.

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Abate-Shen, Cory, Alvaro Aytes Meneses, Carolyn W. Kinkade, Antonina Mitrofanova, Celine Lefebvre, Chee Wai Chua, Mireia Castillo-Martin, Edward Gelmann, Michael M. Shen, and Andrea Califano. "Abstract SY22-01: Interrogating gene expression programs from preclinical analyses of genetically engineered mouse models." In Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL. American Association for Cancer Research, 2011. http://dx.doi.org/10.1158/1538-7445.am2011-sy22-01.

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Chung, Wei-Jen, Anneleen Daemen, Jason Long, Jason Cheng, Chris Tran, Zora Modrusan, Oded Foreman, and Melissa Junttila. "Abstract 2686: The genomic landscape of Kras mutant genetically engineered mouse models of human cancers." In Proceedings: AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LA. American Association for Cancer Research, 2016. http://dx.doi.org/10.1158/1538-7445.am2016-2686.

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Burton, Liza J., Junghui Koo, Carol Tucker-Burden, Wei Zhou, Melissa Gilbert-Ross, Chunzi Huang, Gabriel Sica, and Adam Marcus. "Abstract 865: Isolation of circulating tumors cells from genetically engineered mouse models of lung adenocarcinoma." In Proceedings: AACR Annual Meeting 2019; March 29-April 3, 2019; Atlanta, GA. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/1538-7445.sabcs18-865.

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Burton, Liza J., Junghui Koo, Carol Tucker-Burden, Wei Zhou, Melissa Gilbert-Ross, Chunzi Huang, Gabriel Sica, and Adam Marcus. "Abstract 865: Isolation of circulating tumors cells from genetically engineered mouse models of lung adenocarcinoma." In Proceedings: AACR Annual Meeting 2019; March 29-April 3, 2019; Atlanta, GA. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/1538-7445.am2019-865.

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