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Principal Investigator: Emily Devericks
Organization: UNIV OF NORTH CAROLINA CHAPEL HILL
Fiscal Year: 2024
Award: $14,797
Funding agency: National Cancer Institute
Project Abstract
Breast cancer remains the second-leading cause of cancer-related death in the US. Obesity is an established
risk factor for several aggressive breast cancer subtypes, and is also associated with increased breast cancer
metastasis and mortality. On a mechanistic level, diet-induced obesity drives dysregulation of lipid metabolism
that results in greater extracellular fatty acid availability, providing a rich energy source for tumor proliferation
and migration. While this has been shown to increase the severity of breast cancer progression and metastasis,
the therapeutic potential of this metabolic relationship has not yet been investigated. Dependent upon fatty acid
availability and linked to metastatic progression of several cancer types, ferroptosis, a mechanism of cell death
caused by lipid peroxidation, serves as a targetable mediator between obesity, fatty acid metabolism, and breast
cancer progression. Our preliminary findings support the ferroptosis-metastasis link and suggest obesity-induced
dysregulation of fatty acid metabolism may exacerbate this relationship. This proposal will use murine models of
obesity and metastatic mammary cancer in concert with several advanced mechanistic approaches, including
lipidomic quantification of tumor and plasma as well as high-throughput RNA sequencing for assessing
transcriptional regulation of lipid metabolism in the primary and metastatic tumor microenvironment, to rigorously
test the hypothesis that dysregulation of fatty acid metabolism associated with obesity promotes sensitivity to
ferroptosis in murine models of TNBC. This hypothesis will be tested with two integrated specific aims:
Aim 1. Quantify the impact of obesity and ferroptosis induction on murine mammary tumor growth, metastasis,
and fatty acid metabolism in vivo. To isolate the effect of fatty acid availability from other components of the
tumor microenvironment, in vitro exposure to serum from control or DIO mice will be used to assess changes in
sensitivity to inhibition of xCT and GPX4 in TNBC.
Aim 2. Determine whether the enzyme pyruvate carboxylase (PC), uniquely involved in both fatty acid and
glutamate metabolism, protects against ferroptosis in obesity by assessing if suppression of PC promotes
sensitivity to ferroptosis in both primary and metastatic tumors of DIO mice. Transcriptional dysregulation of lipid
and glutamate metabolism in obese and control shPC TNBC tumors, comparing primary and metastatic tumors,
will be quantified via RNAseq.
This proposal aims to define molecular characteristics of fatty acid metabolism enriched in breast cancer of
patients with obesity to identify therapeutic targets that can decrease breast cancer mortality by limiting tumor
progression and metastasis. Combined with the exceptional training environment at UNC, comprehensive
mentoring from Dr. Hursting, and a focused training plan, this fellowship will provide a critical foundation for
developing my future career as an independently-funded scientist in the fields of nutrition and cancer metabolism.
Terms: <After Care><After-Treatment><Aftercare><Blood Plasma><Blood Serum><Breast Cancer><Breast Cancer Patient><Breast Cancer Risk Factor><Breast Metastasis><Breast Neoplasms><Breast Tumor Patient><Breast Tumors><Cancer Cause><Cancer Etiology><Cancer Patient><Cancer and Nutrition><Cancers><Cause of Death><Cell Body><Cell Death><Cell Death Induction><Cell Growth in Number><Cell Multiplication><Cell Proliferation><Cells><Cellular Proliferation><Cessation of life><Characteristics><Curriculum><Cystine><Death><Dependence><Diet><Dietary Intervention><Disease Progression><Doctor of Philosophy><Educational Curriculum><Energy-Generating Resources><Environment><Enzyme Gene><Enzymes><Exposure to><Fats><Fatty Acid Metabolism Pathway><Fatty Acids><Fatty Change><Fatty acid glycerol esters><Fe element><Fellowship><Female Breast Cancer><Female Breast Carcinoma><Foundations><Funding><Future><Gene Transcription><Genetic><Genetic Transcription><Gln><Glutamate Metabolism><Glutamate Metabolism Pathway><Glutamate Translocase><Glutamate Transport Glycoprotein><Glutamate Transporter><Glutamates><Glutamine><Glutathione><High Fat Diet><High-Throughput RNA Sequencing><Imidazole><In Vitro><Injections><Intercellular Fluid><Interstitial Fluids><Intervention><Intervention Strategies><Investigation><Iron><Ketones><Ketosuccinates><L-Cystine><L-Glutamate><L-Glutamine><Link><Lipid Peroxidation><Lipids><Literature><Lung><Lung Respiratory System><Malignant Breast Neoplasm><Malignant Neoplasms><Malignant Tumor><Mammary Cancer><Mammary Carcinoma of the Female Breast><Mammary Neoplasms><Measurement><Mediating><Mediator><Membrane><Mentors><Metabolic><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Mice><Mice Mammals><Modeling><Molecular><Monitor><Murine><Mus><Neoplasm Metastasis><Nutrition Interventions><Nutritional Biochemistry><Nutritional Interventions><Nutritional Science><Obese Mice><Obesity><Onset of illness><Oxaloacetates><Oxosuccinates><Ph.D.><PhD><Phosphatides><Phospholipids><Plasma><Plasma Serum><Preparation><Primary Neoplasm><Primary Tumor><Proliferating><Pyruvate><Pyruvate Carboxylase><Q Levoglutamide><Q. Levoglutamide><RNA Expression><RNA Seq><RNA sequencing><RNAseq><Reticuloendothelial System, Serum, Plasma><Risk Factors><Role><Scientist><Secondary Neoplasm><Secondary Tumor><Serum><Severities><TM-MKR><TNBC><Tail><Testing><Therapeutic><Training><Transcription><Transcription Regulation><Transcriptional Control><Transcriptional Regulation><Treatment Protocols><Treatment Regimen><Treatment Schedule><Triacylglycerol><Triglycerides><Tumor Markers><Tumor Promotion><Up-Regulation><Upregulation><Veins><Woman><Women's mortality><Work><adiposity><aggressive breast cancer><anti-cancer research><anti-oxidant enzyme><antioxidant enzyme><antiport><breast cancer metastasis><breast cancer progression><breast cancer risk><cancer cell metabolism><cancer diagnosis><cancer metabolism><cancer metastasis><cancer microenvironment><cancer progression><cancer research><cancer sub-types><cancer subtypes><cancer type><career><colonization associated with lung><colonization in the lung><colonization within the lung><corpulence><death among females><death among women><death in females><death in women><death rate among women><death rate in women><diet intervention><diet-associated obesity><diet-induced obesity><diet-related obesity><diets><disease onset><disorder onset><energy source><erastin><extracellular><fat metabolism><fatty acid metabolism><female death><female mortality><gamma-L-Glu-L-Cys-Gly><gamma-L-Glutamyl-L-Cysteinylglycine><glutamatergic><glutathione peroxidase><improved><improved outcome><in vivo><in vivo Model><inhibitor><interventional strategy><lesson plans><lipid metabolism><lipidomics><lung colonization><lung metastatic><malignancy><malignant breast tumor><mammary tumor><membrane structure><migration><mortality><mortality among females><mortality among women><mortality in females><mortality in women><mouse model><murine model><necrocytosis><neoplasm progression><neoplasm/cancer><neoplastic progression><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><nutrition science><ob/ob mouse><obese patients><patients with obesity><pharmacologic><post treatment><pre-clinical><preclinical><preparations><pulmonary><pulmonary colonization><pulmonary metastatic><pyruvic carboxylase><response><shRNA><short hairpin RNA><small hairpin RNA><social role><therapeutic target><transcriptome sequencing><transcriptomic sequencing><translational cancer research><transplant model><triple-negative breast cancer><triple-negative invasive breast carcinoma><tumor><tumor biomarker><tumor cell metabolism><tumor cell metastasis><tumor growth><tumor metabolism><tumor microenvironment><tumor progression><tumor specific biomarker><women's death><women's death rate>