# High-resolution approaches to dissect the role of subcellular redox circuits in vivo

> **NIH NIH DP2** · UT SOUTHWESTERN MEDICAL CENTER · 2024 · $1,476,000

## Abstract

Project Summary
Metastasis is the leading cause of death for cancer patients. Oxidative stress, characterized by excessive
exposure to reactive oxygen species (ROS), kills most metastasizing cancer cells. How highly-metastatic
clones manage to overcome both cell-intrinsic and extrinsic oxidative insults to colonize distant organs is
poorly understood. The precise subcellular circuits enabling tumor adaptation to oxidative stress, and whether
they could be exploited for therapy, have remained elusive. We hypothesize that organellar antioxidant
pathways provide adaptive mechanisms essential for cancers to efficiently metastasize. A major impediment to
testing this hypothesis has been the lack of high-resolution and versatile tools to study ROS in vivo.
To address this major technological gap and address which subcellular redox circuits are necessary or
sufficient for highly metastatic tumors to progress, we will develop and apply tools with exquisite
spatiotemporal resolution in vivo. These tools include an optogenetic protein that produces localized ROS in
tumor subcellular compartments, gene therapy strategies in mice that will pioneer the manipulation of tissue-
extrinsic ROS in mouse tissues, and tumor organelle purification strategies coupled to mass spectrometry
analyses in primary and metastatic tumors.
With these tools in hand, this proposal aims to answer three key questions: Can the subcellular burden of ROS
be exploited to hinder metastasis? Are there specific organelle-based nodes that enhance tumor antioxidant
capacity for metastasis? Are extracellular ROS in the colonized target organ a major metastasis limitation? By
integrating in vivo optogenetic modulation of ROS, high-resolution metabolomics, functional genetics and
metastatic cancer models, our work will uncover targetable, ROS-mediated bottlenecks of metastasis at
subcellular resolution.
The tools and techniques developed in this proposal have the potential to revolutionize our ability to study ROS
and oxidative stress both in vitro and in vivo, and be broadly applied to any disease impacted by ROS and
oxidative stress. As such, my lab’s work has the power to reshape our understanding of these processes not
only in cancer, but across a wide range of diseases, which may pave the way for new therapeutic strategies
and improved patient outcomes.

## Key facts

- **NIH application ID:** 10909611
- **Project number:** 1DP2GM159178-01
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Javier Garcia Bermudez
- **Activity code:** DP2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1,476,000
- **Award type:** 1
- **Project period:** 2024-09-05 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10909611

## Citation

> US National Institutes of Health, RePORTER application 10909611, High-resolution approaches to dissect the role of subcellular redox circuits in vivo (1DP2GM159178-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10909611. Licensed CC0.

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