CAF-secreted periostin promotes tumor aggressiveness in BRAF - mutant papillary thyroid carcinoma by upregulating MMP1

Papillary thyroid carcinoma (PTC) harboring the BRAF V600E mutation sometimes demonstrates higher invasiveness and an increased risk of metastasis; however, the underlying mechanisms are not fully elucidated. Cancer-associated fibroblasts (CAFs) are key components of the tumor microenvironment. This study aims to investigate the role and molecular mechanisms of CAFs in promoting invasiveness in BRAF -mutant PTC. Bioinformatic analysis suggested that high expression of the stromal protein periostin ( POSTN ) is associated with poor prognosis in BRAF V600E-mutant PTC. We demonstrated that the BRAF mutation, via activating the MAPK signaling pathway, promotes the secretion of IL-1beta by PTC cells, which stimulates CAFs to express POSTN . Functional assays further revealed that CAF-secreted POSTN significantly enhances the migration and invasion capabilities of PTC cells by upregulating matrix metalloproteinase-1 (MMP1). Animal experiments further confirmed that the combination of a BRAF inhibitor (encorafenib) with knockdown of POSTN in CAFs most effectively suppressed lung metastasis of PTC and prolonged mouse survival.​ This study uncovers a novel signaling axi- BRAF mutation/IL-1beta/CAFs/ POSTN / MMP1 -that plays a critical role in enhancing the aggressiveness of PTC. Thus, a combined therapeutic strategy targeting BRAF and inhibiting CAF-secreted POSTN represents a promising strategy to improve the prognosis of aggressive BRAF -mutant PTC.