Cytoskeleton reorganization induced by a novel K6-K14 keratin fusion promotes cancer stemness and cellular plasticity via cGAS-STING selection

Abstract Cytoskeletal network dynamics play important roles in regulating cellular functions. Although alterations in cytoskeleton-related genes are frequently detected, limited attention has been paid to their roles in cancer development. A novel keratin fusion variant, K6-K14/V5, was previously identified in head and neck squamous cell carcinoma, and its expression led to catastrophic nuclear collapse, resulting in DNA breaks and cGAS-STING activation. Such cell-killing effects can trigger autophagy induction, which, in turn, promotes cancer cell evolution/clonal selection in a dormant state. Furthermore, due to the disrupted cellular architecture and the loss of mechanosensing, these dormant cells could only survive and adapt within a softer microenvironment, such as collagen gel. Upregulation of the partial epithelial-mesenchymal transition program by cytoskeleton reorganization was defined as a key step for these dormant cells to reactivate and regain their mechanical properties. Striking cell protrusions and increased MMPs were observed in the reactivated cells, facilitating interactions with the surrounding extracellular matrix and enhancing their invasive potential. Elevated extracellular vesicles were also found in the reactivated cells, which actively stimulated tumor growth via the FGF-FGFR axis. Our study offers a model for understanding how genetic alterations in cytoskeletal genes can directly contribute to cancer development and drive cancer evolution.