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Matrix stiffness induces an invasive-dormant subpopulation via cGAS-STING axis in oral cancer
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 imp...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Neoplasia Press
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10165441/ https://www.ncbi.nlm.nih.gov/pubmed/37137218 http://dx.doi.org/10.1016/j.tranon.2023.101681 |
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author | Jingyuan, Li Yu, Liu Hong, Jiang Tao, Wang Kan, Li Xiaomei, Lao Guiqing, Liao Yujie, Liang |
author_facet | Jingyuan, Li Yu, Liu Hong, Jiang Tao, Wang Kan, Li Xiaomei, Lao Guiqing, Liao Yujie, Liang |
author_sort | Jingyuan, Li |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-10165441 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Neoplasia Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-101654412023-05-09 Matrix stiffness induces an invasive-dormant subpopulation via cGAS-STING axis in oral cancer Jingyuan, Li Yu, Liu Hong, Jiang Tao, Wang Kan, Li Xiaomei, Lao Guiqing, Liao Yujie, Liang Transl Oncol Original Research 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. Neoplasia Press 2023-05-01 /pmc/articles/PMC10165441/ /pubmed/37137218 http://dx.doi.org/10.1016/j.tranon.2023.101681 Text en © 2023 Published by Elsevier Inc. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Original Research Jingyuan, Li Yu, Liu Hong, Jiang Tao, Wang Kan, Li Xiaomei, Lao Guiqing, Liao Yujie, Liang Matrix stiffness induces an invasive-dormant subpopulation via cGAS-STING axis in oral cancer |
title | Matrix stiffness induces an invasive-dormant subpopulation via cGAS-STING axis in oral cancer |
title_full | Matrix stiffness induces an invasive-dormant subpopulation via cGAS-STING axis in oral cancer |
title_fullStr | Matrix stiffness induces an invasive-dormant subpopulation via cGAS-STING axis in oral cancer |
title_full_unstemmed | Matrix stiffness induces an invasive-dormant subpopulation via cGAS-STING axis in oral cancer |
title_short | Matrix stiffness induces an invasive-dormant subpopulation via cGAS-STING axis in oral cancer |
title_sort | matrix stiffness induces an invasive-dormant subpopulation via cgas-sting axis in oral cancer |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10165441/ https://www.ncbi.nlm.nih.gov/pubmed/37137218 http://dx.doi.org/10.1016/j.tranon.2023.101681 |
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