Obesity modifies cell fate plasticity of Pdgfrα-expressing mammary adipocyte progenitors to promote an aberrant mammary microenvironment

Abstract

Excess fat gain culminating in obesity is a mounting global pandemic associated with a myriad of diseases including a higher risk of developing multiple cancers such as breast cancer. The underlying biological basis for obesity-linked breast cancer is attributed to alterations in adipose tissue-derived endocrine, metabolic and inflammatory factors. However, the precise cell types responsible for generating a cancer-susceptible mammary gland in obesity are not well understood. Using diet-induced obesity in conjunction with genetic reporter mouse models, we reveal elevated mammary adipocyte progenitors (MAPs) expressing Platelet-Derived Growth Factor Receptor alpha (PDGFR) in the mammary tissue microenvironment during obesity. Single-cell RNA sequencing analysis demonstrate intensified obesity-driven trajectories of MAPs to immune and epithelial progenitor cells. Further, lineage tracing indicates an invasive cellular state of MAPs that confers greater access of MAP descendants into the mammary epithelium concomitant with their transition into immune and epithelial cell fates. MAPs in obesity exhibit heightened activation of cancer-associated and inflammatory pathways where Egfr is identified as a common target upregulated in MAPs. Mechanistic studies on purified MAPs with a major obesity diet component and EGFR stimulation corroborate dynamic EGFR-mediated MAP responses. Our findings uncover MAPs as key contributors to forging an aberrant mammary gland in obesity, providing insight into the potential utility of targeting this cell lineage for eradicating cancer risk related to augmented adiposity.