# Obesity, Metabolism and Breast Cancer Metastasis

> **NIH NIH R01** · PURDUE UNIVERSITY · 2021 · $116,581

## Abstract

Obesity, metabolic reprogramming, and breast cancer metastasis: Role of extracellular vesicles
Abstract
Obesity increases the risk of triple-negative breast cancer(TNBC) and its progression to metastasis. Considering
that only ~ 27% of the subjects survive past 5 years when the disease has metastasized, it is critical to
understand howobesity-associated changes in body composition and metabolic homeostasis are transducedby
the cancer cells and distant organs. In obesity, the hypertrophic and metabolically reprogrammed adipose tissue
secretes high amounts of extracellular vesicles (EVs). In cancer biology, EVs are gaining increasing interest due
to their ability to impact the recipient cells' cellular programming by delivering functional molecules, including
nucleic acids, proteins, lipids, and metabolites. The internalization of EVs' cargo contributes to the epithelial-to-
mesenchymal (EMT) transformation of the recipient cell and the metastatic niche formation. To mitigate
metastatic potential induced by obesity and increase therapeutic response in obese women, it is crucial to
understand the effects of EVs-derived from the obese tumor microenvironment (TME) and their contribution to
metabolic reprogramming and metastatic progression, locally and in distant organs. In this proposal, we
hypothesize that EVs derived from obese versus normoweight mice regulate PC activity promoting
metabolic reprogramming and metastasis. To test this hypothesis, we will use a mouse model of obesity and
TNBC to determine the impact of EVs isolated from a mouse model of obesity and TNBC on PC activity, tumor
metabolism, and activation of EMT. EVs will be isolated from serum, tumor, and adipose tissue. The PC content
of EVs will be screened by targeted proteomics and RNAseq. Tumor cells, MetMwntlung and 4T1, and normal
fibroblasts will be cultured and exposed to isolated EVs. The impact of EVs treatment on the expression of PC
and EMT mediators will be measured by qPCR. The metabolic substrate dependency will be determined by
isotope labeling analysis using GC-MS, and mitochondrial function will be determined by Seahorse metabolic
flux analysis and respirometry. The epithelial/mesenchymal phenotype will be evaluated by
immunohistochemistry and immunofluorescence using a panel of monoclonal antibodies against established
EMT-related proteins. This research will elucidate the role of EVs in the crosstalk between obesity, cancer
metabolism, and TNBC metastasis. The results from these studies will lead to the identification of mechanistic
targets and intervention strategies to reduce the burden of obesity in women with TNBC.

## Key facts

- **NIH application ID:** 10381300
- **Project number:** 3R01CA232589-03S1
- **Recipient organization:** PURDUE UNIVERSITY
- **Principal Investigator:** Stephen D Hursting
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $116,581
- **Award type:** 3
- **Project period:** 2021-06-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10381300

## Citation

> US National Institutes of Health, RePORTER application 10381300, Obesity, Metabolism and Breast Cancer Metastasis (3R01CA232589-03S1). Retrieved via AI Analytics 2026-06-25 from https://api.ai-analytics.org/grant/nih/10381300. Licensed CC0.

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