# Mechanical stress reprograms mitochondrial metabolism to support tumor survival and invasion through the mitochondrial unfolded protein response

> **NIH NIH F32** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2021 · $46,365

## Abstract

Project Summary
 Aberrant metabolic and physical characteristics are the most salient features of tumors when compared
to their tissue of origin. My proposed research program will molecularly define how mechanical stresses alter
mitochondrial metabolism to support metastatic disease. My preliminary data show that genetic and exogenous
mechanical stress can metabolically reprogram mammary epithelial cells by inducing the mitochondrial
unfolded protein response (UPRmt) which induces adaptations known to be enriched in metastatic tumors.
Clarifying the relationship between cellular mechanics, mitochondrial signals, and adaptive stress responses
may uncover unforeseen cancer treatment opportunities while also explaining the interconnectedness of the
mechanical and metabolic abnormalities of cancerous tissues.
 I will use simplified two dimensional ECM functionalized polyacrylamide hydrogels (PA-gels) that
recapitulate the “normal” tissue stroma (400 Pa), the premalignant and early invasive promoting stroma (6
kPa), and the highly rigid tumor stroma (60 kPa) to assess the impact of ECM stiffness on mitochondrial
metabolism, redox signaling, and cancer associated adaptive stress responses (UPRmt mediated by HSF1 and
ATF5). In these models of mechanical stress, I will define the roles of HSF1 and ATF5, mitochondrial structural
transitions, integrin signal transduction (via genetic and pharmacological approaches), and actomyosin
mediated contractility (via genetic and pharmacological approaches). I will then interrogate if the cellular
responses to mechanical signals of the tumor microenvironment require HSF1 and ATF5 to dispose malignant
behavior using mammary tumor models developed in the Weaver lab.
 In summary, Aim 1: Characterize the mitochondrial changes that occur in response to mechanical
stress. Aim 2: Determine if mitochondrial reactive oxygen signals trigger adaptive stress responses and
metastatic cytoskeletal dynamics. Aim 3: Test if viability and invasiveness of mammary tumors catalyzed by
mechanical stresses is disposed through an HSF1- and ATF5-mediated UPRmt induced by mitochondrial
oxidant signals. Additionally, to accomplish this project I will learn and use experimental techniques and
concepts that my mentors and I have identified as important experiential training opportunities that will
engender my independent research career.

## Key facts

- **NIH application ID:** 9985586
- **Project number:** 5F32CA236156-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Kevin Tharp
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $46,365
- **Award type:** 5
- **Project period:** 2019-12-01 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9985586

## Citation

> US National Institutes of Health, RePORTER application 9985586, Mechanical stress reprograms mitochondrial metabolism to support tumor survival and invasion through the mitochondrial unfolded protein response (5F32CA236156-02). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/9985586. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*