Differential Effects of Trp53 Alterations in Murine Colorectal Cancer

Background: Colorectal cancer (CRC) development is a multi-step process resulting in the accumulation of genetic alterations. Despite its high incidence, there are currently no mouse models that accurately recapitulate this process and mimic sporadic CRC. We aimed to develop and characterize a genetically engineered mouse model (GEMM) of Apc/Kras/Trp53 mutant CRC, the most frequent genetic subtype of CRC. Methods: Tumors were induced in mice with conditional mutations or knockouts in Apc, Kras, and Trp53 by a segmental adeno-cre viral infection, monitored via colonoscopy and characterized on multiple levels via immunohistochemistry and next-generation sequencing. Results: The model accurately recapitulates human colorectal carcinogenesis clinically, histologically and genetically. The Trp53 R172H hotspot mutation leads to significantly increased metastatic capacity. The effects of Trp53 alterations, as well as the response to treatment of this model, are similar to human CRC. Exome sequencing revealed spontaneous protein-modifying alterations in multiple CRC-related genes and oncogenic pathways, resulting in a genetic landscape resembling human CRC. Conclusions: This model realistically mimics human CRC in many aspects, allows new insights into the role of TP53 in CRC, enables highly predictive preclinical studies and demonstrates the value of GEMMs in current translational cancer research and drug development.

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DIPG-68. ALPHA-THALASSEMIA X-LINKED MENTAL RETARDATION PROTEIN (ATRX) LOSS-OF-FUNCTION IN A MOUSE MODEL OF DIFFUSE INTRINSIC PONTINE GLIOMA

Neuro-Oncology ◽

10.1093/neuonc/noaa222.111 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii300-iii300

Author(s):

Chen Shen ◽

David Picketts ◽

Oren Becher

Keyword(s):

Mouse Model ◽

Pediatric Brain Tumor ◽

High Grade Glioma ◽

Genetic Alterations ◽

Genetically Engineered ◽

Tumor Incidence ◽

Loss Of Function ◽

Nestin Expression ◽

Genetically Engineered Mouse Model ◽

Clinical Cases

Abstract Diffuse Intrinsic Potine Glioma (DIPG) is a rare pediatric brain tumor for which no cure or efficacious therapies exist. Previous discoveries have revealed that, DIPG harbors distinct genetic alterations, when compared with adult high-grade glioma (HGG) or even with non-DIPG pediatric HGGs. ATRX alteration is found in 9% of clinical cases of DIPG, and significantly overlaps with H3.3K27M mutation and p53 loss, the two most common genetic changes in DIPG, found in 80% and 77% clinical cases, respectively. Here we developed genetically engineered mouse model of brainstem glioma using the RCAS-Tv-a system by targeting PDGF-B overexpression, p53 loss, H3.3K27M mutation and ATRX loss-of function to Nestin-expression brainstem progenitor cells of the neonatal mouse. Specifically, we used Nestin-Tv-a; p53 floxed; ATRX heterozygous female and Nestin-Tv-a; p53 floxed; ATRX floxed male breeders, generated offsprings with ATRX loss of function (n=18), ATRX heterozygous females (n=6), and ATRX WT (n=10). Median survial of the three groups are 65 days, 88 days and 51 days, respectively. Also, ATRX null mice is lower in tumor incidence (44.4%), compared with ATRX WT (80%). We evaluated the pathological features of DIPG with or without ATRX alteration, RNA-seq is performed to identify differentially expressed genes between ATRX WT and loss-of-function. In conclution, this study generated the first genetically modified mouse model studying ATRX loss-of-function in DIPG, and suggested that ATRX loss-of-function in DIPG may slow down tumorigenesis and decrease tumor incidence.

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Abstract 3135: Pre-treatment p-EGFR levels in tumors from a genetically engineered mouse model of BRAFV600E colorectal cancer predict response to combined BRAF/EGFR inhibition

10.1158/1538-7445.am2014-3135 ◽

2014 ◽

Author(s):

Erin M. Coffee ◽

Ryan B. Corcoran ◽

Jeffrey A. Engelman

Keyword(s):

Colorectal Cancer ◽

Mouse Model ◽

Genetically Engineered ◽

Egfr Inhibition ◽

Genetically Engineered Mouse Model ◽

Pre Treatment

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Antioxidant Agents and Colorectal Carcinogenesis: Role of β-Carotene, Vitamin E and Vitamin C

Tumori Journal ◽

10.1177/030089169608200102 ◽

1996 ◽

Vol 82 (1) ◽

pp. 6-11 ◽

Cited By ~ 7

Author(s):

Giuseppe Pappalardo ◽

Antonio Guadalaxara ◽

Giuseppe Maiani ◽

Giovanni Illomei ◽

Mauro Trifero ◽

...

Keyword(s):

Colorectal Cancer ◽

Vitamin E ◽

Vitamin C ◽

Colonic Mucosa ◽

Genetic Alterations ◽

Colorectal Carcinogenesis ◽

Normal Colonic Mucosa ◽

Antioxidant Agents ◽

Β Carotene

In consideration of findings reported in the literature and of our study, we examined the correlation between antioxidants (β-carotene, vitamin C, vitamin E) and colorectal carcinogenesis. Although diagnostic progress has been made in the last decades, no significant improvements in death rates have been achieved in the western world. Exogenous factors might be responsible for a complex alteration process of normal colonic mucosa into adenoma and carcinoma. Free radicals and reactive oxygen metabolites, due to increased production or to reduced inactivation, following a decrease in the antioxidant burden in the mucosa, might cause damage to DNA, thereby resulting in genetic alterations. This might represent the cause of the transformation process: normal mucosa→ adenoma→ carcinoma. In a prospective study, we observed a reduction of β-carotene levels in normal colonic mucosa in patients with polyps and colorectal cancer. We also showed that β-carotene supplementation raises levels of this micronutrient in the colonic mucosa of these patients. Findings from the literature and our trials show a significant decrease in the antioxidant capacity of colorectal mucosa in patients affected by colorectal cancer, although there is a significant interindividual variability. Such results suggest a possible chemopreventive role of antioxidant agents in colorectal cancer.

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Abstract 67: Establishment and in-depth characterization of a genetically engineered mouse model of metastatic colorectal cancer

10.1158/1538-7445.am2014-67 ◽

2014 ◽

Author(s):

Sebastian Schölch ◽

Linda Blickensdörfer ◽

Wilko Weichert ◽

Michael Muders ◽

Jürgen Weitz ◽

...

Keyword(s):

Colorectal Cancer ◽

Mouse Model ◽

Metastatic Colorectal Cancer ◽

Genetically Engineered ◽

Genetically Engineered Mouse Model

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The Dual PI3K/mTOR Inhibitor NVP-BEZ235 Induces Tumor Regression in a Genetically Engineered Mouse Model of PIK3CA Wild-Type Colorectal Cancer

PLoS ONE ◽

10.1371/journal.pone.0025132 ◽

2011 ◽

Vol 6 (9) ◽

pp. e25132 ◽

Cited By ~ 78

Author(s):

Jatin Roper ◽

Michael P. Richardson ◽

Wei Vivian Wang ◽

Larissa Georgeon Richard ◽

Wei Chen ◽

...

Keyword(s):

Colorectal Cancer ◽

Mouse Model ◽

Mtor Inhibitor ◽

Tumor Regression ◽

Genetically Engineered ◽

Wild Type ◽

Genetically Engineered Mouse Model

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HGG-11. LEPTOMENINGEAL DISEASE AND TUMOR DISSEMINATION ALONG CSF PATHWAYS IN A MURINE DIPG MODEL: IMPLICATIONS FOR STUDY OF THE TUMOR-CSF-EPENDYMAL MICROENVIRONMENT

Neuro-Oncology ◽

10.1093/neuonc/noab090.077 ◽

2021 ◽

Vol 23 (Supplement_1) ◽

pp. i19-i19

Author(s):

Shelei Pan ◽

Dezhuang Ye ◽

Yimei Yue ◽

Lihua Yang ◽

Christopher Pacia ◽

...

Keyword(s):

Tumor Cells ◽

Genetic Alterations ◽

Diffuse Intrinsic Pontine Glioma ◽

Genetically Engineered ◽

Leptomeningeal Disease ◽

Tumor Spread ◽

Csf Dissemination ◽

Tumor Dissemination ◽

Genetically Engineered Mouse Model ◽

Ventricle Volume

Abstract Background Leptomeningeal disease and hydrocephalus are present in up to 30% of patients with diffuse intrinsic pontine glioma (DIPG), however there are no animal models of cerebrospinal fluid (CSF) dissemination. As the tumor-CSF-ependymal microenvironment may play an important role in tumor pathogenesis, we identified characteristics of the Nestin-tumor virus A (Nestin-Tva) genetically engineered mouse model (GEMM) that make it ideal to study the interaction of tumor cells with the CSF and its associated pathways with implications for the development of treatment approaches to address CSF dissemination in DIPG. Methods A Nestin-TVa model of DIPG utilizing the three most common DIPG genetic alterations (H3.3K27M, PDGF-B, p53) was used for this study. All animals underwent MR imaging and a subset underwent histopathologic analysis with H&E and beta-IV tubulin. Results Tumor dissemination within the CSF pathways (ventricles, leptomeninges) was present in 76% (25/33) of animals, with invasion of the choroid plexus, disruption of the ciliated ependyma and regional subependymal fluid accumulation. Ventricular enlargement consistent with hydrocephalus was present in 94% (31/33). Ventricle volume correlated with region specific transependymal CSF flow (periventricular T2 signal), localized anterior to the lateral ventricles. Subependymal tumor cells were also present subjacent to the 4th ventricle in a post-mortem human specimen. Conclusions This is the first study to report CSF pathway tumor dissemination an animal model of DIPG and is representative of CSF dissemination seen clinically. Understanding the CSF-tumor-ependymal microenvironment has significant implications for treatment of DIPG through targeting mechanisms of tumor spread within the CSF pathways.

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453 – Therapeutic Dose of Pelvic Radiation Slows Tumor Growth and Improves Survival in a Genetically Engineered Mouse Model of Colorectal Cancer

Gastroenterology ◽

10.1016/s0016-5085(19)37026-x ◽

2019 ◽

Vol 156 (6) ◽

pp. S-95

Author(s):

Daniel R. Schmidt ◽

Jatin Roper ◽

Sebastian Santos ◽

Omer H. Yilmaz ◽

Matthew G. Vander Heiden

Keyword(s):

Colorectal Cancer ◽

Mouse Model ◽

Tumor Growth ◽

Therapeutic Dose ◽

Genetically Engineered ◽

Pelvic Radiation ◽

Genetically Engineered Mouse Model

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Adaptation and Selection Shape Clonal Evolution During Residual Disease and Recurrence

10.1101/2020.04.22.055780 ◽

2020 ◽

Author(s):

Andrea Walens ◽

Jiaxing Lin ◽

Jeffrey S. Damrauer ◽

Ryan Lupo ◽

Rachel Newcomb ◽

...

Keyword(s):

De Novo ◽

Residual Disease ◽

Tumor Regression ◽

Clonal Evolution ◽

Genetic Alterations ◽

Genetically Engineered ◽

Primary Tumors ◽

Recurrent Tumors ◽

Genetically Engineered Mouse Model ◽

Clonal Composition

SummaryThe survival of residual tumor cells following therapy and their eventual recurrence constitutes one of the biggest obstacles to obtaining cures in breast cancer, but it remains unclear how the clonal composition of tumors changes during tumor relapse. We used cellular barcoding to directly monitor clonal dynamics during tumor recurrence in a genetically engineered mouse model. We found that the clonal diversity of tumors progressively decreased during tumor regression, residual disease, and recurrence. Only a fraction of subclones survived oncogene withdrawal and persisted in residual tumors. The minimal residual disease phase itself was accompanied by a continued attrition of clones, suggesting an ongoing process of selection during dormancy. The reactivation of dormant residual cells into recurrent tumors followed several distinct evolutionary routes. Approximately half of the recurrent tumors exhibited a striking clonal dominance in which one or two subclones comprised the vast majority of the tumor. The majority of these clonal recurrent tumors exhibited evidence of de novo acquisition of Met amplification, and were sensitive to small-molecule Met inhibitors. A second group of recurrent tumors exhibited marked polyclonality, with thousands of subclones and a clonal architecture very similar to primary tumors. These polyclonal recurrent tumors were not sensitive to Met inhibitors, but were instead dependent upon an autocrine IL-6 – Stat3 pathway. These results suggest that the survival and reactivation of dormant tumors can proceed via multiple independent routes, producing recurrent tumors with distinct clonal composition, genetic alterations, and drug sensitivities.

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