间皮瘤是一种侵袭性间皮层癌症，与广泛的纤维化反应相关。后者很大程度上是由癌症相关成纤维细胞介导的，其介导肿瘤进展和不良预后。然而，人们对这种疾病中癌细胞和成纤维细胞之间的串扰大多缺乏了解。在这里，利用患者来源的间皮瘤细胞系和肺成纤维细胞的共培养，我们证明成纤维细胞活化是一种自我繁殖的过程，产生纤维化细胞外基质（ECM）并引发间皮瘤细胞的耐药性。在对间皮瘤细胞/成纤维细胞信号串扰进行表征后，我们发现 FDA 批准的几种靶向疗法在 ECM 嵌入的共培养球体模型中比标准护理顺铂/培美曲塞更有效。特别是，SRC 家族激酶抑制剂 Saracatinib 在间皮瘤基因工程小鼠模型中将总体生存期延长至远远超出护理标准。简而言之，我们为合理设计针对间皮瘤/成纤维细胞通讯的新型治疗策略以治疗间皮瘤患者奠定了基础。© 2023。作者。

Mesothelioma is an aggressive cancer of the mesothelial layer associated with an extensive fibrotic response. The latter is in large part mediated by cancer-associated fibroblasts which mediate tumour progression and poor prognosis. However, understanding of the crosstalk between cancer cells and fibroblasts in this disease is mostly lacking. Here, using co-cultures of patient-derived mesothelioma cell lines and lung fibroblasts, we demonstrate that fibroblast activation is a self-propagated process producing a fibrotic extracellular matrix (ECM) and triggering drug resistance in mesothelioma cells. Following characterisation of mesothelioma cells/fibroblasts signalling crosstalk, we identify several FDA-approved targeted therapies as far more potent than standard-of-care Cisplatin/Pemetrexed in ECM-embedded co-culture spheroid models. In particular, the SRC family kinase inhibitor, Saracatinib, extends overall survival well beyond standard-of-care in a mesothelioma genetically-engineered mouse model. In short, we lay the foundation for the rational design of novel therapeutic strategies targeting mesothelioma/fibroblast communication for the treatment of mesothelioma patients.© 2023. The Author(s).