定义肿瘤发生的驱动因素可以提供控制癌症进展的机会。本文报告了在胰腺癌细胞暴露于环境压力或化疗时，赖氨酸磷酸酯酸受体4（LPAR4）在短时间内上调，促进环境压力耐受、药物耐受、自我更新和肿瘤发生。胰腺癌细胞通过下调一个肿瘤抑制因子miR-139-5p来应对压力并获得LPAR4表达。即使在没有外源性赖氨酸磷酸酯酸的情况下，表达LPAR4的肿瘤细胞也显示出富含细胞外基质的基因增加，这些基因已被证实是癌症干性的驱动因素。机制上，通过LPAR4 / AKT / CREB轴升高纤维连接蛋白在LPAR4诱导的肿瘤发生和压力耐受中是不可或缺的。此外，通过α5β1或αVβ3整合素与含有纤维连接蛋白的基质结合可以向LPAR4阴性细胞传递应激耐受性。因此，应激或药物诱导的LPAR4增强了富含纤维连接蛋白的细胞自主产生，使细胞能够在“隔离应激”中存活，并通过创建自己的肿瘤发生基质来弥补缺乏基质来源的因素。 © 2023年作者，专为Springer Nature Limited独家许可。

Defining drivers of tumour initiation can provide opportunities to control cancer progression. Here we report that lysophosphatidic acid receptor 4 (LPAR4) becomes transiently upregulated on pancreatic cancer cells exposed to environmental stress or chemotherapy where it promotes stress tolerance, drug resistance, self-renewal and tumour initiation. Pancreatic cancer cells gain LPAR4 expression in response to stress by downregulating a tumour suppressor, miR-139-5p. Even in the absence of exogenous lysophosphatidic acid, LPAR4-expressing tumour cells display an enrichment of extracellular matrix genes that are established drivers of cancer stemness. Mechanistically, upregulation of fibronectin via an LPAR4/AKT/CREB axis is indispensable for LPAR4-induced tumour initiation and stress tolerance. Moreover, ligation of this fibronectin-containing matrix via integrins α5β1 or αVβ3 can transfer stress tolerance to LPAR4-negative cells. Therefore, stress- or drug-induced LPAR4 enhances cell-autonomous production of a fibronectin-rich extracellular matrix, allowing cells to survive 'isolation stress' and compensate for the absence of stromal-derived factors by creating their own tumour-initiating niche.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.