Cancer-associated fibroblast-derived periostin promotes papillary thyroid tumor growth through integrin-FAK-STAT3 signaling

Background: Periostin (POSTN) is a critical extracellular matrix protein in various tumor microenvironments. However, the function of POSTN in thyroid cancer progression remains largely unknown. Methods: Postn and Rag1 knock -out mice and orthotopic mouse models were used to determine the role of POSTN on papillary thyroid tumor progression. Immunofluorescence, cell co -culture, fluorescence in situ hybridization, chromatin immunoprecipitation assay, recombinant protein and inhibitor treatment were performed to explore the underlying mechanisms of POSTN-promoted papillary thyroid tumor growth. Results: POSTN is up -regulated in papillary thyroid tumors and negatively correlates with the overall survival of patients with thyroid cancer. Cancer -associated fibroblast (CAF) -derived POSTN promotes papillary thyroid tumor growth in vivo and in vitro . POSTN deficiency in CAFs significantly impairs CAF -promoted papillary thyroid tumor growth. POSTN promotes papillary thyroid tumor cell proliferation and IL -4 expression through integrin-FAK-STAT3 signaling. In turn, tumor cell -derived IL -4 induces the activation of CAFs and stimulates POSTN expression by activating STATE. We reveal the crucial role of CAF -derived POSTN and tumor cell -derived IL -4 in driving the development of papillary thyroid tumors through the POSTN-integrin-FAK-STAT3-IL-4 pathway in tumor cells and IL-4-STATE-POSTN signaling in CAFs. Conclusion: Our findings underscore the significance of POSTN and IL -4 as critical molecular mediators in the dynamic interplay between CAFs and tumor cells, ultimately supporting the growth of papillary thyroid tumors.