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Principal Investigator: Brandon Chen
Organization: UNIVERSITY OF MICHIGAN AT ANN ARBOR
Fiscal Year: 2024
Award: $42,094
Funding agency: National Cancer Institute
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.
Terms: <Anabolism><Automobile Driving><Autoregulation><Bioenergetics><CRISPR editing screen><CRISPR screen><CRISPR-based screen><CRISPR/Cas9 screen><Cancer Cause><Cancer Etiology><Cancers><Cell Body><Cell Differentiation><Cell Differentiation process><Cell Survival><Cell Viability><Cells><Cessation of life><Coenzyme Q><Coenzyme Q-Cytochrome-c Reductase><Coenzyme QH2-Cytochrome-c Reductase><Coenzymes><Colon Cancer><Colon Carcinoma><Colon Neoplasms><Colon Tumor><Colonic Mass><Colonic Neoplasms><Colonic Tumor><Colorectal Cancer><Colorectal Neoplasms><Colorectal Tumors><Common Neoplasm><Common Tumor><Communication><Complex III><Cytochrome b-c2 Oxidoreductase><Data><Death><Development><Dihydroubiquinone-Cytochrome-c Reductase><Electron Microscopy><Electron Transport><Electron Transport Complex III><Electrons><Endoplasmic Reticulum><Enzyme Cofactors><Enzyme Gene><Enzymes><Epithelium><Ergastoplasm><Fellowship><Foundations><GEM model><GEMM model><Genetic><Genetic Screening><Genetically Engineered Mouse><Goals><Homeostasis><Hypoxia><Hypoxic><Hypoxic tumor><Image><In Vitro><Intermediary Metabolism><Intestinal><Intestines><Investigators><Ions><Knowledge><Large Bowel Tumor><Large Intestine Neoplasm><Large Intestine Tumor><Lipids><Maintenance><Malignant Cell><Malignant Neoplasms><Malignant Tumor><Mentorship><Metabolic><Metabolic Pathway><Metabolic Processes><Metabolism><Metaplasia><Metaplastic Change><Methods><Mice><Mice Mammals><Mitochondria><Modeling><Molecular><Monitor><Murine><Mus><Negative Beta Particle><Negatrons><Organelles><Organoids><Oxidation-Reduction><Oxidative Phosphorylation><Oxidative Phosphorylation Pathway><Oxygen Deficiency><Pathway interactions><Patients><Phase><Physiological Homeostasis><Postdoc><Postdoctoral Fellow><Pre-Clinical Model><Preclinical Models><Principal Investigator><Process><Progenitor Cells><Proliferating><Pyrimidine><QH(2)-Cytochrome-c Reductase><QH(2)-Ferricytochrome-c Oxidoreductase><Reaction><Redox><Regulation><Reporter><Repression><Research><Research Associate><Research Personnel><Research Proposals><Researchers><Respiration><Role><Sampling><Scanning Electron Microscopy><Science><Shapes><Site><Sterols><Stimulus><System><Therapeutic><Training><Tumor Cell><Ubihydroquinone-Cytochrome-c Reductase><Ubiquinol-Cytochrome-c Reductase><Ubiquinol-ferricytochrome-c oxidoreductase><Ubiquinone><Ubiquinone-Cytochrome b-c2 Oxidoreductase><Work><adipogenesis><biosynthesis><bowel><cancer cell><cancer cell metabolism><cancer in the colon><cancer metabolism><cancer microenvironment><cancer progression><career><career development><cellular differentiation><clustered regularly interspaced short palindromic repeats screen><coenzyme analog><colon cancer cell line><colon cancer patients><colon neoplasia><colorectal cancer cell line><colorectal cancer patients><colorectal cancer progression><colorectal neoplasia><complex IV><developmental><driving><electron transfer><genetically engineered mouse model><genetically engineered murine model><genome scale><genome-wide><genomewide><graduate school><imaging><improved outcome><in vivo><in vivo Model><induced Cre><inducible Cre><innovate><innovation><innovative><knowledge base><large bowel neoplasm><lipid biosynthesis><lipidomics><lipogenesis><malignancy><metabolic fitness><metabolism measurement><metabolomics><metabonomics><mitochondrial><mouse model><murine model><neoplasm progression><neoplasm/cancer><neoplastic cell><neoplastic progression><new drug target><new drug treatments><new druggable target><new drugs><new pharmacological therapeutic><new pharmacotherapy target><new therapeutic target><new therapeutics><new therapy><new therapy target><next generation therapeutics><novel><novel drug target><novel drug treatments><novel druggable target><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel pharmacotherapy target><novel therapeutic target><novel therapeutics><novel therapy><novel therapy target><oxidation><oxidation reduction reaction><pathway><pharmacologic><post-doc><post-doctoral><post-doctoral trainee><pressure><progenitor cell expansion><progenitor expansion><research associates><respiratory mechanism><response><response to therapy><response to treatment><social role><stem and progenitor cell expansion><stem cell expansion><stem cells><stressor><therapeutic response><therapy response><treatment response><treatment responsiveness><tumor><tumor cell metabolism><tumor growth><tumor hypoxia><tumor metabolism><tumor microenvironment><tumor progression>