Adipose-tumor crosstalk in colorectal cancer: Identifying (Epi)genetic biomarkers for tumor progression and cachexia.

Colorectal cancer (CRC) is a leading cause of cancer-related deaths and obesity is a known risk factor for its development and poor prognosis. Adipose tissue (AT) actively contributes to CRC progression and cachexia. Here, we investigated molecular crosstalk between tumor cells and different visceral AT depots (normal, intra- and peri-tumoral), focusing on metabolic and (epi)genetic alterations. Using WGS analysis, we explored VAT role in CRC progression, demonstrating how its proximity to the tumor impacts metabolic and phenotypic changes. Intra-VAT (within 5 cm of lesion), closest to the tumor, underwent significant metabolic remodeling, characterized by upregulation of markers of the white-brown AT transition (UCP-1, TMEM26), lipid metabolism (PON3) and a reduction in adipocyte turnover (Pref-1, adiponectin). Peri-VAT (within 15 cm) and HVAT (over 15 cm) exhibited progressively fewer alterations, suggesting a gradient effect of tumor on surrounding AT. Intra-VAT displayed increased fibrosis (TGF-β, collagen) and cachexia-related markers (IL-8), and mutations in key oncogenes (KRAS, HLA, MET), highlighting a direct interaction between tumor cells and AT driving CRC progression. Mutations in genes such as KRAS, HLA, and PIK3CA were shared between CRC and its Intra-VAT, indicating potential biomarkers for tumor progression and immune evasion. miRNA analysis revealed upregulation of miR-21 and miR-92a in Intra-VAT, with circulating miR-92a correlating with increased body fat and decreased lean mass in CRC patients, suggesting their involvement in both local metabolic remodeling and systemic changes. Altered PON3 DNA methylation patterns were also observed, correlating with metabolic parameters. Our findings underscore AT's critical role in the CRC microenvironment as an active player in CRC progression and cachexia. Metabolic and genetic alterations decreased in VAT with increasing distance from the tumor. Intra-VAT may serve as a critical therapeutic target and biomarker for CRC progression, impacting surgical and postoperative strategies. Future studies should focus on targeting tumor-adipose crosstalk to improve treatment outcomes, including experimental validation of the identified genetic alterations and investigation of their functional roles in tumor progression and immune evasion.