Obesity-Driven Tumor Resistance: Role of Hypertrophic Adipocytes and Metabolic Stress

Adipose tissue plays a crucial role in regulating critical biological processes. Dysfunctional adipose tissue observed in obesity fosters a tumor-promoting microenvironment through the release of pro-inflammatory factors and metabolic alterations. These changes enhance the proliferation and migration of tumor cells, as well as their resistance to therapies. This study aims to characterize the interaction model between hypertrophic adipocytes and colon tumor cells. A secondary goal is to evaluate their resistance to antineoplastic drugs such as irinotecan and 5-fluorouracil.

A co-culture model was established between HCT-116 colon tumor cells and mature and hypertrophic adipocytes derived from SGBS preadipocytes. Migration and lipid metabolism were assessed via a Western blot analysis of key proteins, including fibronectin, CPT1, FABP4, pAKT, mTOR, and PPARγ. Reactive oxygen species (ROS) levels were measured, and the mitochondrial metabolic activity in tumor cells was evaluated using a Seahorse analyzer. Additionally, drug resistance was analyzed using cell viability assays and IC50 determination, including the effect of conditioned media (CM) from hypertrophic adipocytes. The impact of CM on the tumor cell cycle was measured with flow cytometry.

The HCT-116 cells co-cultured with hypertrophic adipocytes exhibited morphological and metabolic changes, including spheroid formation and the overexpression of CPT1, pAKT, and mTOR, suggesting increased reliance on fatty acids as an energy source. Tumor cells exposed to CM showed reduced oxidative phosphorylation, consistent with metabolic reprogramming, along with significantly elevated ROS levels. CM exposure also significantly increased resistance to irinotecan and 5-fluorouracil, reflected by higher IC50 values. Furthermore, the CM-treated cells showed a significant arrest in the G0/G1 phase of the cell cycle, potentially linked to the activation of survival pathways. Furthermore, in silico docking was also developed, aiming to identify inhibitors of key metabolic and survival pathways, paving the way for novel therapeutic strategies targeting the adipose–tumor axis in obesity-related cancers.