# Visualizing tumor heterogeneity in an immune intact and autochthonous mouse model of breast cancer

> **NIH NIH R01** · DUKE UNIVERSITY · 2021 · $365,458

## Abstract

ABSTRACT
Genetically modified mouse models of breast cancer have been used for decades as premier basic
science tools for mechanistic discovery. However, the successful implementation of mouse models as
surrogates of therapeutic efficacy and translational research has been challenging. One major challenge
for status quo approaches is their limited ability to model the genetic heterogeneity observed in breast
cancers. Metastatic and treatment resistant HER2+ breast cancers are incurable largely due to this
heterogeneity, the source of which may stem from the competition and evolution of multiple oncogenic
isoforms of the driver gene HER2. The objective for this proposal is to recapitulate the genetic
heterogeneity of HER2 oncogenes in a genetically tractable model more closely resembling the human
condition – including an intact immune system and stromal network. Published preliminary data
recently described a Cancer rainbow (Crainbow) modeling system for fluorescently barcoding and
expressing multiple tumor driver genes in a single immune intact mouse. The fluorescent barcode is
retrieved by multispectral imaging and single-cell “omics” techniques providing a simple solution for
inducing intratumor heterogeneity and visualizing its evolution. Any tumor driver gene can be
incorporated into Crainbow mice. Therefore, this proposal will test the central hypothesis that
modeling the oncogenic heterogeneity of HER2 in a Cancer rainbow mouse
recapitulates the phenotypic heterogeneity found in treatment resistant and metastatic
HER2+ breast cancers. The central hypothesis will be tested by completing four specific aims
seeking to: (Aim 1) Validate a HER2 Crainbow mouse model of tumor heterogeneity, (Aim 2)
Demonstrate heterogeneity within the tumor epithelium, (Aim 3) Demonstrate heterogeneity of the
tumor microenvironment and its contribution to tumor biology, and (Aim 4) Demonstrate
heterogeneity and differential response to therapy. HER2 Crainbow mice will provide an autochthonous
mouse model of the genetic heterogeneity found in HER2+ breast cancer, all while maintaining the
endogenous contributions of the tumor microenvironment to invasion and metastasis. Completing this
proposal is expected to validate the HER2 Crainbow mouse as a shareable resource strain for more
predictive preclinical trials and a framework for illuminating the molecular and cellular ontogeny of
invasive breast cancer.

## Key facts

- **NIH application ID:** 10097864
- **Project number:** 1R01CA255372-01
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Joshua Clair Snyder
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $365,458
- **Award type:** 1
- **Project period:** 2021-02-09 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10097864

## Citation

> US National Institutes of Health, RePORTER application 10097864, Visualizing tumor heterogeneity in an immune intact and autochthonous mouse model of breast cancer (1R01CA255372-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10097864. Licensed CC0.

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