Novel Kinase Inhibitors Library Screen Differentially Impacts Adipose Stem Cells (ASCs) from Lean and Obese Donors

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2022

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Rinderle, Caroline

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Purpose: Breast cancer is the second leading cause of death among women in the United States. Obesity increases the risk of developing breast cancer and ultimately leads to poorer outcomes. Obesity is defined as the excess accumulation of adipose tissue, evidenced by a BMI of 30 kg/m² or greater. Adipose tissue consists primarily of adipocytes, but the stromal vascular fraction (SVF) consists of numerous other cell types as well, including adipose-derived stem cells (ASCs). ASCs are self-renewing, multipotent, mesenchymal stem cells that have been intensely studied for their role in regenerative medicine. Our lab has shown that ASCs extracted from obese patients are recruited to breast tumors more than ASCs extracted from lean patients. This made breast cancer outcomes worse in our xenograft models, indicating a connection between ASCs in obesity and breast cancer. These changes in cancer behavior may be due to the activity of important protein kinases. Kinases are essential to cellular function, activating necessary proteins to propagate signal cascades, without which survival would be impossible. Little is known about the 538 kinases encoded in the human genome, and therefore, they need to be researched more thoroughly. If the obese ASC-breast tumor crosstalk can be interrupted via prevention of specific kinase activity, then poor breast cancer outcomes may be prevented and novel therapeutics can be uncovered. Methods: Pools of ASCs from lean and obese donors were treated 100nM of KCGS Drug Library kinase inhibitors obtained from Dr. David Drewry at the SGC at UNC Chapel Hill. After 72 hours, cells were stained with crystal violet and imaged for cellular viability and morphologic changes. Results: Fifteen kinase inhibitor drugs affected ASCs from both lean and obese donors. Nine kinase inhibitor drugs affected ASCs from obese donors only. No kinase inhibitors affected ASCs from lean donors alone. Conclusions: Obesity changes the biology of ASCs in a way that can potentially be therapeutically targeted. In the future, testing the ability of ASCs to differentiate into mature adipocytes after treatment with kinase inhibitors will give greater insight into the role specific kinases play in the biology of an obese patient. We will also study the roles of the kinase inhibitors and kinases in the biology of ASCs more thoroughly.

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