Elucidating the Mechanisms of Adipose Tissuederived Signaling and Microenvironmental Remodeling in Obesity-related Cancer

Abstract

Obesity is a well-established risk factor for multiple malignancies, particularly hormone- responsive cancers such as breast and endometrial cancers. Beyond systemic metabolic alterations, obesity profoundly affects the tumor microenvironment (TME) through inflammation, extracellular matrix (ECM) remodeling, and altered adipokine secretion. These changes transform adipose tissue from a passive energy reservoir into an active endocrine organ that modulates tumor behavior. However, the molecular mediators that connect adipose dysfunction to tumor progression remain incompletely defined. This dissertation investigates two representative adipose-derived factors—FAM3C and Endotrophin (ETP)—and delineates how they remodel the TME to promote obesity-associated cancer progression. In the first part, I examined how cancer-associated adipocytes (CAAs) acquire tumor- promoting properties in the breast cancer (BC) microenvironment. When exposed to tumor-derived cues, adipocytes underwent phenotypic changes accompanied by loss of lipid content, induction of inflammatory and fibrotic markers, and increased expression of FAM3C, a cytokine-like secreted protein. Analysis of BC tissues revealed that FAM3C expression was elevated in tumor-adjacent adipose regions, correlating with poor outcomes. Functional assays demonstrated that adipocyte-derived FAM3C enhanced BC cell survival, migration, and epithelial–mesenchymal transition (EMT) through paracrine signaling. These findings indicate that FAM3C acts as a key mediator that facilitates the crosstalk between adipocytes and cancer cells, reinforcing a microenvironment favorable for tumor progression. Furthermore, the data suggest that tumor-secreted factors, such as transforming growth factor-beta (TGF-β), stimulate FAM3C production in adipocytes, establishing a feed-forward signaling loop that amplifies adipose–tumor communication within the TME. The second part of this dissertation focused on ETP, the C-terminal cleavage fragment of collagen VI α3 (COL6A3), as a critical mediator linking obesity to endometrial cancer (EC) progression. Analysis of mouse endometrial tissues revealed that obesity was associated with increased expression and accumulation of ETP. Elevated ETP levels correlated with enhanced activation of oncogenic signaling pathways, particularly the WNT and estrogen receptor (ER) pathways, which are key drivers of endometrial tumorigenesis. Experimental models demonstrated that ETP overexpression in the endometrium promoted cancer proliferation and activation of WNT and ER signaling, supporting a tumor-promoting phenotype in obesity-related contexts. Together, these results indicate that ETP serves as a key intermediary between obesity-induced extracellular matrix dysregulation and oncogenic signaling activation in the endometrial microenvironment. By elucidating the roles of FAM3C and ETP, this dissertation provides a comprehensive perspective on how obesity-driven alterations in adipose tissue reshape the tumor microenvironment to promote cancer progression. FAM3C-mediated paracrine signaling enhances epithelial plasticity and survival, while ETP-mediated activation of WNT and estrogen receptor pathways fosters hormone- dependent tumor growth. Together, these findings demonstrate that metabolic dysfunction in obesity extends beyond systemic effects to actively influence local signaling networks that sustain malignancy. This work advances our understanding of the molecular links between adipose biology and cancer and underscores the importance of targeting adipose-derived mediators and their downstream pathways as potential therapeutic strategies for obesity-associated cancers.