Abstract 6048: CAF-secreted periostin promotes tumor aggressiveness in BRAF <i>-</i> mutant papillary thyroid carcinoma by upregulating MMP1

Abstract 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-1β 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-1β/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. Citation Format: ZHUORAN LIU, JINYUE LIU, JIE KUANG, WEIHUA QIU. CAF-secreted periostin promotes tumor aggressiveness in BRAF-mutant papillary thyroid carcinoma by upregulating MMP1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6048.