Li Xiang, Zhao Hui, Jiang Erhui, Liu Pan, Chen Yang, Wang Yue, Li Ji, Wu Yufei, Liu Zhenan, Shang Zhengjun
State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China.
Department of Oral and Maxillofacial-Head and Neck Oncology, School of Stomatology-Hospital of Stomatology, Wuhan University, Wuhan, China.
Oncogene. 2025 Jun;44(20):1530-1544. doi: 10.1038/s41388-025-03317-z. Epub 2025 Mar 5.
Cancer stem cells (CSCs) contribute to chemotherapy resistance and poor prognosis, posing significant challenges in the treatment of oral squamous cell carcinoma. The extracellular matrix (ECM)-constructed microenvironment remodels the niche of CSCs. Yet mechanisms by which biophysical properties of ECM relate to CSCs remain undefined. Here, our findings link ECM mechanical stimuli to CSCs phenotype transition, and propose that ECM stiffening mechanoactivates tumor cells to dedifferentiate and acquire CD44 stem cell-like characteristics through noncanonical mechanotransduction. ITGB1 senses and transduces biomechanical signals, while FERMT1 acts as an intracellular mechanotransduction downstream, activating CSCs. Mechanistically, FERMT1 promotes the proteasomal degradation of CK1α by E3 ubiquitin ligase MIB1, thereby triggering Wnt signaling pathway. Combining targeted ECM softening with mechanotransduction inhibition strategy significantly attenuates tumor stemness and chemoresistance in vivo. Therefore, our findings highlight the role of ECM in regulating CSCs via biomechanical-dependent manner, suggesting the ECM/ITGB1/FERMT1/Wnt axis as a promising therapeutic target for CSCs therapy.
癌症干细胞（CSCs）导致化疗耐药和预后不良，给口腔鳞状细胞癌的治疗带来了重大挑战。细胞外基质（ECM）构建的微环境重塑了CSCs的生态位。然而，ECM的生物物理特性与CSCs相关的机制仍不明确。在此，我们的研究结果将ECM机械刺激与CSCs表型转变联系起来，并提出ECM硬化通过非经典机械转导机制激活肿瘤细胞去分化并获得CD44干细胞样特征。整合素β1（ITGB1）感知并转导生物力学信号，而FERMT1作为下游的细胞内机械转导因子，激活CSCs。机制上，FERMT1促进E3泛素连接酶MIB1介导的酪蛋白激酶1α（CK1α）的蛋白酶体降解，从而触发Wnt信号通路。将靶向ECM软化与机械转导抑制策略相结合可显著减弱体内肿瘤干性和化疗耐药性。因此，我们的研究结果突出了ECM通过生物力学依赖方式调节CSCs的作用，表明ECM/ITGB1/FERMT1/Wnt轴是CSCs治疗的一个有前景的治疗靶点。
