Zhang Huan, Zhu Hongyuan, Feng Jinteng, Zhang Zheng, Zhang Simei, Wang Zheng, Sun Lin, Zhang Wencheng, Gao Bin, Zhang Ying, Lin Min
The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, PR China; Bioinspired Engineering and Biomechanics Center (BEBC), Xi'an Jiaotong University, Xi'an 710049, PR China.
Bioinspired Engineering and Biomechanics Center (BEBC), Xi'an Jiaotong University, Xi'an 710049, PR China; Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, PR China.
J Mol Biol. 2023 Jan 15;435(1):167819. doi: 10.1016/j.jmb.2022.167819. Epub 2022 Sep 8.
Cancer has been the leading cause of death due mainly to tumor metastasis. The tumor microenvironment plays a key role in tumor metastasis. As the main stromal cells in tumor microenvironment originated from activated fibroblast, cancer-associated fibroblasts (CAFs) play a major role in promoting tumor metastasis. A promising therapeutic avenue is reprogramming of CAFs into tumor-restraining quiescence state. In this study, we observed that CAF-like active pancreatic stellate cells (PSCs) interact with each other via N-cadherin, a force-sensitive transmembrane receptor. Since N-cadherin ligation mediated mechanotransduction has been reported to restrict integrin mediated signalling, we thus hypothesized that the reprogramming of activated PSCs by mechanical modulation of N-cadherin ligation might be possible. To test this hypothesis, we grafted N-cadherin ligand (HAVDI peptide) onto soft polyethylene glycol hydrogel substrate prior to cell adhesion to mimic cell-cell interaction via N-cadherin ligation. We found that the activated PSCs could be reprogrammed to their original quiescent state when transferred onto the substrate with immobilized HAVDI peptide. These results reveal a key role of mechanosensing by intercellular transmembrane receptor in reprogramming of activated PSCs, and provide a potential way for designing novel therapeutic strategies for cancer treatment.
癌症一直是主要因肿瘤转移导致的首要死因。肿瘤微环境在肿瘤转移中起关键作用。作为肿瘤微环境中的主要基质细胞，癌症相关成纤维细胞（CAFs）起源于活化的成纤维细胞，在促进肿瘤转移中起主要作用。一个有前景的治疗途径是将CAFs重编程为肿瘤抑制静止状态。在本研究中，我们观察到CAF样活性胰腺星状细胞（PSCs）通过N-钙黏蛋白（一种力敏感跨膜受体）相互作用。由于据报道N-钙黏蛋白连接介导的机械转导会限制整合素介导的信号传导，因此我们推测通过对N-钙黏蛋白连接进行机械调节来重编程活化的PSCs可能是可行的。为了验证这一假设，我们在细胞黏附之前将N-钙黏蛋白配体（HAVDI肽）接枝到柔软的聚乙二醇水凝胶基质上，以模拟通过N-钙黏蛋白连接的细胞间相互作用。我们发现，当将活化的PSCs转移到固定有HAVDI肽的基质上时，它们可以被重编程为原始的静止状态。这些结果揭示了细胞间跨膜受体的机械传感在重编程活化的PSCs中的关键作用，并为设计癌症治疗的新型治疗策略提供了一条潜在途径。
