Feng Xueyan, Zhang Di, Wang Guoxun, Lu Liwei, Feng Feng, Wang Xiuyu, Yu Chanchan, Chai Yahong, Zhang Jin, Li Wenchao, Liu Jing, Sun Hongxia, Yao Li
State Key Laboratory for Structural Chemistry of Unstable and Stable Species, Institute of Chemistry, CAS Research/Education Center for Excellence in Molecular Sciences, Chinese Academy of Science, Beijing, 100190, P. R. China.
University of Chinese Academy of Sciences, Beijing, 100049, P. R. China.
Adv Sci (Weinh). 2025 Jun;12(22):e2417805. doi: 10.1002/advs.202417805. Epub 2025 Apr 24.
Chemotherapy remains a prevalent strategy in cancer therapy; however, the emergence of drug resistance poses a considerable challenge to its efficacy. Most drug resistance arises from the accumulation of genetic mutations in a minority of resistant cells. The mechanisms underlying the emergence and progression of cancer resistance from these minority-resistant cells (MRCs) remain poorly understood. This study employs force-induced remnant magnetization spectroscopy (FIRMS) alongside various biological investigations to reveal the mechanical pathways for MRCs fostering drug resistance and tumor progression. The findings show that minority Paclitaxel-resistant cancer cells have enhanced mechanical properties. These cells can transmit high-intensity forces to surrounding sensitive cells (SCs) through the force transducer, Merlin. This force transmission facilitates the assimilation of surrounding SCs, subsequently strengthening the contraction and adhesion of tumor cells. This process is termed "mechano-assimilation," which accelerates the development of drug resistance and tumor progression. Interestingly, disturbances and reductions of mechano-assimilation within tumors can restore sensitivity to Paclitaxel both in vitro and in vivo. This study provides preliminary evidence highlighting the contribution of MRCs to the development of drug resistance and malignancy, mediated through mechanical interactions. It also establishes a foundation for future research focused on integrating mechanical factors into innovative cancer therapies.
化疗仍然是癌症治疗中的一种普遍策略；然而，耐药性的出现对其疗效构成了相当大的挑战。大多数耐药性源于少数耐药细胞中基因突变的积累。这些少数耐药细胞（MRCs）产生和导致癌症耐药性进展的机制仍知之甚少。本研究采用力诱导剩余磁化光谱法（FIRMS）以及各种生物学研究，以揭示MRCs促进耐药性和肿瘤进展的机械途径。研究结果表明，少数耐紫杉醇癌细胞具有增强的机械性能。这些细胞可以通过力传感器Merlin将高强度力传递给周围的敏感细胞（SCs）。这种力传递促进了周围SCs的同化，随后增强了肿瘤细胞的收缩和粘附。这个过程被称为“机械同化”，它加速了耐药性的发展和肿瘤进展。有趣的是，肿瘤内机械同化的干扰和减少可以在体外和体内恢复对紫杉醇的敏感性。本研究提供了初步证据，强调了MRCs通过机械相互作用对耐药性和恶性肿瘤发展的贡献。它还为未来专注于将机械因素整合到创新癌症治疗中的研究奠定了基础。
