The mechanistic study of cancer-associated adipocytes promoting colorectal cancer peritoneal metastasis via FKBP5/UCP1-mediated lipid metabolism reprogramming.

Abstract

178 Background: Colorectal cancer (CRC) is a prevalent malignant tumor globally, with peritoneal metastasis as a significant late-stage dissemination pathway, severely impacting patient prognosis. Recent research increasingly suggests the critical role of lipid metabolism within the tumor microenvironment in tumor progression. Cancer associated adipocytes (CAAs), a vital component, contribute to tumor progression, yet the exact molecular mechanisms remain unclear. We aim to explore the role of CAAs in CRC peritoneal metastasis and their specific regulatory mechanisms. Methods: In this study, we analyzed clinical samples from 312 CRC patients to assess the expression levels of FKBP5 and UCP1 proteins in tumor-adjacent tissues. Purified exosomes from co-cultured adipocytes and tumor cells, along with exosomes from ordinary tumor cells, underwent miRNA profiling via sequencing to evaluate exosomal miR-200a-3p expression. We established FKBP5 stable knockdown (FKBP5-/-) transgenic mouse models, organotypic co-culture models, and patient-derived xenograft (PDX) models. Through experiments involving metabolomics, mass spectrometry, immunoprecipitation, western blotting, and qPCR, we investigated the role of the miR-200a-3p/FKBP5/PPARγ/UCP1 signaling pathway in CAAs in CRC peritoneal metastasis. Results: After co-culturing adipocytes and tumor cells, we observed brown adipocyte differentiation, resulting in significant downregulation of FKBP5 protein expression. FKBP5 exhibited a strong association with UCP1 expression. Tumor cells highly expressed miR-200a-3p, released via exosomes into the tumor microenvironment and internalized by adipocytes. Within adipocytes, miR-200a-3p orchestrated metabolic reprogramming via the FKBP5/PPARγ/UCP1 pathway, inducing brown adipocyte differentiation, generating CAAs. CAAs released FFAs, promoting tumor peritoneal metastasis by activating tumor cell surface G-protein coupled receptors (GPCRs). Conversely, miR-200a-3p inhibition in tumor cells yielded opposing effects. In a spontaneous mouse model of colorectal cancer using azoxymethane (AOM)/dextran sulfate sodium salt (DSS), FKBP5-/- mice exhibited increased brown adipocyte content in the tumor microenvironment, along with notably higher spontaneous colorectal tumor numbers and sizes compared to wild-type mice. Conclusions: This study elucidates the pivotal role of CAAs in the peritoneal metastasis of CRC, confirming the regulatory role of the FKBP5/UCP1 pathway-mediated lipid metabolism reprogramming in this process. These findings offer a fresh perspective for further exploration of the molecular mechanisms underlying CRC peritoneal metastasis, and provide a theoretical foundation for the identification of novel therapeutic targets.