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NATURE CELL BIOLOGY
Volume -, Issue -, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41556-022-01055-y
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Wu et al. identify LPAR4 as a mechanistic driver of tumour initiation in pancreatic cancer, promoting a fibronectin-rich extracellular matrix through AKT, CREB and integrins. LPAR4 upregulation enhances stress tolerance, drug resistance, self-renewal and tumour initiation. This study highlights the importance of LPAR4 in creating a niche for pancreatic cancer initiation.
Wu et al. identify a mechanistic role for LPAR4 in promoting a fibronectin-rich extracellular matrix via AKT, CREB and integrins, thereby generating a niche that facilitates initiation of pancreatic cancer. 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 alpha 5 beta 1 or alpha V beta 3 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.
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