马萨诸塞州总医院David Lagares小组宣布他们的论文发现了Durotaxis是肺纤维化和转移性胰腺癌的驱动因子和潜在治疗靶点。该研究于2025年9月9日发表于国际一流学术期刊《自然—细胞生物学》杂志上。

在这里，研究小组证明了在肺纤维化和转移性胰腺癌的无主题模型中，Durotaxis积极推动疾病进展。在肺纤维化中，硬原性引导成纤维细胞募集到损伤部位，在那里它们被机械激活成瘢痕形成的肌成纤维细胞。在胰腺癌中，肿瘤微环境的硬化诱导癌细胞的硬化性，促进转移性扩散。从机制上讲，硬化性是由局灶黏着激酶(FAK) -paxillin相互作用介导的，这是一种机械感觉模块，通过YAP信号将僵硬线索与转录程序联系起来。

为了从遗传学上探索这一点，研究组产生了一个FAK-FATL994E敲入母主题，它破坏了FAK-paxillin结合，阻断了耐药性并减轻了疾病的严重程度。FAK-paxillin与小分子JP-153相互作用的药理抑制模拟了这些作用。他们的发现证实了Durotaxis在体内是一种疾病机制，并支持抗Durotactic治疗作为治疗纤维化和癌症的潜在策略。

据介绍，硬度趋向性，细胞沿硬度梯度迁移，与胚胎发育、组织修复和疾病有关。尽管有确凿的体外证据，但其在体内的作用在很大程度上仍是推测性的。

附：英文原文

Title: Durotaxis is a driver and potential therapeutic target in lung fibrosis and metastatic pancreatic cancer

Author: Al-Hilal, Taslim A., Chrysovergi, Maria-Anna, Grasberger, Paula E., Liu, Fei, Auernheimer, Vera, Zhou, Yan, Xiao, Zebin, Leon-Duque, Mark Anthony, Santos, Alba, Islam, Tamanna, Ligorio, Matteo, Sicard, Delphine, Probst, Clemens K., Vrbanac, Vladimir, Reddi, Tejaswini S., Vincent, Ludovic, Happe, Cassandra, Chaum, Edward, Yates, Charles R., Daneshvar, Kaveh, Mullen, Allan C., Ting, David, White, Eric S., Kalluri, Raghu, Woo, Christina M., Pur, Ellen, Goldmann, Wolfgang H., Alonso, Jose Luis, Tager, Andrew M., Engler, Adam J., Tschumperlin, Daniel J., Lagares, David

Issue&Volume: 2025-09-09

Abstract: Durotaxis, cell migration along stiffness gradients, is linked to embryonic development, tissue repair and disease. Despite solid in vitro evidence, its role in vivo remains largely speculative. Here we demonstrate that durotaxis actively drives disease progression in vivo in mouse models of lung fibrosis and metastatic pancreatic cancer. In lung fibrosis, durotaxis directs fibroblast recruitment to sites of injury, where they undergo mechano-activation into scar-forming myofibroblasts. In pancreatic cancer, stiffening of the tumour microenvironment induces durotaxis of cancer cells, promoting metastatic dissemination. Mechanistically, durotaxis is mediated by focal adhesion kinase (FAK)–paxillin interaction, a mechanosensory module that links stiffness cues to transcriptional programmes via YAP signalling. To probe this genetically, we generated a FAK-FATL994E knock-in mouse, which disrupts FAK–paxillin binding, blocks durotaxis and attenuates disease severity. Pharmacological inhibition of FAK–paxillin interaction with the small molecule JP-153 mimics these effects. Our findings establish durotaxis as a disease mechanism in vivo and support anti-durotactic therapy as a potential strategy for treating fibrosis and cancer.

DOI: 10.1038/s41556-025-01697-8

Source: https://www.nature.com/articles/s41556-025-01697-8