Objectives: Dormancy is a crucial machinery for cancer cells to survive hostile microenvironment. It is considered as the major cause of post-treatment relapse and metastases. However, its regulatory mechanism in oral squamous cell carcinoma (OSCC) remains unclear. Here we sought to decipher the impacts of matrix stiffness on OSCC-cell dormancy. Materials and methods: Clinicopathological relevance of matrix stiffness in OSCC was analyzed in a 127 patients’ cohort. Impacts of stiffness-related mechanical stress (MS) on OSCC-cell behaviors were investigated in vitro and in vivo. Transcriptomic profiling of MS induced dormant cells were performed, following by mechanistic investigations on MS-induced dormancy. The functional relevance of cGAS in OSCC were analyzed through a bioinformatic approach. Results: Stiffened matrix correlated with poor survival and post-surgical recurrence in OSCC. Stiffness-related MS induces a dormant subpopulation in OSCC cells, which showed increased drug resistance, enhanced tumor repopulating ability, and an unexpected upregulation of epithelial-mesenchymal transition (EMT) and invasiveness. Mechanistically, MS caused DNA damage, resulted in activation of cGAS-STING signaling. Either blocking of cGAS or STING dramatically impeded the MS-induced production of this invasive-dormant subpopulation. Moreover, cGAS was found being central to the cell-cycle regulation and correlated with poor prognosis in OSCC. Discussion: We revealed a previously unsuspected role of cGAS-STING axis in mediating the induction of an invasive-dormant subpopulation in response to mechanical cues. Our findings indicated an adaptive machinery whereby tumor cells survive and escape from harsh microenvironment. Targeting this machinery may be a potential strategy for preventing post-therapeutic recurrence and lymphatic metastasis in OSCC.
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