2. Academic Validation
  3. Matrix stiffness drives squamous cell carcinoma progression via a Piezo1-mediated mechanotransduction feedback loop

Matrix stiffness drives squamous cell carcinoma progression via a Piezo1-mediated mechanotransduction feedback loop

  • J Adv Res. 2025 Oct 26:S2090-1232(25)00836-7. doi: 10.1016/j.jare.2025.10.041.
Zixi Jiang 1,  Yantao Xu 2,  Ying Wang 3,  Zhuxin Dong 4,  Wenjihao Hu 5,  Juan Su 3,  Lisha Wu 3,  Yi He 3,  Lin Zhu 3,  Dan Jian 6,  Jia-Chen Liu 7,  Hui Li 8,  Zeyu Chen 9,  Xiang Chen 10,  Shuang Zhao 11
Affiliations

Affiliations

  • 1 Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, China; National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Xiangya Hospital, Central South University, Changsha 410008, China; Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha 410008, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha 410008, China; Department of Dermatology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China.
  • 2 Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, China; National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Xiangya Hospital, Central South University, Changsha 410008, China; Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha 410008, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha 410008, China; Department of Dermatology, the Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China.
  • 3 Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, China; National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Xiangya Hospital, Central South University, Changsha 410008, China; Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha 410008, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha 410008, China; National Clinical Research Center of Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China; Furong Laboratory (Precision Medicine), Changsha 410008, China.
  • 4 Furong Laboratory (Precision Medicine), Changsha 410008, China; Department of Biomedical Engineering, School of Basic Medical Sciences, Central South University, Changsha 410013, China.
  • 5 Furong Laboratory (Precision Medicine), Changsha 410008, China; School of Minerals Processing and Bioengineering, Central South University, Changsha 410083, China.
  • 6 Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, China; National Clinical Research Center of Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China; Hunan Key Laboratory of Aging Biology, Xiangya Hospital, Central South University, Changsha 410008, China.
  • 7 Washington University School of Medicine, St Louis, MO 63110, USA.
  • 8 Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, China; National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Xiangya Hospital, Central South University, Changsha 410008, China; Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha 410008, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha 410008, China; National Clinical Research Center of Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China; Furong Laboratory (Precision Medicine), Changsha 410008, China. Electronic address: lihuiscience@163.com.
  • 9 Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, China; National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Xiangya Hospital, Central South University, Changsha 410008, China; Furong Laboratory (Precision Medicine), Changsha 410008, China; School of Mechanical and Electrical Engineering, Central South University, Changsha 410083, China. Electronic address: zeyuchen@csu.edu.cn.
  • 10 Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, China; National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Xiangya Hospital, Central South University, Changsha 410008, China; Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha 410008, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha 410008, China; National Clinical Research Center of Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China; Furong Laboratory (Precision Medicine), Changsha 410008, China. Electronic address: chenxiangck@126.com.
  • 11 Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, China; National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Xiangya Hospital, Central South University, Changsha 410008, China; Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha 410008, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha 410008, China; National Clinical Research Center of Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China; Furong Laboratory (Precision Medicine), Changsha 410008, China. Electronic address: shuangxy@csu.edu.cn.
PMID: 41151627 DOI: 10.1016/j.jare.2025.10.041
Abstract

Introduction: Squamous cell carcinoma (SCC) is one of the most frequent solid tumor accounting for more than one million Cancer deaths annually. Emerging evidence highlights the critical role of mechanical signaling in tumor progression, yet the mechanobiological interplay between extracellular matrix (ECM) stiffness and SCC pathogenesis remains poorly understood.

Objectives: This study aimed to investigate how matrix stiffness drives SCC progression via Piezo1-mediated mechanotransduction and its clinical implications.

Methods: Atomic force microscopy quantified tissue stiffness in human cutaneous, oral, and lung SCC samples. Spatial transcriptomics and single-cell RNA Sequencing (scRNA-seq) analyzed ECM- and mechanoreceptor-related gene expression. In vitro models using tunable-stiffness gels assessed SCC cell proliferation, invasion, and Piezo1/YAP activity. Xenograft models evaluated Piezo1's role in tumor growth and stiffness regulation. Clinical correlation studies analyzed Piezo1 expression and outcomes in a cutaneous SCC cohort (n = 53).

Results: SCC tissues exhibited elevated stiffness compared to adjacent normal tissues. Stiff matrices activated Piezo1, promoting proliferation and invasion in SCC cells via a non-canonical Hippo pathway involving RCC2. Piezo1 knockdown reduced tumor growth and stiffness in vivo. Mechanistically, Piezo1 activation induced TGFβ1 secretion, driving fibroblast-to-myofibroblast transition and Collagen deposition, thereby reinforcing matrix stiffness. Clinically, high Piezo1 expression correlated with poor differentiation (p = 0.0034), recurrence (p = 0.047), and shorter disease-free survival (HR = 181.03, p = 0.01).

Conclusions: This study identifies a self-reinforcing Piezo1-RCC2-YAP axis that translates mechanical cues into pro-tumorigenic signaling, fostering fibroblast-mediated ECM remodeling. Piezo1 emerges as a prognostic biomarker and therapeutic target to disrupt stiffness-driven SCC progression.

Keywords

Fibroblasts; Piezo1; RCC2; Squamous cell carcinoma; Stiffness; YAP.

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