# Project 2: Systemic Understanding of Cellular Mechanisms of Metabolic Adaptations in Cancer

> **NIH NIH U54** · FRED HUTCHINSON CANCER CENTER · 2024 · $226,350

## Abstract

ABSTRACT
Cancers are characterized by alterations to cellular metabolism that promote tumorigenesis, however our
understanding of how these metabolic changes are enacted and how they mechanistically support cancer cell
function remains lacking. While some metabolic changes reproducibly occur as a direct result of oncogenic
mutations, other metabolic alterations occur over time through adaptive metabolic protein expression changes
that allow cells to surmount metabolic deficiencies during cancer progression. Notably, this latter group is
predicted to be enriched for functionally important metabolic changes, suggesting that their identification would
have particularly relevance for cancer research. However, detailed understanding of which metabolic
alterations are the result of adaptations is hampered by the lack of models for directly studying reproducible
metabolic adaptations in cancer. Additionally, data on differences in cancer-related adaptations based on race
or ethnicity that contribute to health disparities are lacking. Here, we propose to address this knowledge gap
by investigating the mechanisms of metabolic adaptation system that we have recently established, where loss
of function mutations in the tumor suppressor succinate dehydrogenase (SDH) selects for cells with
concordant expression of components of mitochondrial electron transport chain complex I, which ultimately
supports cell metabolism and cell proliferation. Using this system, we will investigate the metabolic drivers of
complex I adaptations in SDH deficient cells (Aim 1) and use polyomics measurements of gene expression
processes, such a epigenetics, transcription, and proteostasis, to identify the cellular processes that enact
adaptive changes to complex I expression (Aim 2). We will also take a systematic approach using state-of-the-
art statistical methods to leverage publicly available patient tumor datasets containing polyomic measurements
and patient metadata in order to identify adaptive changes to metabolic protein expression during cancer
progression (Aim 3). This multidisciplinary Full Project also addresses the Partnership’s Guiding Principles
(see Overall section) for inclusive mentoring of diverse research teams and for research dissemination to
underserved communities, helping to educate and provide opportunities for next generation of researchers.

## Key facts

- **NIH application ID:** 10931570
- **Project number:** 5U54CA132381-18
- **Recipient organization:** FRED HUTCHINSON CANCER CENTER
- **Principal Investigator:** Lucas Bryan Sullivan
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $226,350
- **Award type:** 5
- **Project period:** 2007-09-30 → 2028-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10931570

## Citation

> US National Institutes of Health, RePORTER application 10931570, Project 2: Systemic Understanding of Cellular Mechanisms of Metabolic Adaptations in Cancer (5U54CA132381-18). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10931570. Licensed CC0.

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