PROJECT SUMMARY The Arkansas Integrative Metabolic Research Center (AIMRC) is a Phase I COBRE at the University of Arkansas at Fayetteville (04/01/2021-02/28/2026; PI: Dr. Kyle P. Quinn). The scientific objective of the AIMRC is to investigate the role of cell and tissue metabolism in disease, development, and repair through research involving advanced imaging, bioenergetics, and data science. The long-term objective of the AIMRC is to establish a sustainable interdisciplinary research center that can support biomedical research at the U of A and grow the emerging strengths in metabolic research on campus. The overall goal of this supplement research is to probe the specific effects of obesity-driven altered extracellular matrix (ECM) topography in breast tumor innervation. Obesity is marked by metabolic dysregulation and a well-known comorbidity in female breast cancer. Interestingly, obese mammary adipose tissue contains significantly thicker and aligned collagen I fibers. The altered ECM topography might be crucial in driving breast tumor innervation, as neurites are known to prefer extending along aligned ECM fiber organization. A link between 1) aligned collagen and innervation, 2) innervation and tumor malignancy, 3) obesity and aligned collagen, and 4) obesity and metabolism dysregulation are well-established. However, how these factors concertedly drive breast tumor innervation remains unclear. We hypothesize that aligned collagen I fibers present in the obese breast tumor microenvironment (TME) potentiate breast tumor innervation. To test our hypothesis, we will use our in-house optimized composite hydrogels comprising decellularized white adipose tissue and collagen type I combined with a custom-designed uniaxial stretching device to align collagen I fibers. Using this platform, we will determine 1) metabolic profiles of the embedded co-cultures of adipose stromal cells and normal or malignant human mammary epithelial cells, 2) neurotrophic factor secretion from the co-cultures, and 3) neurite infiltration as an in vitro model of breast tumor innervation. Given our expertise in tissue-engineered models of the breast TME, we are confident that we can determine the specific effects of aligned collagen fibers on breast tumor innervation by means of dysregulated cellular metabolism in breast cancer. This administrative supplement award will enable us to establish this line of research by investigating obesity's effects on breast tumor innervation. In the future, we can better recapitulate obese TME, e.g., by incorporating adipocytes in the 3D cultures and procuring cells from lean and obese animals and/or patients. Notably, this research aligns with the National Cancer Institute’s interest in “fundamental mechanisms of cancer initiation, progression, and metastasis”, and the Office of Research on Women's Health’s interest in “research that addresses women’s health issues across the lifespan with an emphasis on chronic diseases and comorbidities including obesity.”

PROJECT NARRATIVE Obesity is marked by metabolic dysregulation and a well-known comorbidity in female breast cancer. Interestingly, obese mammary adipose tissue contains significantly thicker and aligned collagen I fibers, which might drive breast tumor innervation, as neurites are known to prefer extending along aligned extracellular matrix fiber organization. The overall goal of this supplement research is to probe the specific effects of obesity-driven altered extracellular matrix topography in breast tumor innervation.