Fibroblast-derived POSTN promotes colorectal cancer progression under high-fat diet by reprogramming fatty acid metabolism in tumor cell

Abnormal expression of POSTN is closely related to the development of cancer, especially in colorectal cancer (CRC). However, the effects and mechanisms of POSTN on CRC progression under high-fat diet (HFD) have not been thoroughly studied. The effect of POSTN on HFD-induced CRC was evaluated in vitro and in vivo, and the dynamic changes of different lipid metabolizing enzyme expression were analyzed. Molecular and biological experiments have revealed the underlying mechanisms of POSTN regulating the production of fat accumulation and fatty acid oxidation (FAO) dysregulation. POSTN expression was significantly increased in CRC patients, and was correlated with clinical poor prognosis, mainly derived from myCAF. Deletion of fibroblast-derived POSTN inhibits CRC progression under HFD. Mechanistically, fibroblast-derived POSTN promotes the expression of SREBP1 in tumor cells by regulating the AKT signaling pathway, thereby promoting fatty acid (FA) synthesis. At the same time, fibroblast-derived POSTN inhibits the activity of FAO-related enzyme CPT1A in tumor cells through the ERK signaling pathway, thus inhibiting the FAO process. In addition, we found that CD51 (POSTN receptor) inhibitor Cilengitide effectively inhibits abnormal proliferation of CRC cells, thereby inhibiting tumor development in the HFD environment.