# A network approach to interrogate cellular plasticity and drug resistance in cancer

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2024 · $671,594

## Abstract

ABSTRACT
We will address a critical problem in clinical oncology, namely how highly heterogeneous, drug resistant tumor
cell populations develop, and how they can be targeted. Most tumors develop resistance to almost every type
of therapy, including targeted-, radiation-, chemo- or immunotherapy, ultimately leading to cancer deaths. It is
essential to develop novel methods to understand the processes leading to drug resistance under complex in
vivo conditions where stromal and immune elements interact with malignant cells. We will study squamous cell
carcinomas (SCCs), a major contributor to human cancer burden and one of the most common solid tumor
types that arise in a range of tissues including head and neck, lung, esophagus, bladder, and skin. We will use
a well-established multistage, carcinogen-induced, cutaneous SCC mouse model and credential its’
representation of human cancer drug resistance. Mouse cSCCs display many genetic alterations seen in
human SCCs, including mutation of Ras, PI3 Kinase and Notch pathways. The model also incorporates the
critical role played by non-mutagenic tumor promoting factors as cancer drivers. This proposal will build on our
previous work, accessing our extensive in-house mouse tumor genomics and transcriptomics databases. In
Aim 1, we will use single cell analyses of primary papillomas, carcinomas and metastases induced by chemical
carcinogenesis in situ and analyzed before and during chemo- or immunotherapies. We will use our novel
biocomputational Metagene approach to identify rewiring of transcriptomic networks within single tumor cells
after therapy. Single cell analyses, namely scRNAseq, CyTOF, MIBI, and FISH, will be combined with our in-
house developed analytical tools, to identify high plasticity state tumor cell populations enriched or depleted in
response to therapy and their molecular and spatial relationship to other cells and structures within the tumor.
In Aim 2, we will test the fidelity of the chemical carcinogenesis model as a robust representation of human
cSCC biology by undertaking longitudinal validation studies of fresh human cSCC tissue collected before and
during chemo- or immuno-therapy and analyzed using the same technology. In Aim 3, we will empirically test
the function of candidate genes (Metagene components) expressed in the high plasticity state, for their
contribution to drug resistance. CRISPRi/dCas9 and CRISPR/MultiCas12a technology will be used to test gene
activities during drug therapy by single or combinatorial gene knockdown in syngeneic tumor models in vivo.
Our strategy will credential the use of the skin chemical carcinogenesis system to model features of human
cancer drug resistance. The project is responsive to PAR-23-281, as it undertakes cross-species discovery of
the molecular basis for development of drug resistant tumor cells. The knowledge to be gained will contribute
to discovery of biomarkers and therapeutic targets for this drug resistant cell populatio...

## Key facts

- **NIH application ID:** 10982082
- **Project number:** 1R01CA285426-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** ROSEMARY J AKHURST
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $671,594
- **Award type:** 1
- **Project period:** 2024-06-15 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10982082

## Citation

> US National Institutes of Health, RePORTER application 10982082, A network approach to interrogate cellular plasticity and drug resistance in cancer (1R01CA285426-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10982082. Licensed CC0.

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