# Defining metabolic adaptations within the PDAC "arid" tumor microenvironment

> **NIH NIH R01** · WISTAR INSTITUTE · 2021 · $598,666

## Abstract

PROJECT SUMMARY
The goal of our proposal is to identify therapeutic vulnerabilities associated with nutrient-poor conditions in
tumors. Pancreatic ductal adenocarcinoma (PDAC) remains a major clinical challenge and is characterized by
a dense stroma and paucity of blood vessels. The resulting hypoxia and scarcity of nutrients forces cancer
cells to seek alternative sources of nutrients for growth. Paradoxically, cells residing in these nutrient-
deprived microenvironments are among the most resistant to therapy as a result of poor drug diffusion
and reduced cell proliferation (rendering DNA-damaging agents less effective). To target these cells, therefore,
a better understanding of the adaptive mechanisms by which they cope with nutrient deprivation is urgently
needed.
In preliminary studies, we developed a culture protocol – limiting for oxygen, glucose, amino acids, and serum
– to model the “arid conditions” of pancreatic tumors. Under such conditions, tumor cells slow down
proliferation and metabolic activity. Using this system, we performed a whole genome CRISPR screen to
identify genes required under arid conditions but dispensable under nutrient-replete (“fertile”) conditions. This
revealed a strong dependency on the TCA cycle and oxidative phosphorylation for survival, but also suggested
that genes involved in many biosynthetic activities (e.g. translation and cell division) are detrimental under arid
conditions. Based on these results, we hypothesize that cells survive severe nutrient and oxygen deprivation
by maximizing energy generation from limited fuel supplies while minimizing the use of such resources for
macromolecule production. We further hypothesize that nutrient and oxygen deprivation alters the dynamic
crosstalk between cancer cells and other cells comprising the tumor microenvironment (TME). Importantly,
individual tumors may respond to these metabolic changes in different ways, contributing to inter-tumoral
heterogeneity. Our proposal will explore these ideas to develop strategies that target therapy-resistant
cancer cells residing in these nutrient-deprived niches.
Aim 1. Characterize the heterogeneity in metabolic adaptations to arid conditions.
Aim 2. Determine how arid conditions influence cellular crosstalk in the TME.
Aim 3. Test the activity of metabolic inhibitors against cells in arid conditions in vitro and in vivo.

## Key facts

- **NIH application ID:** 10205608
- **Project number:** 1R01CA252225-01A1
- **Recipient organization:** WISTAR INSTITUTE
- **Principal Investigator:** CHI V. DANG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $598,666
- **Award type:** 1
- **Project period:** 2021-05-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10205608

## Citation

> US National Institutes of Health, RePORTER application 10205608, Defining metabolic adaptations within the PDAC "arid" tumor microenvironment (1R01CA252225-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10205608. Licensed CC0.

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