# Spatial functional genomics to identify regulators of the tumor microenvironment and cancer immunity

> **NIH NIH U01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2024 · $964,277

## Abstract

PROJECT SUMMARY
 Tumor growth and response to therapy, particularly immunotherapy, are all highly dependent on the tumor
microenvironment (TME): the collection of cells and extracellular factors (cytokines, chemokines, collagens, etc.)
that form around cancer cells. This is evident from the major impact drugs targeting TME components can have
on cancers, including immune checkpoint blockade (ICB). Though there is a relatively good understanding of
key genes regulating cancer cell intrinsic processes, such as cell cycle, there is less known about genes
controlling the extrinsic environment that protects cancer cells from immunity and aids growth.
 The objective of this project is to determine the genes controlling tumor composition and facilitating tumor
growth and resistance to immunity & immunotherapy, with the goal of identifying vulnerability factors that can
be targeted to enhance tumor immunity and improve cancer treatment. The overarching hypothesis, which
forms the rationale for this U01, is that malignant cells turn on or off genes, including intrinsically operating genes,
through mutations and selective gene expression, that act extrinsically to recruit, position, & polarize immune &
stroma cells into a state that subverts immunity & facilitates tumor growth1, 2. To reach our objective, we will
employ a first-of-its-kind spatial functional genomics platform, called Perturb-map, which permits extensive
phenotypic analysis of dozens of single or multiple gene perturbations in a tumor at single cell resolution and
with spatial architecture preserved. With Perturb-map, CRISPR knockout (KO) or cDNA overexpression (OE)
screens are resolved by multiplex imaging & spatial transcriptomics (ST), and this allows study of entire classes
of genes (e.g. secreted factors) and phenotypes (e.g. TME composition) not feasible with existing screens.
 We will use Perturb-map to determine the role of 100s of genes in controlling many critical tumor processes,
including tumor: (i) growth, (ii) morphology, (iii) metastasis, (iv) cell-cell interactions, (v) subclonal interactions,
(vi) immune/stroma recruitment & polarization, (vii) resistance to immunotherapy & other treatments. The breadth
& depth of analysis of each gene will be achieved at a scale and efficiency not previously feasible. We will focus
on 3 broad categories of genes, identified through analysis of TCGA, ICB-treated cohorts, single cell-omics, and
other patient data, including: commonly mutated cancer genes in solid tumors (Aim 1), genes correlating with
resistance or response to ICB immunotherapy (Aim 2), and cancer cell-derived ligands and secreted molecules
(Aim 3). Studies will be carried out in immunocompetent, orthotopic models of non-small cell lung carcinoma,
high grade serous ovarian carcinoma, pancreatic adenocarcinoma, and oral squamous cell carcinoma.
 The study outcome will determine the roles of 100s of genes in many processes critical to unimpeded cancer
growth, including identif...

## Key facts

- **NIH application ID:** 10931761
- **Project number:** 5U01CA282114-02
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Brian D Brown
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $964,277
- **Award type:** 5
- **Project period:** 2023-09-19 → 2028-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10931761

## Citation

> US National Institutes of Health, RePORTER application 10931761, Spatial functional genomics to identify regulators of the tumor microenvironment and cancer immunity (5U01CA282114-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10931761. Licensed CC0.

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