# (PQ5) Mitochondrial Heterogeneity in Melanoma Tumor and Immune Responses

> **NIH NIH R01** · SALK INSTITUTE FOR BIOLOGICAL STUDIES · 2020 · $731,547

## Abstract

PROJECT SUMMARY
This proposal directly responds to RFA-CA-17-017 PQ5: How does mitochondrial heterogeneity
influence tumorigenesis or progression? Tumor initiation, growth, death and metastasis are associated with
significant changes in cell metabolism and signaling, central to which are mitochondria. Mitochondria
are complex organelles that regulate energy metabolism, signaling and apoptosis, and contain mitochondrial
DNA (mtDNA) that hardwires respiration and ATP production from within. It is often underappreciated that
mitochondria in different cell types, and even within individual cells of the same type, vary in function and
dynamics (location, shape and movement) basally and in response to stress. It is presently unclear
how these aspects of mitochondrial heterogeneity contribute to tumorigenesis. Striking changes in
glucose metabolism and mitochondrial respiration occur in tumors (the “Warburg effect”); however, these
metabolic adaptations are neither uniform nor static. For example, mitochondria and metabolism of tumor
cells, infiltrating immune cells and stromal cells, are diverse and responsive to ever-changing environmental
stresses, including alterations in nutrient and oxygen availability, pH, and growth factors. The overarching
theme of this proposal is that the heterogeneity in mitochondrial respiration, network dynamics and
mtDNA-interferon (IFN) signaling not only affects cancer cell metabolism and growth, but also impacts
their sensitivity to immune responses and immunotherapy. In Aim 1, unique mouse melanoma cell lines
will be employed that exhibit significant differences in immunogenicity as well as mitochondrial
respiration and mtDNA levels. In these cells, mitochondrial respiration will be activated or inhibited via
knock-out of the Mcj or Cox10 genes, respectively, and tumor growth, immunoreactivity, and responses to
anti-PD1 checkpoint blockade (immunotherapy) will be addressed to directly examine how mitochondrial
heterogeneity links with immunogenicity/immunoevasion. Heterogeneity in mitochondrial dynamics and
metabolism will also be assessed directly using microfluidic, single-cell approaches. Finally, as a potential
therapeutic avenue to enhance anti-tumor immunity, T cells will be engineered to increase mitochondrial
respiration and ATP production. In Aim 2, the focus will be on the role of mtDNA-stress mediated IFN signaling
and whether it underlies differences in tumor growth, immune responses and sensitivity to immunotherapy. In
Aim 3, models that pair patient-derived xenografts with their tumor infiltrating lymphocytes (PDX-TIL models)
will be analyzed to probe the relevance of heterogeneity in mitochondrial respiration and mtDNA-stress
signaling in human cancer. This work has the potential to illuminate new candidate pathways in tumor and
immune cells to enhance anti-cancer therapies and stimulate anti-tumor immunity.

## Key facts

- **NIH application ID:** 9993415
- **Project number:** 5R01CA216101-03
- **Recipient organization:** SALK INSTITUTE FOR BIOLOGICAL STUDIES
- **Principal Investigator:** Susan M Kaech
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $731,547
- **Award type:** 5
- **Project period:** 2018-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9993415

## Citation

> US National Institutes of Health, RePORTER application 9993415, (PQ5) Mitochondrial Heterogeneity in Melanoma Tumor and Immune Responses (5R01CA216101-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9993415. Licensed CC0.

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