# Systems genetics analysis of tumor evolution in the mouse

> **NIH NIH R35** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $951,000

## Abstract

Abstract
Systems Genetics Analysis of Tumor Evolution in the Mouse.
Metastasis is the major cause of death due to cancer in humans, but many factors play a role in determining
the route taken by initiated cells to reach this end stage. We know that tumors arise due to the combined
effects of inherited genetic factors and environmental exposures, and have taken the long term view that
successful modeling of human cancer in the mouse requires us to take account of interactions between
genetics and environment. The over-arching goal of this research is to develop an integrated systems genetics
view of the cells, signaling pathways and mutations in specific genes involved in evolution of metastasis from
single initiated cells, using one of the best characterized models of multistage carcinogenesis of the skin.
Based on major funding from the NCI MMHCC over the past 15 years, we have built up a unique tissue and
tumor bank comprising thousands of samples of Ras-mutant squamous tumors from a genetically
heterogeneous mouse population. These samples encompass all stages from benign lesions to metastases,
and in particular include hundreds of matched primary carcinomas and distant metastases from the same
animals. All tumors were induced by exposure to mutagens and tumor promoting agents, resulting in complex
genomic landscapes that resemble, in mutation frequency and type, the genomic profiles of human squamous
carcinomas of the skin, head and neck, and lung. All mice in the cohort have been genotyped genome-wide to
facilitate linkage and eQTL analysis to identify genetic determinants of initiation, benign tumor formation,
progression and metastatic dissemination. This project will exploit this unique tissue bank and database by
using genomic technologies, together with novel mouse strains, to identify the cells of origin of benign and
malignant tumors, biomarkers of risk of malignant progression, and genetic drivers of metastasis.
Computational network analysis tools will be used to study the evolution of signaling pathways, for example the
Ras pathway, through multiple stages of carcinogenesis, to identify changes in these networks that will identify
potential novel cancer target genes. Finally we will initiate a new series of translational studies of
immunotherapy, based on our observation that these chemically induced tumors harbor novel neo-antigens
and show promising responses to inhibitors of immune checkpoint proteins.

## Key facts

- **NIH application ID:** 9929960
- **Project number:** 5R35CA210018-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** ALLAN BALMAIN
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $951,000
- **Award type:** 5
- **Project period:** 2017-06-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9929960

## Citation

> US National Institutes of Health, RePORTER application 9929960, Systems genetics analysis of tumor evolution in the mouse (5R35CA210018-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9929960. Licensed CC0.

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