# Investigating the role of the mitochondrial pyruvate carrier in colon tumorigenesis

> **NIH NIH F30** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2020 · $50,520

## Abstract

Project Abstract:
Metabolic shifts, such as loss of the mitochondrial pyruvate carrier (MPC) have prognostic value in colorectal
cancer: in this case, loss of MPC predicts poorer prognosis. In publicly available datasets, we have observed
that MPC1 is commonly deleted in colorectal cancers and appears to be lost early in tumorigenesis, when
comparing normal tissue to adenomas and to carcinomas. Loss of MPC, a heterodimeric transporter
composed of MPC1 and MPC2, uncouples glucose metabolism by preventing pyruvate, a byproduct of glucose
metabolism, from entering the mitochondria to undergo oxidation, resulting in the majority of pyruvate
converting to lactate. Colon stem cells, the predominant cell of origin in this cancer, normally express lower
MPC than their differentiated progeny, thus suggesting a developmental mechanism for uncoupling pyruvate
oxidation and glycolysis. Through studies in which we deleted MPC in non-transformed stem cells or re-
express MPC in cancer cell lines, we observe an inverse causal relationship between MPC expression,
proliferation capacity, and markers of stemness. This proposal is based upon the similar phenotypic findings
between these stem cells and their cancerous counterparts, and we hypothesize that reinforcement of stem
cell glucose metabolism confers susceptibility towards cancer initiation. Preliminary results support that loss of
MPC expression is sufficient to increase susceptibility malignant transformation and to accelerate
tumorigenesis in colorectal carcinoma. The following proposal tests whether MPC acts as a tumor suppressor
when a stem cell is environmentally or genetically tipped towards cancer. In AIM 1, we will utilize both loss and
gain of function experiments in both the azoxymethane-dextran sodium sulfate model and the APC loss of
function model of colorectal cancer induction. Each polyp has the potential to be molecularly unique as well as
convergent on distinct signatures, and we assess this as a function of glucose metabolic partitioning. In AIM 2,
we will test the role and function of pyruvate oxidation on cell identity in the various proliferating cell
populations of the crypt. Defining the role of metabolism in cancer initiation, from environmental exposures and
from genetic risk factors, holds promise in identifying metabolic targets in treatment for the growing number of
colorectal cancer patients, and ultimately utilizing metabolism to protect stem cells from transformation.

## Key facts

- **NIH application ID:** 9850222
- **Project number:** 5F30CA225110-03
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** CLAIRE BENSARD
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $50,520
- **Award type:** 5
- **Project period:** 2018-02-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9850222

## Citation

> US National Institutes of Health, RePORTER application 9850222, Investigating the role of the mitochondrial pyruvate carrier in colon tumorigenesis (5F30CA225110-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9850222. Licensed CC0.

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