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Pancreatic cancer cells upregulation of LPA receptor 4 in response to stress create a tumor-initiating niche

ABSTRACT: We report that the lysophosphatidic acid receptor 4 (LPAR4) is specifically upregulated on cells exposed to environmental stress or cancer drugs where it promotes stress tolerance, self-renewal, and tumor initiation. We find that ectopic LPAR4-expressing tumors display an enrichment of key extracellular matrix (ECM)-related genes that are established drivers of cancer stemness, and surprisingly do not require stimulation with the canonical LPAR4 ligand, LPA. From this RNAseq data, we observed that LPAR4 promotes a subset of genes, mainly extracellular matrix related genes, independent of its ligand LPA in patient-derived xenograft cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE198002 | GEO | 2022/08/15

REPOSITORIES: GEO

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Chemotaxis in pancreatic ductal adenocarcinoma metastasis: An unexpected role of N-WASP in response of cells to self-generated gradients and LPA receptor trafficking

Project description:Pancreatic ductal adenocarcinoma is one of the most invasive and metastatic cancers and has a dismal 5-year survival rate. Here we show that N-WASP is required for the metastatic process, with roles in both chemotaxis, steering cells out of primary tumours, and matrix remodelling, allowing them to escape. Lysophosphatidic acid, a signalling lipid abundant in blood and ascites fluid, is both a mitogen and chemoattractant for PDAC cells. Pancreatic cancer cells efficiently break LPA down as they respond to it, setting up a self-generated gradient that directs cells out of the tumour. N-WASP depleted cells are unable to respond to LPA gradients and show altered RhoA activation, leading to a loss of cell contractility and traction forces, and reduced metastasis in vitro and in vivo. N-WASP couples LPA receptor signalling to RhoA via the endocytic adapter SNX18, and promotes sensitivity by preventing receptor degradation and promoting recycling of the LPA receptor back to the cell surface. Coordinated by N-WASP, the LPA-LPAR signalling loop promotes RhoA-mediated contractility and force generation. Perturbing this pathway chemically, or by CRISPR deletion severely impairs invasion through complex 3D environments or peritoneal explants, and impairs remodelling of fibrillar collagen. We thus reveal N-WASP as a central controller of a chemotactic loop between PDAC cells and microenvironmental conditions that drives metastasis.

2020-03-06 | PXD014506 | Pride

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Pancreatic cancer cells upregulation of LPA receptor 4 in response to stress create a tumor-initiating niche

Project description:Pancreatic cancer cells upregulation of LPA receptor 4 in response to stress create a tumor-initiating niche

| PRJNA813316 | ENA

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Influence of lysophosphatidic acid (LPA) and LPA together with interferon tau (IFNt) on transcriptional profiling of bovine endometrial cells.

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Influence of lysophosphatidic acid (LPA) and LPA together with interferon tau (IFNt) on transcriptional profiling of bovine endometrial cells.

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