2. Academic Validation
  3. Matrix stiffness induces an invasive-dormant subpopulation via cGAS-STING axis in oral cancer

Matrix stiffness induces an invasive-dormant subpopulation via cGAS-STING axis in oral cancer

  • Transl Oncol. 2023 May 1;33:101681. doi: 10.1016/j.tranon.2023.101681.
Li Jingyuan 1,  Liu Yu 1,  Jiang Hong 1,  Wang Tao 1,  Li Kan 1,  Lao Xiaomei 1,  Liao Guiqing 2,  Liang Yujie 3
Affiliations

Affiliations

  • 1 Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China; Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China.
  • 2 Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China; Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China. Electronic address: liaogq@mail.sysu.edu.cn.
  • 3 Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China; Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China. Electronic address: liangyj35@mail.sysu.edu.cn.
PMID: 37137218 DOI: 10.1016/j.tranon.2023.101681
Abstract

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.

Keywords

Dormancy; Epithelial-mesenchymal transition (EMT); Matrix stiffness; Oral squamous cell carcinoma (OSCC); cGAS-STING.

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