美国加州大学David A. Cheresh课题组发现胰腺癌细胞在隔离应激下上调溶血磷脂酸受体4 (LPAR4)以促进ECM富集的壁龛并支持肿瘤启动。2023年1月16日出版的《自然—细胞生物学》发表了这项成果。

他们报道LPAR4在接触环境应激或化疗的胰腺癌细胞上短暂上调，促进应激耐受、耐药、自我更新和肿瘤启动。胰腺癌细胞通过下调肿瘤抑制因子miR-139-5p来应对压力，从而获得LPAR4的表达。即使在缺乏外源性溶血磷脂酸的情况下，表达ECM的肿瘤细胞显示出丰富的细胞外基质基因，这些基因是确定的癌症干性驱动因素。在机制上，通过LPAR4/AKT/CREB轴上调纤维连接蛋白对于LPAR4诱导的肿瘤启动和应激耐受是必不可少的。

此外，通过整合素α5β1或αVβ3连接含纤维连接蛋白的基质可以将应激耐受性传递给LPAR4阴性细胞。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外基质的细胞自主生产，允许细胞在“隔离应激”中生存，并通过创建自己的肿瘤起始生态位来弥补基质来源因子的缺失。

附：英文原文

Title: Pancreatic cancer cells upregulate LPAR4 in response to isolation stress to promote an ECM-enriched niche and support tumour initiation

Author: Wu, Chengsheng, Rakhshandehroo, Taha, Wettersten, Hiromi I., Campos, Alejandro, von Schalscha, Tami, Jain, Shashi, Yu, Ziqi, Tan, Jiali, Mose, Evangeline, Childers, Betzaira G., Lowy, Andrew M., Weis, Sara M., Cheresh, David A.

Issue&Volume: 2023-01-16

Abstract: 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.

DOI: 10.1038/s41556-022-01055-y

Source: https://www.nature.com/articles/s41556-022-01055-y