# Mitochondria-to-Nucleus Signaling in Colorectal Cancer

> **NIH NIH R01** · SALK INSTITUTE FOR BIOLOGICAL STUDIES · 2023 · $510,093

## Abstract

PROJECT SUMMARY
This project responds directly to PAR-17-203 “Inter-organelle Communication in Cancer.” A new pathway was
discovered called the “mtDNA-IRDS” pathway, through which mitochondria send a stress signal to the nucleus
to regulate expression of interferon-stimulated genes (ISGs), which are usually associated with antiviral
immunity. The mtDNA-IRDS pathway was elucidated during investigations of a unique mouse model of mtDNA
stress caused by haploinsufficiency of the nucleus-encoded mtDNA-packaging factor TFAM (i.e. Tfam+/- mice).
These mice have altered mitochondria and nucleoid structures (the mitochondrial version of chromatin) that
promotes release of mtDNA into the cytoplasm. The surprising feature of these mice (and cells isolated from
them) is that this released mtDNA promotes innate immune signaling, resulting in upregulation of a unique
subset of ISGs known as the Interferon-Related DNA-damage resistance Signature (IRDS). The IRDS
promotes chemotherapy resistance of tumor cells. The Tfam+/- condition enhances spontaneous intestinal
tumorigenesis In the APCMin/+ mouse model of human colorectal cancer (CRC) and new preliminary results
show that knock-out of the tumor suppressor commonly mutated in CRC, ARID1A (a subunit of the nuclear
SWI/SNF chromatin remodeling complex) also induces the mtDNA-IRDS pathway. Thus, the main premise of
this proposal is that the mtDNA-IRDS pathway increases tumorigenesis and/or chemoresistance in CRC,
which will be tested through completion of the following three Specific Aims. Aim 1 is to understand how
mutations in ARID1A lead to mtDNA-IRDS pathway induction. Aim 2 is to elucidate the mechanism through
which the mtDNA-IRDS pathway enhances nuclear DNA repair using the Tfam+/- model of mtDNA-mediated,
mitochondria-to-nucleus signaling. Aim 3 is to investigate the role of the mtDNA-IRDS pathway in
tumorigenesis and/or chemoresistance in vivo using the Tfam+/-, APCMin/+ and intestinal Arid1a knock-out
mouse models of CRC and human CRC tumor samples. That the PARP9-DTX3L complex is a major driver of
tumorigenesis and chemoresistance in vivo will be tested by crossing these CRC models to Parp9 knock-out
mice. CRC is a leading cause of cancer-related deaths in both men and women, and treatment of this disease
is plagued by resistance to chemotherapy. The significance of this proposal is that it probes a novel
mechanism of tumorigenesis and chemoresistance due to mtDNA-IRDS pathway activation that has the
potential for therapeutic targeting.

## Key facts

- **NIH application ID:** 10529300
- **Project number:** 5R01CA228211-04
- **Recipient organization:** SALK INSTITUTE FOR BIOLOGICAL STUDIES
- **Principal Investigator:** Diana Clare Hargreaves
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $510,093
- **Award type:** 5
- **Project period:** 2019-12-01 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10529300

## Citation

> US National Institutes of Health, RePORTER application 10529300, Mitochondria-to-Nucleus Signaling in Colorectal Cancer (5R01CA228211-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10529300. Licensed CC0.

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