POSTN+ Cancer-Associated Fibroblasts Promote Gastric Cancer Invasion by Activating AKT Signaling

Metastasis is the primary cause of death in advanced/recurrent cancer patients. Cancer metastatic capability depends not only on cancer cells but also on the cancer microenvironment, particularly cancer-associated fibroblasts (CAFs), a highly heterogeneous population. Our prior work identified a POSTN-secreting CAFs subpopulation linked to gastric cancer (GC) invasion and poor survival. The Cancer Genome Atlas analysis in GC showed POSTN association with epithelial-mesenchymal transition and extracellular matrix degradation pathways. In vitro, GC exosomes induced adipose-derived mesenchymal stem cells (MSCs) into POSTN-expressing CAFs. Lentiviral POSTN overexpression in CAFs enhanced GC cell migration/invasion, while knockdown had the opposite effect. These results were validated in a nude mouse GC model. As POSTN is an integrin ligand, POSTN-positive CAFs (POSTN+ CAFs) activated integrin downstream AKT signaling. AKT inhibition significantly diminished the pro-migratory/invasive effect of POSTN-overexpressing CAFs. In summary, POSTN+ CAFs promote GC invasion via AKT pathway activation.