Pancreatic cancer cells upregulate LPAR4 in response to isolation stress to promote an ECM-enriched niche and support tumour initiation
Menée à l'aide de lignées cellulaires et de xénogreffes de cancer du pancréas sur des modèles murins, cette étude met en évidence un mécanisme par lequel les cellules cancéreuses, via l'augmentation de l'expression du récepteur LPAR4 induite par le stress environnemental ou la chimiothérapie, favorisent la production d'une matrice extracellulaire riche en fibronectine ainsi que l'initiation tumorale
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.