Keratin intermediate filament is one major cytoskeleton architecture in epithelial cells, providing necessary mechanical support to maintain cell shape and tissue integrity. In a previous study, we discovered the existence of a novel K6-K14 keratin fusion variant (K6-K14/V7) in oral squamous cell carcinoma (OSCC) cells which can promote cancer stemness and aggressiveness. However, the underlying mechanism remains to be elucidated. Here, we report that overexpression of K6-K14/V7 in OSCC cells can influence the mechanical properties of the cells, leading to cell protrusion and enhanced extracellular vesicle (EV) secretion. Consequently, the expression levels of inflammatory cytokines (e.g. IL-6, TGF-[[Unsupported Character - Symbol Font β]]) in the culture medium can be also increased. Normal oral fibroblast cells co-cultured with K6-K14/V7-expressing OSCC cells can be converted into a pro-inflammatory type of cancer-associated fibroblasts (iCAFs). Those findings suggest the ability of K6-K14/V7-expressing OSCC cells in remodeling tumor microenvironment. In this study, we will discuss how K6-K14/V7-expressing OSCC cells educate iCAFs to promote cancer cell migration and invasion via intercellular communication by EVs. The key signaling cascades and the associated regulatory networks will be also discussed. Our study, therefore, uncovers the pro-tumorigenic functionality of K6-K14/V7 by creating an inflammatory tumor microenvironment. Citation Format: Brian Yu-Ting Kuo, Yen-Ting Lin, Senthilkumar Ravichandran, Jim Jinn-Chyuan Sheu. K6-K14 keratin fusion variant (K6-K14/V7) in OSCC cells promotes tumor microenvironment remodeling through activating inflammatory CAFs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6101.

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