# Inter-organellar communication in metabolic reprogramming of colorectal cancer

> **NIH NIH F99** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $42,094

## Abstract

PROJECT SUMMARY
Colorectal cancers (CRC) are characterized as having a hierarchical organization requiring proliferating and
de-differentiated stem cells to maintain tumor growth and progression. Cellular plasticity underlying colorectal
cancer is essential for a process which occurs following selective pressures of the tumor microenvironment
and chemotherapeutics. The colonic tumor microenvironment is characterized by extreme hypoxia due to the
anoxic lumen. Hypoxia promotes metabolic rewiring, and such processes are utilized by cancer cells to support
biosynthesis, cell survival and dynamic alteration in cell fates. A critical feature of cellular metabolism is
organellar interaction and coordination, yet how these contribute to CRC plasticity, survival, progression and
treatment response are unclear. Endoplasmic reticulum-mitochondria contact sites (ERMCS) are the most
abundant inter-organellar interaction. I generated a panel of ERMCS reporter CRC cell lines, and through
unbiased high content imaging and CRISPR screens, I have identified essential mechanisms required for ER-
mitochondrial interactions in CRC. Moreover, I show a key role of tumor hypoxia in modulating ERMCS.
Hypoxia inhibited mitochondrial complex III and IV to decrease ERMCS. Treating cells with the mitochondrial
electron carrier, coenzyme (CoQ) rescued ERMCS suppression following hypoxia. I hypothesize that tumor
hypoxia regulates ER-mitochondrial contacts (ERMCS) by altering mitochondrial respiration and CoQ redox for
metabolic adaptation and survival. In aim 1 (F99 phase), I will focus on identifying the molecular mechanism of
hypoxia dependent ERMCS inhibition and expand into in vivo models with our novel ERMCS reporter mouse
model. During the K00 phase, I will apply knowledge gained during graduate school in cancer metabolism and
organellar interaction to an independent postdoctoral project. The plasticity of colorectal tumor epithelium
depends on integration of organellar functions to sustain metabolic demands. Therefore, my goal as a
postdoctoral fellow is to understand the dynamic changes and requirement for organellar interactions and
metabolic compartmentalization during cell fates alterations in CRC. I plan to use genetic murine and primary
patient organoid models of CRC, volumetric electron microscopy, in vivo organellar metabolomics, and
functional CRISPR screens to answer these questions. Lastly, in addition to the proposed studies, this training
plan includes activities important for career development, mentorship, networking, and scientific
communication to prepare me for successful transition to a postdoctoral fellowship and my career as an
independent investigator studying cancer metabolism.

## Key facts

- **NIH application ID:** 10914267
- **Project number:** 5F99CA284256-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Brandon Chen
- **Activity code:** F99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $42,094
- **Award type:** 5
- **Project period:** 2023-09-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10914267

## Citation

> US National Institutes of Health, RePORTER application 10914267, Inter-organellar communication in metabolic reprogramming of colorectal cancer (5F99CA284256-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10914267. Licensed CC0.

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