# Rewired Signaling at the Nexus of Melanoma Metastasis and Resistance

> **NIH NIH R35** · CEDARS-SINAI MEDICAL CENTER · 2024 · $826,436

## Abstract

Summary
This R35 focuses on novel mechanisms underlying control of key UPR components that impact melanoma
metastasis in aged rather than young mice by (i) tumor-intrinsic mechanisms (NRF2, ATF4) implicated in
resistance or sensitivity to therapy, and (ii) tumor-extrinsic mechanisms that define intestinal microbiota
composition and impact anti-tumor immunity. This OIA application leverages discoveries made during our R35
support period, which enabled us to define the regulation and function of ATF4, one of the main UPR signaling
components, in pro- and anti-apoptotic signaling. Several fundamental discoveries will be pursued. (1) the effect
of aging on altered metabolic signaling, as exemplified by effects of asparagine synthase (ASNS) and glutaryl-
CoA dehydrogenase (GCDH) on ATF4. Specifically, while ASNS inhibition promotes melanoma resistance to
therapy, GCDH inhibition causes melanoma cell death, although both phenotypes are ATF4-dependent. (2) the
effect of aging on gut microbiota composition with concomitant impact on the degree of anti-tumor immunity and
tumor propensity to metastasize. Among fundamental questions we will address are: (i) What confers ATF4 pro-
apoptotic vs. anti-apoptotic activities and how are these affected during aging (ii) How do gut microbiota, and
changes in bacterial commensals that occur with aging, impact anti-tumor immunity and tumor metastasis? (iii)
Could ATF4 inhibition (through targeting some of its modulators) be used as a novel strategy to enhance tumor
sensitization to therapy in young and aged animals? To answer these questions, we will employ innovative
technologies, including conditional knock-out mice, CRISPR-Cas9 technology, single-cell RNAseq, spatial
transcriptomics, metabolomics, and computational approaches. Models of young (2 months) and aged (12-15
months = 55–70-year-old human) mice will be used to define mechanisms underlying how a key UPR signaling
component, ATF4, impacts melanoma metastasis mechanisms. In all, these studies should reveal novel
paradigms in melanoma biology impacting metastasis under relevant physiological conditions.

## Key facts

- **NIH application ID:** 11218647
- **Project number:** 7R35CA283706-02
- **Recipient organization:** CEDARS-SINAI MEDICAL CENTER
- **Principal Investigator:** Zeev A. Ronai
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $826,436
- **Award type:** 7
- **Project period:** 2024-08-01 → 2031-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11218647

## Citation

> US National Institutes of Health, RePORTER application 11218647, Rewired Signaling at the Nexus of Melanoma Metastasis and Resistance (7R35CA283706-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/11218647. Licensed CC0.

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