Abstract 1234: Mechanical control of cancer-associated adipocyte plasticity orchestrates pancreatic cancer progression

Abstract Cancer-associated adipocytes (CAAs) are key components of the pancreatic tumor microenvironment, yet how their phenotype and function are regulated by environmental conditions remains poorly understood. Here, we demonstrate that oxygen tension and matrix stiffness dramatically alter CAA behavior and their subsequent effects on pancreatic ductal adenocarcinoma (PDAC) progression. Under normoxic conditions and soft matrix, CAAs exhibit an activated phenotype characterized by extended podia formation and enhanced secretion of matrix-degrading enzymes, particularly MMP-2 and MMP-9, leading to dissolution of organoid extracellular matrix (ECM) and restriction of PDAC cell growth through direct cell-cell contact. In contrast, when cultured within stiff ECM environments (∼30 kPa), CAAs maintain a rounded, stem cell-like morphology without matrix-degrading activity, but notably promote PDAC cell migration. Gene expression confirmed that ECM-primed CAAs revealed upregulation of stemness markers including OCT4, SOX2, and SOX9, along with enhanced expression of pro-inflammatory cytokines. Using ectopic pancreatic tumor models, we found that CAAs primed in stiff ECM significantly accelerate tumor progression and invasion compared to controls, with increased tumor volume and invasion into the muscle layer 4 weeks post-implantation. Mechanistically, stiff ECM-primed CAAs showed distinct stem cell-like phenotype and altered secretome profiles. When cocultured with PDAC cells, their crosstalk promoted increased secretion of pro-inflammatory cytokines IL-6 and TNF-α while downregulating anti-inflammatory cytokine IL-10, creating a more tumor-supportive microenvironment. IHC reveals macrophage F4/80 showed no significant difference between groups, however, CD163+ macrophages were more prevalent at the early stage in the inactivated CAA-PDAC group. These findings reveal previously unrecognized plasticity in CAA function regulated by mechanical and oxygen tension cues, suggesting that the spatial distribution of these environmental factors within pancreatic tumors may create distinct zones of tumor promotion versus restriction. Our results highlight the complex role of CAAs in PDAC progression and suggest that targeting ECM stiffness could be a strategy to modify CAA behavior for therapeutic benefit. Understanding this mechanical control of CAA function could lead to novel therapeutic strategies for PDAC treatment. Citation Format: Bo Han, Zhi Yang, Shuqing Zhao, Thomas Schmittgen, Jamel Ali, Jonathan Barajas, Carolyn Ruiz-Rivera, Ba Xuan Hoang. Mechanical control of cancer-associated adipocyte plasticity orchestrates pancreatic cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1234.