# Metabolic rewiring regulates cancer growth and tumor-associated immune responses

> **NIH NIH K00** · SALK INSTITUTE FOR BIOLOGICAL STUDIES · 2022 · $88,834

## Abstract

Project Summary
 Metabolic reprogramming is recognized as a hallmark of cancer cells, and a deeper understanding of
these metabolic changes can lead to the development of novel and promising therapeutics. Activation of de
novo lipid synthesis and epigenetic reprogramming are both common features of many cancers. Acetyl-CoA is
the metabolic building block for newly synthesized lipids in the cell. Deregulated lipid synthesis is a key
problem in metabolic disorders, and has been shown to support tumor growth. Acetyl-CoA is also the donor
substrate for all histone and non-histone protein acetylation. Previous studies in our lab show that histone
acetylation is metabolically sensitive in cancer cell lines and tissues in vivo. How metabolic regulation of
histone acetylation subsequently affects gene expression and signaling in tumorigenesis remains an area of
active investigation. Another hallmark of cancer is the ability to evade immune detection or destruction through
a wide variety of mechanisms. Studies identifying metabolic rewiring of immune cells during differentiation or
activation have prompted research into how immunometabolism is disrupted within tumors to suppress anti-
tumor immunity. However, the exact mechanisms of interplay between cancer and immune cell metabolism
within a tumor remain largely unknown.
 The aims presented in the pre-doctoral phase of this proposal are designed to further understand the
role of cellular metabolism in promoting tumorigenesis. In Aim 1, I investigate the role of ACLY in regulating
processes such as de novo lipid synthesis and histone acetylation in cells using genetic and pharmacological
perturbations of cellular metabolism coupled with mass-spectrometry based metabolomic techniques and other
biochemical methods. In Aim 2, my previous findings will be translated in vivo to investigate how ACLY loss
impacts hepatocellular carcinoma development in the context of non-alcoholic fatty liver disease, which has
been identified as a risk factor for hepatocellular carcinoma in human patients. I will utilize a dietary stress and
carcinogen-induced model of HCC in mice harboring a liver-specific knockout of Acly to study how processes
such as de novo lipid synthesis and epigenome remodeling are impacted in this context. The ultimate goal of
these aims is to define ACLY functions in cellular metabolism in the context of dietary stress and hepatocellular
carcinoma for the application of ACLY inhibitors as a therapeutic strategy in the prevention and treatment of
HCC. In Aim 3, I propose to build upon the technical and conceptual expertise in cellular and tumor metabolism
acquired in my pre-doctoral training by pursuing a post-doctoral fellowship in tumor immunology and
immunometabolism. I describe potential methods to investigate how metabolic reprogramming by cancer cells
can impact immune cell function within a tumor. The goal of these studies is to identify how modulating cancer
or immune cell metabolism can favor ...

## Key facts

- **NIH application ID:** 10328477
- **Project number:** 5K00CA222741-05
- **Recipient organization:** SALK INSTITUTE FOR BIOLOGICAL STUDIES
- **Principal Investigator:** Steven Zhao
- **Activity code:** K00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $88,834
- **Award type:** 5
- **Project period:** 2020-02-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10328477

## Citation

> US National Institutes of Health, RePORTER application 10328477, Metabolic rewiring regulates cancer growth and tumor-associated immune responses (5K00CA222741-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10328477. Licensed CC0.

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