# A systems-metabolism approach to identify mitochondria-dependent vulnerabilities in colorectal cancer

> **NIH NIH U54** · UNIVERSITY OF VIRGINIA · 2024 · $370,878

## Abstract

PROJECT ABSTRACT/SUMMARY
During tumorigenesis, mitochondrial function is altered by fusion/fission dynamics that control organelle
structure and impact overall cell metabolism. Signaling from oncogenic RAS fragments mitochondrial tubules
and causes metabolic changes that support tumor growth. However, the precise role of these oncogene-
driven mitochondrial changes on cancer metabolism is unclear, especially when considering the diverse
metabolic environments in which tumors develop. For example, colorectal cancer (CRC) initiates in the gut
where the microbiota produces high quantities of short chain fatty acids (SCFAs) that are metabolized by
normal colonocytes. During CRC tumorigenesis, mutations in the KRAS oncogene occur at the transition to
adenomas, suggesting that mitochondrial adaptation in the gut may be critical for progression of primary
tumors. And yet, the primary site of CRC metastasis is the liver, which provides a very different set of nutrients
for metabolism and growth. Recognizing the complexity of metabolic networks both inside and outside a
developing tumor, we propose a systems biology approach to examine the role of RAS-induced mitochondrial
fission in CRC. Specifically, our objective is to identify metabolic adaptations that permit mitochondrially
fragmented CRC cells to grow in the unique metabolic environment of the gut and metastatic CRC cells to
grow in the liver. While the fragmentation of the mitochondrial network can impact tumor metabolism in
multiple ways, we hypothesize that RAS-induced mitochondrial fragmentation leads to hyper-
compartmentalization of specific metabolic reactions within the mitochondrial matrix that depend on low-
abundance mitochondrial proteins. We predict that these adaptations create unique vulnerabilities in CRC
cells as they switch from normal SCFA metabolism to promote biosynthesis and energy generation. The
specific aims are to 1) curate a metabolic model of human CRC cells that incorporates the system-wide impact
of mitochondrial fragmentation and the availability of microbe-derived SCFAs; 2) instantiate metabolic models
of CRC with data characterizing in vivo metabolic states to assess impacts of gut microbiota metabolism and
mitochondrial fragmentation; and 3) evaluate the impact of metabolic adaptations to mitochondrial organelle
stress on CRC colonization and growth as liver metastases. Successful completion of this project will provide
a better understanding of CRC metabolism that may one day point to dietary interventions or shifts in the gut
microbiota that predictably influence organelle adaptation.

## Key facts

- **NIH application ID:** 10903896
- **Project number:** 5U54CA274499-03
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** David Francis Kashatus
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $370,878
- **Award type:** 5
- **Project period:** 2022-09-12 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10903896

## Citation

> US National Institutes of Health, RePORTER application 10903896, A systems-metabolism approach to identify mitochondria-dependent vulnerabilities in colorectal cancer (5U54CA274499-03). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10903896. Licensed CC0.

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