Journal articles: '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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Zamler, Daniel, Er-Yen Yen, Takashi Shingu, Jiangong Ren, Cynthia Kassab, Jintan Liu, Amy Heimberger, Jian Hu, Giulio Draetta, and Michael Curran. "IMMU-10. ESTABLISHING EFFECTIVE MODELS FOR IMMUNOTHERAPY IN GBM." Neuro-Oncology 21, Supplement_6 (November 2019): vi121. http://dx.doi.org/10.1093/neuonc/noz175.504.

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Abstract The introduction of immunotherapies has been paradigm shifting for cancers that were previously a death sentence. However, preclinical/clinical studies on glioblastoma (GBM) have generated mixed outcomes in patients, likely due to its great heterogeneity of immune microenvironment, particularly the myeloid cell populations. Primary patient studies have been limited by a difficulty in performing longitudinal studies, uncontrolled environmental conditions, and genetic variability. There is also, unfortunately, a paucity of mouse models that effectively re-capitulate the immune microenvironment of the human disease. To address these difficulties, we have established the Qk/p53/Pten (QPP) triple knockout mouse model established in our lab. The QPP model uses a cre-lox system to induce Qk deletion on a Pten−/−; p53−/− background which helps NSCs maintain their stemness outside the SVZ in Nes-CreERT2;QkiL/L PtenL/L p53L/L mice, which develops glioblastoma with survival of ~105 days. We have preliminarily assessed the QPP tumors as a faithful model to study the immune response to GBM and found them to recapitulate human GBM with respect to differential response to checkpoint blockade therapy and myeloid and T-cells histopathologically, particularly regarding upregulation of Arginase-1 (Arg1). Arg1 is the canonical marker for tumor-associated macrophages (TAMs), which is a major population of myeloid cells that greatly infiltrate in human GBM, sometimes making up more than ~30% of all GBM cells. Given TAMs’ prevalence in the tumor microenvironment and their upregulation of Arg1 in both human GBM and our QPP model, we are testing whether manipulation of Arg1 will impact TAM function and influence GBM growth. We are also evaluating arginine metabolism in TAMs effect on T cell function in GBM. Lastly, we have developed a genetically engineered mouse model to study the role of Arg1 knockout in a GBM context in-vivo. Our studies suggest that Arg1 plays an important role in GBM immune interaction.

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Miki, Shunichiro, Tomoyuki Koga, Alison Parisian, and Frank Furnari. "TMOD-09. MODELING TERT PROMOTER MUTATION IN ISOGENIC NEXT GENERATION GBM MODELS." Neuro-Oncology 21, Supplement_6 (November 2019): vi264. http://dx.doi.org/10.1093/neuonc/noz175.1108.

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Abstract Telomere reverse transcriptase (TERT) promotor mutations increase TERT expression and are known to be the most common single genetic abnormality in Glioblastoma (GBM). Recent studies have revealed this mutation to be an early event in gliomagenesis but it is detected subclonally in a considerable number of cases. Due to the long telomere length and TERT expression in somatic cells of mice, genetically engineered mouse models of GBM do not address the function of this mutation and thus an ideal heterozygous TERT promotor mutation model is yet to be established. Recently, our lab established strategies for generating GBM models using neural progenitor cells (NPCs) derived from human induced pluripotent stem cells (hiPSCs) that have been CRISPR/Cas9 engineered with different combinations of authentic GBM-related genetic drivers which can be used for introduction of mutant TERT promotor (MTP) sequence and examination of its function. We obtained multiple heterozygous MTP hiPS clones in the context of GBM genetic alterations, CDKN2A/B and PTEN deletion, using a two-step targeting approach. Two single-strand guide RNAs (sgRNAs) were used to delete the TERT promotor and a portion of exon 1 followed by repair of the locus with wild type TERT promoter (WTP) and MTP sequence. Following promoter reconstitution, TERT promotor function was tested in iPSCs, NPCs, and astrocytes. This analysis revealed successful TERT expression silencing in WTP astrocytes. Furthermore, orthotopic injection of WTP and MTP NPCs into immunodeficient mice formed pathologically similar GBM-like tumors in same period of time. TERT expression was only detected in cell lines derived from MTP tumors, indicating TERT promotor mutation has little impact in initiation of tumor formation from NPCs, explaining its subclonality in patient tumors. Our model enables further research on MTP function and dependency during gliomagenesis.

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Harris, William Proctor, Sunil R. Hingorani, Joseph Thaddeus Beck, Boris A. Berdov, Stephanie Ann Wagner, Eduard M. Pshevlotsky, Sergei Tjulandin, et al. "Pharmacokinetic (PK)/pharmacodynamic (PD) results from a phase Ib study of pegylated hyaluronidase PH20 (PEGPH20) in combination with gemcitabine (Gem) in patients with pancreatic cancer." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): e15005-e15005. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.e15005.

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e15005 Background: Enzymatic degradation of hyaluronan (HA) is a novel strategy to target the desmoplastic stroma of pancreatic cancer. PEGPH20, a pegylated form of recombinant human hyaluronidase PH20, is an investigational drug in clinical trials. Preclinical studies demonstrate that sustained HA removal by PEGPH20 inhibits tumor growth and enhances chemotherapeutic activity in HA-rich xenografts and genetically engineered mouse tumor models. Ph1 PEGPH20 monotherapy studies show increased tumor perfusion by DCE-MRI, metabolic partial responses by FDG-PET, and stromal remodeling in tumor biopsies from selected advanced cancer patients (pts). Methods: This was a dose-escalation study to find the recommended Ph2 dose of PEGPH20 in combination with Gem in pts with Stage IV previously untreated pancreatic cancer. Pts received Gem at 1000 mg/m2 IV qwk for Wks 1-7 plus PEGPH20 at 1, 1.6, or 3 μg/kg IV twice a week for Wks 1-4 and qwk for Wks 5-7. Wk 8 was a rest week. Thereafter, PEGPH20 + Gem were given qwk for 3 wks in 4-wk cycles. Serial plasma samples were collected and hyaluronidase activity measured by an ultrasensitive assay to assess PEGPH20 exposure. Plasma HA catabolites were measured by quantitative HPLC to assess PD. Results: 28 pts were enrolled. Plasma PEGPH20 concentrations were proportional to dose, and kinetics were well-characterized by a 2-compartment PK model. Estimates for clearance (0.5-2 mL/hr/kg) were consistent with long t1/2 (1-2 days) previously seen with single-dose PEGPH20 monotherapy. Wks 1 and 4 PK profiles were similar, suggesting no changes to PEGPH20 clearance mechanisms after multiple doses or effects of Gem on PEGPH20 exposure. Most pretreatment plasma HA levels were <1 μg/mL and increased in a time- and dose-dependent manner after dosing. Circulating HA concentration was >500 µg/mL in several pts given 3 μg/kg PEGPH20. Conclusions: PEGPH20 plasma levels can be predicted using a linear PK model and circulating HA catabolites can be used as a quantitative measure of PEGPH20 PD. Results are consistent with the mechanism of action of hyaluronidase and support further study of PEGPH20 with anticancer agents. Clinical trial information: NCT01453153.

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Gardell, Jennifer L., Lisa R. Matsumoto, Harrison Chinn, Kole R. DeGolier, Shannon A. Kreuser, Brooke Prieskorn, Stephanie Balcaitis, Amira Davis, Richard G. Ellenbogen, and Courtney A. Crane. "Human macrophages engineered to secrete a bispecific T cell engager support antigen-dependent T cell responses to glioblastoma." Journal for ImmunoTherapy of Cancer 8, no. 2 (October 2020): e001202. http://dx.doi.org/10.1136/jitc-2020-001202.

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BackgroundTargeted and effective treatment options are needed for solid tumors, including glioblastoma (GBM), where survival rates with standard treatments are typically less than 2 years from diagnosis. Solid tumors pose many barriers to immunotherapies, including therapy half-life and persistence, tumor penetrance, and targeting. Therapeutics delivered systemically may not traffic to the tumor site. If cellular therapies or drugs are able to access the tumor site, or can be delivered directly within the tumor, treatments may not persist for the duration necessary to reduce or eliminate tumor burden. An approach that allows durable and titratable local therapeutic protein delivery could improve antitumor efficacy while minimizing toxicities or unwanted on-target, off-tissue effects.MethodsIn this study, human monocyte-derived macrophages were genetically engineered to secrete a bispecific T cell engager (BiTE) specific to the mutated epidermal growth factor variant III (EGFRvIII) expressed by some GBM tumors. We investigated the ability of lentivirally modified macrophages to secrete a functional BiTE that can bind target tumor antigen and activate T cells. Secreted BiTE protein was assayed in a range of T cell functional assays in vitro and in subcutaneous and intracranial GBM xenograft models. Finally, we tested genetically engineered macrophages (GEMs) secreting BiTE and the proinflammatory cytokine interleukin (IL)-12 to amplify T cell responses in vitro and in vivo.ResultsTransduced human macrophages secreted a lentivirally encoded functional EGFRvIII-targeted BiTE protein capable of inducing T cell activation, proliferation, degranulation, and killing of antigen-specific tumor cells. Furthermore, BiTE secreting macrophages reduced early tumor burden in both subcutaneous and intracranial mouse models of GBM, a response which was enhanced using macrophages that were dual transduced to secrete both the BiTE protein and single chain IL-12, preventing tumor growth in an aggressive GBM model.ConclusionsThe ability of macrophages to infiltrate and persist in solid tumor tissue could overcome many of the obstacles associated with systemic delivery of immunotherapies. We have found that human GEMs can locally and constitutively express one or more therapeutic proteins, which may help recruit T cells and transform the immunosuppressive tumor microenvironment to better support antitumor immunity.

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Gurumurthy, Channabasavaiah B., Poonam S. Joshi, Scott G. Kurz, Masato Ohtsuka, Rolen M. Quadros, Donald W. Harms, and K. C. Kent Lloyd. "Validation of Simple Sequence Length Polymorphism Regions of Commonly Used Mouse Strains for Marker Assisted Speed Congenics Screening." International Journal of Genomics 2015 (2015): 1–17. http://dx.doi.org/10.1155/2015/735845.

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Marker assisted speed congenics technique is commonly used to facilitate backcrossing of mouse strains in nearly half the time it normally takes otherwise. Traditionally, the technique is performed by analyzing PCR amplified regions of simple sequence length polymorphism (SSLP) markers between the recipient and donor strains: offspring with the highest number of markers showing the recipient genome across all chromosomes is chosen for the next generation. Although there are well-defined panels of SSLP makers established between certain pairs of mice strains, they are incomplete for most strains. The availability of well-established marker sets for speed congenic screens would enable the scientific community to transfer mutations across strain backgrounds. In this study, we tested the suitability of over 400 SSLP marker sets among 10 mouse strains commonly used for generating genetically engineered models. The panel of markers presented here can readily identify the specified strains and will be quite useful in marker assisted speed congenic screens. Moreover, unlike newer single nucleotide polymorphism (SNP) array methods which require sophisticated equipment, the SSLP markers panel described here only uses PCR and agarose gel electrophoresis of amplified products; therefore it can be performed in most research laboratories.

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Berg, Tracy, Carolina Marques, Vasiliki Pantazopoulou, Elinn Johansson, Kristoffer von Stedingk, David Lindgren, Elin Pietras, et al. "TAMI-05. THE IRRADIATED BRAIN MICROENVIRONMENT SUPPORTS GLIOMA STEMNESS AND SURVIVAL VIA ASTROCYTE-DERIVED TRANSGLUTAMINASE 2." Neuro-Oncology 22, Supplement_2 (November 2020): ii213—ii214. http://dx.doi.org/10.1093/neuonc/noaa215.894.

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Abstract The highest-grade gliomas invariably recur as incurable tumors following standard of care comprising surgery, radiotherapy, and chemotherapy. The majority of the recurrent tumors form within the area of the brain receiving high-dose irradiation during treatment of the primary tumor, indicating that the recurrent tumor forms in an irradiated microenvironment. The tumor microenvironment has been demonstrated to influence the therapeutic response and stemness characteristics of tumor cells, but the influence of radiation on the microenvironment and its subsequent consequences for tumor cells are incompletely understood. Here, we used genetically engineered glioma mouse models and human glioma samples to characterize the impact of standard of care radiotherapy on the brain tumor microenvironment. We found that tumor-associated astrocytes subjected to radiation in vitro could enhance tumor cell stemness and survival of co-cultured glioma cells. More aggressive gliomas formed in vivo when mouse brains were irradiated prior to tumor cell implantation, suggesting that the irradiated brain microenvironment supports tumor growth. We isolated the effect of irradiated astrocytes to extracellular matrix secreted by these cells, and specifically found that astrocyte-derived transglutaminase 2 (TGM2) is a stromal promoter of glioma stemness and radioresistance. TGM2 levels were increased after radiation in glioma mouse models. Recombinant TGM2 enhanced, and TGM2 inhibitors blocked, glioma cell stemness. In human GBM tissue, TGM2 levels were increased in recurrent vs. primary tumors. In summary, in addition to supporting TGM2 as a potential therapeutic target in glioma, our data indicate that radiotherapy results in a tumor-supportive microenvironment, the targeting of which may be necessary to overcome tumor cell therapeutic resistance and recurrence.

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Yeo, Alan, Bethany Delcuze, Laura Strauss, Vassiliki Boussiotis, and Al Charest. "IMMU-31. DRIVER GENE MUTATIONS DICTATE THE COMPOSITION OF THE IMMUNE LANDSCAPE OF GLIOBLASTOMA AND CONFER SELECTIVE RESPONSE TO IMMUNOTHERAPY." Neuro-Oncology 21, Supplement_6 (November 2019): vi125. http://dx.doi.org/10.1093/neuonc/noz175.523.

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Abstract The characterization of the immune landscape of glioblastoma multiforme (GBM) is rapidly emerging. Current immunotherapeutic efforts for GBM would benefit from a comprehensive and mechanistic understanding of the relationship between distinct driver gene mutations and the composition and function of the immune tumor microenvironment. The majority of GBM tumors overexpress EGFR and EGFRvIII and ~40% are mutated for PTEN. Using genetically engineered and accurate preclinical mouse models of GBM built on combinations of these driver genes, we demonstrate that the compositions of the immune landscape and the response to checkpoint blockade immunotherapy vary according to the genotype of the GBM. Mechanistically, we show that signaling networks downstream of EGFR and PTEN establish chemokine and cytokine profiles that parallel the levels of intra-tumoral polymorphonuclear myeloid-derived suppressor cells and regulatory T cells. Additionally, tumor-associated microglia/macrophages number, function and polarization are heavily influenced by specific driver-gene mutation combinations. Furthermore, we demonstrate that efficacy of checkpoint blockade therapy using anti PD-1 as a single agent or in combination with anti CTLA-4 is dependent on EGFR and PTEN status. Taken together, our findings demonstrate that important components of the tumor immune microenvironment are influenced by specific driver gene mutations. Our results suggest that stratifying patients based on tumor genotype or signaling events may be informative for selection of appropriate candidates for checkpoint blockade therapy and present an opportunity to pharmacologically modulate GBM signaling with targeted therapeutics to sensitize patients to immunotherapy.

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Zhao, Ming, Matthew H. G. Katz, Jason B. Fleming, Atsushi Suetsugu, Yong Zhang, Ali Maawy, Takashi Chishima, et al. "Salmonella typhimurium A1-R effectively targets human-patient pancreatic tumorgrafts in nude mice." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): e22012-e22012. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.e22012.

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e22012 Background: Genetically-modified Salmonella typhimurium A1-R selectively targets tumors of cancer in mouse models of human cancer. The aim of this study was to determine the efficacy S. typhimurium A1-R on human-patient pancreatic tumorgrafts growing orthothopically in nude mice. Methods: Pancreatic-cancer-patient tumor specimens were initially established subcutaneously in NOD/SCID mice immediately after surgery. The patient tumors were then harvested from NOD/SCID mice and passed orthotopically in transgenic nude mice, expressing fluorescent proteins in order for the tumors to acquire fluorescent stroma for imaging. After confirmation of tumor growth by fluorescence imaging, the nude mice were treated in the following groups: (1) 5-fluorouracil (5-FU) (10 mg/kg, ip); (2) cisplatin (CDDP) (10 mg/kg, ip); (3) gemcitabine (GEM) (150 mg/kg, ip); (4) S. typhimurium A1-R (1.5x108 cfu/body, ip); and (5) PBS (vehicle/control) (ip). Control, 5-FU, CDDP, GEM and S. typhimurium A1-R injections were performed on a weekly basis from day-21 after tumor implantation for 4 weeks. Animals were sacrificed at 7 weeks, and tumors were harvested for analysis. Each treatment arm involved 5 tumor-bearing mice. Results: No significant effects on body weight, morbidity, or severe toxicities were observed in any treatment arm. The tumor weight of each group was as follows: (1) 5-FU, 0.044 ± 0.027g; (2) CDDP, 0.04 ± 0.032g; (3) GEM, 0.058 ± 0.051g; (4) S. typhimurium A1-R, 0.106 ± 0.038g; and (5) PBS control, 0.258 ± 0.209g. S. typhimurium A1-R treatment significantly reduced the tumor weight compared to control treatment (p = 0.011), as did the other treatments including 5-FU (p = 0.005), CDDP (p = 0.004), and GEM (p = 0.001). Conclusions: S. typhimurium A1-R treatment was effective on human pancreatic tumorgrafts and should be tested in combination with chemotherapy.

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Comba, Andrea, Patrick Dunn, Anna E. Argento, Padma Kadiyala, Sebastien Motsch, Phillip Kish, Alon Kahana, et al. "3131 ONCOSTREAMS: NOVEL DYNAMICS PATHOLOGICAL MULTICELLULAR STRUCTURES INVOLVED IN GLIOBLATOMA GROWTH AND INVASION." Journal of Clinical and Translational Science 3, s1 (March 2019): 111. http://dx.doi.org/10.1017/cts.2019.253.

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OBJECTIVES/SPECIFIC AIMS: Oncostreams represent a novel growth pattern of GBM. In this study we uncovered the cellular and molecular mechanism that regulates the oncostreams function in GBM growth and invasion. METHODS/STUDY POPULATION: We studied oncostreams organization and function using genetically engineered mouse gliomas models (GEMM), mouse primary patient derived GBM model and human glioma biopsies. We evaluated the molecular landscape of oncostreams by laser capture microdissection (LCM) followed by RNA-Sequencing and bioinformatics analysis. RESULTS/ANTICIPATED RESULTS: Oncostreams are multicellular structures of 10-20 cells wide and 2-400 μm long. They are distributed throughout the tumors in mouse and human GBM. Oncostreams are heterogeneous structures positive for GFAP, Nestin, Olig2 and Iba1 cells and negative for Neurofilament. Using GEMM we found a negative correlation between oncostream density and animal survival. Moreover, examination of patient’s glioma biopsies evidenced that oncostreams are present in high grade but no in low grade gliomas. This suggests that oncostreams may play a role in tumor malignancy. Our data also indicated that oncostreams aid local invasion of normal brain. Transcriptome analysis of oncostreams revealed 43 differentially expressed (DE) genes. Functional enrichment analysis of DE genes showed that “collagen catabolic processes”, “positive regulation of cell migration”, and “extracellular matrix organization” were the most over-represented GO biological process. Network analysis indicated that Col1a1, ACTA2, MMP9 and MMP10 are primary target genes. These genes were also overexpressed in more malignant tumors (WT-IDH) compared to the less malignant (IDH1- R132H) tumors. Confocal time lapse imagining of 3D tumor slices demonstrated that oncostreams display a collective motion pattern within gliomas that has not been seen before. DISCUSSION/SIGNIFICANCE OF IMPACT: In summary, oncostreams are anatomically and molecularly distinctive, regulate glioma growth and invasion, display collective motion and are regulated by the extracellular matrix. We propose oncostreams as novel pathological markers valuable for diagnosis, prognosis and designing therapeutics for GBM patients.

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Scotto, Luigi, Marianna Kruithof de Julio, Luca Paoluzzi, Matko Kalac, Enrica Marchi, Jairo Baquero Buitrago, and Owen A. O'Connor. "Generation and Characterization of a Novel CD19-CherryLuciferase (CD19CL) Mouse Model: A New Fluorescent/Bioluminescent Model for the Study of B-Cell Development and Lymphomagenesis." Blood 116, no. 21 (November 19, 2010): 3940. http://dx.doi.org/10.1182/blood.v116.21.3940.3940.

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Abstract Abstract 3940 Existing mouse models available to study the effects of new treatment strategies for lymphoma almost exclusively rely on xenograft models of the disease. These models, while informative, do not mirror the natural history of a disease that arises in the bone marrow or lymphatic system, as seen in patients. While spontaneous models may be less contrived, they pose numerous obstacles regarding the optimal strategies to image changes in tumor volume as a function of time and or treatment. The prospect of integrating both fluorescence and bioluminescence detection capabilities into a single genetically engineered mouse (GEM) model may offer a unique opportunity to assess this biology in a more realistic, cost-effective, and efficient manner. We first constructed a fusion protein consisting of the monomeric mutant red fluorescent mCherry, and the synthetic-firefly Luciferase by cloning the mCherry gene into the plasmid vector pGL4.13[luc2/SV40] (Promega) carrying the luciferase gene, thus obtaining the pGLCherryLuciferase plasmid, where the Cherry and the luciferase genes formed one open reading frame. Analysis of pGLCherryluciferase transfected human embryonic kidney 293 (HEK 293) cells via flow cytometry and luciferase activity confirmed that the cherryluciferase fusion protein retained its dual bioluminescent/fluorescent activity in vitro. In order to express the Cherry-Luciferase fusion protein in cells of the B lineage in mice we then generated a CD19cherryluciferase targeting vector, a modified version of the CD19cre targeting vector (Rickert R C et al, Nature 1995), where a cre/neo gene cassette was substituted by a Cherry-luciferase/neo cassette and the 330 bp fragment upstream of exon1 by a 1741 bp fragment obtained by PCR-amplification of ES(E14-1)-cell DNA using oligonucleotides tagged with restriction sites at their 5' end. Positive clones of transfected mouse embryonic stem (ES) cells were injected into C57BL/6J blastocysts to obtain the CD19cherryluciferase transgenic mouse, which retain one functional CD19 allele. Characterization of the transgenic mice showed that the CD19cherryluciferase transgenic mice are phenotypically normal with no underlying pathology as confirmed by necropsy and histologic analysis. Confocal microscopy followed by in vivo imaging of transgenic animals demonstrated that, as expected, expression of the cherryluciferase fusion protein is under the control of the CD19 locus regulatory elements and that the high sensitivity of bioluminescence imaging allows for the noninvasive quantification of luciferase expression in the secondary lymphoid organs. One of the more flexible aspects of the model is retained in the fact that the CD19 Cherryluciferase mouse can be crossed with most other models that spontaneously develop lymphoma representing a unique opportunity to study B-cell trafficking, in vivo measurement of tumor burden over the entire spectrum of the disease in individual animal and or response to therapy. To demonstrate its application double transgenic mice were produced by breeding CD19CherryLuciferase heterozygous transgenic animals with a Burkitt Lymphoma mouse model (Engel P et al Immunity 1995). A bioluminescent signal in double transgenic affected animals allowed tracking of B-cell lymphoma growth during a 4 week time period and evaluation of the response of an established B-cell lymphoma to a drug therapy (dexamethasone injected intraperitoneally at a dose of 4mg/kg). Relapse and accelerated tumor repopulation in a 5 day time period followed the rescue attempt. The possibility of sequential measurements of tumor growth as a function of an intervention allows essentially real time assessment and identification of micro- and macro-metastases in the living animals. At present there are no other models that allow in vivo imaging of spontaneously generated lymphoma and the mouse model described here is intended to be used to hasten translational studies of novel agents in lymphoma, with the intent that understanding the relevant pharmacology prior to clinical study will hasten successful development in clinical studies. Disclosures: No relevant conflicts of interest to declare.

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Comba, Andrea, Patrick J Dunn, Anna E Argento, Padma Kadiyala, Sebastien Motsch, Alon Kahana, Phillip E Kish, Maria Castro, and Pedro Lowenstein. "TMIC-58. THE CELLULAR AND MOLECULAR BASIS FOR MESENCHYMAL TRANSFORMATION IN GLIOMAS." Neuro-Oncology 21, Supplement_6 (November 2019): vi260. http://dx.doi.org/10.1093/neuonc/noz175.1092.

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Abstract Mesenchymal gliomas are the most aggressive tumors that carry the worst prognosis. The origins of mesenchymal cells within brain tumors, remains poorly understood. They could originate either from invading mesenchymal cells, from perivascular smooth muscle actin+ cells, or from a mesenchymal transformation of tumor cells. Identifying the origin and function of mesenchymal cells within gliomas is essential as these cells contribute to increased glioma aggressiveness and tumor progression. In this study we used human biopsies and implantable and genetically engineered mouse models (GEMM) of GBM to study tumor mesenchymal transformation. GBM implantable models were used to analyze the molecular landscape by laser microdissection followed by RNA-Seq and bioinformatics analysis. Time lapse confocal imagining was implemented to analyze GBM cells dynamics. Our results indicate the existence of a complex intratumoral and peritumoral dynamic organization of glioma cells (i.e., Oncostreams). Multicellular structures of elongated cells compatible with mesenchymal differentiation. These structures play important roles in intratumoral movements, peritumoral invasion of normal brain, and overall glioma progression. We also show that oncostreams are molecularly distinct and display increased expression of mesenchymal genes such as Col1a1. Knocking down of Col1a1 in a GEMM of aggressive gliomas reduced tumor progression and significantly increased animal survival. Histological examination confirmed absence of Col1a1, and absence of morphologically identifiable oncostreams. Our results show that tumor cells, especially within oncostreams, display a fibroblastic-like morphology and express proteins typical of mesenchymal cells. The knockout of Col1a1 from tumoral cells eliminated oncostreams from tumors and delayed tumor progression. These data suggest that tumor cells expressing mesenchymal genes regulate the organization of mesenchymal multicellular structures, and determine glioma progression. We propose that inhibiting mesenchymal transformation of glioma cells will assist in the treatment of glioblastoma.

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IJICHI, Hideaki. "Genetically-engineered mouse pancreatic cancer models." Suizo 25, no. 1 (2010): 28–34. http://dx.doi.org/10.2958/suizo.25.28.

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Pérez-Guijarro, Eva, Chi-Ping Day, Glenn Merlino, and M. Raza Zaidi. "Genetically engineered mouse models of melanoma." Cancer 123, S11 (May 19, 2017): 2089–103. http://dx.doi.org/10.1002/cncr.30684.

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Smithberger, Erin, Abigail Shelton, Madison Butler, Allie Stamper, Ryan Bash, Steven Angus, Michael East, et al. "CSIG-10. GENOTYPE – KINOME GUIDED DEVELOPMENT OF PRECISION EGFR-TARGETED THERAPEUTICS FOR GLIOBLASTOMA." Neuro-Oncology 22, Supplement_2 (November 2020): ii29. http://dx.doi.org/10.1093/neuonc/noaa215.122.

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Abstract Glioblastoma (GBM) is an aggressive primary brain tumor with poor survival and limited treatment options. However, it is an attractive candidate for precision therapeutic approaches due to the frequency of amplification and/or activating mutations in the epidermal growth factor receptor (EGFR) gene and the availability of several brain penetrant second- and third-generation EGFR tyrosine kinase inhibitors (TKI). We used comprehensive molecular profiling of a panel of genetically engineered mouse astrocyte models to examine whether mutational profiles, particularly EGFR and PTEN status, could be used to identify kinases upregulated in specific mutational backgrounds. Using RNA-seq and multiplex inhibitor bead/mass spectrometry (MIB-MS) to analyze the kinase transcriptomes and proteomes, respectively, we have identified several potential targets for combination therapy. Overexpression of wild type EGFR in immortalized, Cdkn2a-/- astrocytes resulted in mild rewiring of the GBM kinome. Only 5 kinases aside from EGFR itself were overexpressed on either the transcript or protein levels. One overexpressed kinase, Hck, has been shown to be involved in cell survival, proliferation, adhesion, and migration. In contrast, overexpression of EGFRvIII, a constitutively active, extracellular domain truncation mutant of EGFR, resulted in significant alteration of the GBM kinome – 81 kinases showed differential expression, with 27 upregulated. One potentially attractive target among these was Cdk6, a drug-targetable, prognostically significant cyclin-dependent kinase implicated in proliferation, migration, and invasion. Finally, overexpression of EGFRvIII in cells lacking Pten dysregulated 46 kinases, including 15 upregulated. One particularly interesting target in these cells was Ddr2, a tyrosine kinase involved in migration, invasion, and extracellular matrix remodeling. We conclude that Hck, Cdk6, and Ddr2 represent attractive targets for therapeutic intervention in their relevant genetic contexts. These findings also suggest that molecular diagnostics for EGFR and PTEN status may be useful in guiding development of rational, EGFR TKI-centric drug combinations.

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Guerra, Carmen, and Mariano Barbacid. "Genetically engineered mouse models of pancreatic adenocarcinoma." Molecular Oncology 7, no. 2 (February 11, 2013): 232–47. http://dx.doi.org/10.1016/j.molonc.2013.02.002.

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Parisotto, Maxime, and Daniel Metzger. "Genetically engineered mouse models of prostate cancer." Molecular Oncology 7, no. 2 (February 14, 2013): 190–205. http://dx.doi.org/10.1016/j.molonc.2013.02.005.

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Li, Huaiguang, Inseok Kwak, and Francesco J. DeMayo. "Genetically engineered mouse models for lung cancer." Drug Discovery Today: Disease Models 2, no. 1 (March 2005): 35–40. http://dx.doi.org/10.1016/j.ddmod.2005.05.020.

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Wong, Philip C., Huaibin Cai, David R. Borchelt, and Donald L. Price. "Genetically engineered mouse models of neurodegenerative diseases." Nature Neuroscience 5, no. 7 (July 2002): 633–39. http://dx.doi.org/10.1038/nn0702-633.

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Kwak, I., S. Y. Tsai, and F. J. DeMayo. "Genetically Engineered Mouse Models for Lung Cancer." Annual Review of Physiology 66, no. 1 (March 2004): 647–63. http://dx.doi.org/10.1146/annurev.physiol.66.032102.134301.

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Ng, Alvin JM, Anthony J. Mutsaers, Emma K. Baker, and Carl R. Walkley. "Genetically engineered mouse models and human osteosarcoma." Clinical Sarcoma Research 2, no. 1 (2012): 19. http://dx.doi.org/10.1186/2045-3329-2-19.

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Westphalen, Christoph Benedikt, and Kenneth P. Olive. "Genetically Engineered Mouse Models of Pancreatic Cancer." Cancer Journal 18, no. 6 (2012): 502–10. http://dx.doi.org/10.1097/ppo.0b013e31827ab4c4.

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Nawijn, Martijn C., Andreas M. Bergman, and Henk G. van der Poel. "Genetically Engineered Mouse Models of Prostate Cancer." European Urology Supplements 7, no. 8 (August 2008): 566–75. http://dx.doi.org/10.1016/j.eursup.2008.01.019.

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Crabtree, Donna M., and Jianhua Zhang. "Genetically engineered mouse models of Parkinson's disease." Brain Research Bulletin 88, no. 1 (May 2012): 13–32. http://dx.doi.org/10.1016/j.brainresbull.2011.07.019.

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Schmid, Ralf S., Mark Vitucci, and C. Ryan Miller. "Genetically engineered mouse models of diffuse gliomas." Brain Research Bulletin 88, no. 1 (May 2012): 72–79. http://dx.doi.org/10.1016/j.brainresbull.2011.06.002.

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Mahmoudian, Reihaneh Alsadat, Moein Farshchian, and Mohammad Reza Abbaszadegan. "Genetically engineered mouse models of esophageal cancer." Experimental Cell Research 406, no. 2 (September 2021): 112757. http://dx.doi.org/10.1016/j.yexcr.2021.112757.

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Cai, Linzhi, Sabrina V. Kirchleitner, Dongxu Zhao, Min Li, Jörg-Christian Tonn, Rainer Glass, and Roland E. Kälin. "Glioblastoma Exhibits Inter-Individual Heterogeneity of TSPO and LAT1 Expression in Neoplastic and Parenchymal Cells." International Journal of Molecular Sciences 21, no. 2 (January 17, 2020): 612. http://dx.doi.org/10.3390/ijms21020612.

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Molecular imaging is essential for diagnosis and treatment planning for glioblastoma patients. Positron emission tomography (PET) with tracers for the detection of the solute carrier family 7 member 5 (SLC7A5; also known as the amino acid transporter light chain L system, LAT1) and for the mitochondrial translocator protein (TSPO) is successfully used to provide additional information on tumor volume and prognosis. The current approaches for TSPO-PET and the visualization of tracer ([18F] Fluoroethyltyrosine, FET) uptake by LAT1 (FET-PET) do not yet exploit the full diagnostic potential of these molecular imaging techniques. Therefore, we investigated the expression of TSPO and LAT1 in patient glioblastoma (GBM) samples, as well as in various GBM mouse models representing patient GBMs of different genetic subtypes. By immunohistochemistry, we found that TSPO and LAT1 are upregulated in human GBM samples compared to normal brain tissue. Next, we orthotopically implanted patient-derived GBM cells, as well as genetically engineered murine GBM cells, representing different genetic subtypes of the disease. To determine TSPO and LAT1 expression, we performed immunofluorescence staining. We found that both TSPO and LAT1 expression was increased in tumor regions of the implanted human or murine GBM cells when compared to the neighboring mouse brain tissue. While LAT1 was largely restricted to tumor cells, we found that TSPO was also expressed by microglia, tumor-associated macrophages, endothelial cells, and pericytes. The Cancer Genome Atlas (TCGA)-data analysis corroborates the upregulation of TSPO in a bigger cohort of GBM patient samples compared to tumor-free brain tissue. In addition, AIF1 (the gene encoding for the myeloid cell marker Iba1) was also upregulated in GBM compared to the control. Interestingly, TSPO, as well as AIF1, showed significantly different expression levels depending on the GBM genetic subtype, with the highest expression being exhibited in the mesenchymal subtype. High TSPO and AIF1 expression also correlated with a significant decrease in patient survival compared to low expression. In line with this finding, the expression levels for TSPO and AIF1 were also significantly higher in (isocitrate-dehydrogenase wild-type) IDHWT compared to IDH mutant (IDHMUT) GBM. LAT1 expression, on the other hand, was not different among the individual GBM subtypes. Therefore, we could conclude that FET- and TSPO-PET confer different information on pathological features based on different genetic GBM subtypes and may thus help in planning individualized strategies for brain tumor therapy in the future. A combination of TSPO-PET and FET-PET could be a promising way to visualize tumor-associated myeloid cells and select patients for treatment strategies targeting the myeloid compartment.

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Dabydeen, Sarah A., and Priscilla A. Furth. "Genetically engineered ERα-positive breast cancer mouse models." Endocrine-Related Cancer 21, no. 3 (January 30, 2014): R195—R208. http://dx.doi.org/10.1530/erc-13-0512.

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The majority of human breast cancers are estrogen receptor-positive (ER+), but this has proven challenging to model in genetically engineered mice. This review summarizes information on 21 mouse models that develop ER+ mammary cancer. Where available, information on cancer pathology and gene expression profiles is referenced to assist in understanding which histological subtype of ER+ human cancer each model might represent.ESR1,CCDN1, prolactin,TGFα,AIB1,ESPL1, andWNT1overexpression,PIK3CAgain of function, as well as loss ofP53(Trp53) orSTAT1are associated with ER+ mammary cancer. Treatment with the PPARγ agonist efatutazone in a mouse withBrca1andp53deficiency and 7,12-dimethylbenz(a)anthracene exposure in combination with an activated myristoylated form of AKT1 also induce ER+ mammary cancer. A spontaneous mutant in nude mice that develops metastatic ER+ mammary cancer is included. Age of cancer development ranges from 3 to 26 months and the percentage of cancers that are ER+ vary from 21 to 100%. Not all models are characterized as to their estrogen dependency and/or response to anti-hormonal therapy. Strain backgrounds include C57Bl/6, FVB, BALB/c, 129S6/SvEv, CB6F1, and NIH nude. Most models have only been studied on one strain background. In summary, while a range of models are available for studies of pathogenesis and therapy of ER+ breast cancers, many could benefit from further characterization, and opportunity for development of new models remains.

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Castle, Katherine D., Mark Chen, Amy J. Wisdom, and David G. Kirsch. "Genetically engineered mouse models for studying radiation biology." Translational Cancer Research 6, S5 (July 2017): S900—S913. http://dx.doi.org/10.21037/tcr.2017.06.19.

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Robles, Ana I., and Lyuba Varticovski. "Harnessing genetically engineered mouse models for preclinical testing." Chemico-Biological Interactions 171, no. 2 (January 2008): 159–64. http://dx.doi.org/10.1016/j.cbi.2007.01.014.

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Shelton, Abigail, Erin Smithberger, Madison Butler, Allie Stamper, Ryan Bash, Steven Angus, Mike East, et al. "DDRE-24. ACQUIRED RESISTANCE TO TARGETED INHIBITORS IN EGFR-DRIVEN GLIOBLASTOMA: IDENTIFICATION OF DUAL KINASE TARGETS." Neuro-Oncology 22, Supplement_2 (November 2020): ii66. http://dx.doi.org/10.1093/neuonc/noaa215.269.

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Abstract Glioblastoma (GBM) is a devastating primary brain tumor with 5-year survival < 5%. CDKN2A deletion (~60%) and EGFR amplification (55–60%) mutations frequently co-occur in these tumors. EGFR is an attractive therapeutic target due to its mutational frequency and availability of multiple brain-penetrant tyrosine kinase inhibitors (TKI). Several EGFR TKI have failed clinically, due in part to acquired resistance. To mechanistically examine this type of resistance, we used genetically engineered mouse astrocytes harboring Cdkn2a deletion and EGFRvIII, a common (35%) activating mutation. Resistant cells were generated via chronic exposure to gefitinib or erlotinib, either in vitro or in vivo. Resistance to these first-generation EGFR TKI conferred cross resistance (up to 36-fold ΔIC50) to a panel of second- and third-generation TKI relative to sensitive parental lines. Moreover, integrated RNA sequencing (RNA-seq) and chemical proteomics (multiplexed inhibitor beads and mass spectrometry (MIB-MS)) showed that the kinase transcriptome and proteome were rewired in resistant cells: 113 of ~300 detected kinases were differentially expressed (p< 0.05). We then used these techniques to examine acute (≤ 48 h) kinome changes in both sensitive and resistant cells upon treatment with a CNS-penetrant, second-generation EGFR TKI, afatinib. Whereas exposure of treatment-naïve, sensitive cells to afatinib significantly rewired the kinome (120 differentially expressed kinases), the response of resistant cells to drug re-challenge was significantly blunted (13 differentially expressed kinases). A subset of expressed kinases (35 of 263) dynamically responded to afatinib in both sensitive and resistant cells. Overall, upregulated kinases include those implicated in the biology of gliomas (Bmx, Fgfr2) and of other cancers (Pdgfrb, Mapk3/4, Ddr1/2, Pdk2). These kinases thus represent putative druggable targets for dual inhibition therapy. Integrated kinome profiling using MIB-MS and RNA-seq in GBM models with defined mutational profiles provides a powerful framework to identify novel therapeutic targets that could significantly alter current treatment paradigms.

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Ganeshan, Radhika, Jiangli Chen, and Peter J. Koch. "Mouse Models for Blistering Skin Disorders." Dermatology Research and Practice 2010 (2010): 1–7. http://dx.doi.org/10.1155/2010/584353.

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Genetically engineered mice have been essential tools for elucidating the pathological mechanisms underlying human diseases. In the case of diseases caused by impaired desmosome function, mouse models have helped to establish causal links between mutations and disease phenotypes. This review focuses on mice that lack the desmosomal cadherins desmoglein 3 or desmocollin 3 in stratified epithelia. A comparison of the phenotypes observed in these mouse lines is provided and the relationship between the mutant mouse phenotypes and human diseases, in particular pemphigus vulgaris, is discussed. Furthermore, we will discuss the advantages and potential limitations of genetically engineered mouse lines in our ongoing quest to understand blistering skin diseases.

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Berul, Charles I. "Electrophysiological phenotyping in genetically engineered mice." Physiological Genomics 13, no. 3 (May 13, 2003): 207–16. http://dx.doi.org/10.1152/physiolgenomics.00183.2002.

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Advances in transgene and gene targeting technology have enabled sophisticated manipulation of the mouse genome, providing important insights into the molecular mechanisms underlying cardiac conduction, arrhythmogenesis, and sudden cardiac death. The mouse is currently the principal mammalian model for studying biological processes, particularly related to cardiac pathophysiology. Murine models have been engineered harboring gene mutations leading to inherited structural and electrical disorders of the heart due to transcription factor mutations, connexin protein defects, and G protein and ion channelopathies. These mutations lead to phenotypes reminiscent of human clinical disease states including congenital heart defects, cardiomyopathies, and long-QT syndrome, creating models of human electrophysiological disease. Functional analyses of the underlying molecular mechanisms of resultant phenotypes require appropriate and sophisticated experimental methodology. This paper reviews current in vivo murine electrophysiology study techniques and genetic mouse models pertinent to human arrhythmia disorders.

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Sharpless, Norman E., and Ronald A. DePinho. "The mighty mouse: genetically engineered mouse models in cancer drug development." Nature Reviews Drug Discovery 5, no. 9 (August 18, 2006): 741–54. http://dx.doi.org/10.1038/nrd2110.

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Olive, Kenneth P., and Katerina Politi. "Translational Therapeutics in Genetically Engineered Mouse Models of Cancer." Cold Spring Harbor Protocols 2014, no. 2 (February 2014): pdb.top069997. http://dx.doi.org/10.1101/pdb.top069997.

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Mizoguchi, Atsushi, Takahito Takeuchi, Hidetomo Himuro, Toshiyuki Okada, and Emiko Mizoguchi. "Genetically engineered mouse models for studying inflammatory bowel disease." Journal of Pathology 238, no. 2 (November 14, 2015): 205–19. http://dx.doi.org/10.1002/path.4640.

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Doetschman, Thomas. "GI GEMs: Genetically Engineered Mouse Models of Gastrointestinal Disease." Gastroenterology 140, no. 2 (February 2011): 380–85. http://dx.doi.org/10.1053/j.gastro.2010.12.013.

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Joshi, Suhasini, Sushil Kumar, Sangeeta Bafna, Satyanarayana Rachagani, Kay-Uwe Wagner, Maneesh Jain, and Surinder K. Batra. "Genetically engineered mucin mouse models for inflammation and cancer." Cancer and Metastasis Reviews 34, no. 4 (January 30, 2015): 593–609. http://dx.doi.org/10.1007/s10555-015-9549-1.

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ROTTENBERG, S., and J. JONKERS. "Modeling therapy resistance in genetically engineered mouse cancer models." Drug Resistance Updates 11, no. 1-2 (February 2008): 51–60. http://dx.doi.org/10.1016/j.drup.2007.11.002.

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Proetzel, Gabriele, Michael V. Wiles, and Derry C. Roopenian. "Genetically Engineered Humanized Mouse Models for Preclinical Antibody Studies." BioDrugs 28, no. 2 (October 23, 2013): 171–80. http://dx.doi.org/10.1007/s40259-013-0071-0.

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Lee, Ho. "Genetically Engineered Mouse Models for Drug Development and Preclinical Trials." Biomolecules & Therapeutics 22, no. 4 (July 31, 2014): 267–74. http://dx.doi.org/10.4062/biomolther.2014.074.

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

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