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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

Identification of LPA-LPAR-GNA12 driven Gene signatures and Key Pathways in Ovarian Cancer

Project description:Lysophosphatidic acid (LPA) and LPA-receptor (LPAR)-activated G-protein alpha subunits encoded by GNAi2, GNA12, and GNA13 play a crucial role in ovarian cancer progression. While the general signaling mechanism regulated by LPA-LPAR-signaling had previously been characterized, the global transcriptomic network regulated by individual G protein alpha-subunits in ovarian cancer pathophysiology remains largely unknown. To define the specific oncogenic networks regulated by LPA-stimulated GNAi2, GNA12, and GNA13 in ovarian cancer, transcriptomic analyses were carried out using SKOV3 cells in which the expression of GNAi2, GNA12, or GNA134 was silenced in an Agilent SurePrint G3 Human Comparative Genomic Hybridization 8x60 microarray platform.

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RNA-Seq of LPA derived macrophages

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Comprehensive and comparative analysis of gene expression induced by LPA- and CP-609,550 in normal human epidermal keratinocytes (NHEKs)

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2018-11-01 | GSE122023 | GEO

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Gene expression in glucose-grown L-pipecolic acid production strains C.glutamicum LPA-1A and LPA-5 compared to the non-L-pipecolic acid-producing strain C. glutamicum LPA-0 [1]

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

2014-01-10 | GSE53457 | GEO

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

Project description:The endometrium plays a crucial role in the reproductive organs in the aspect of embryo-maternal communication and pregnancy. This study investigated transcriptome profiles of endometrial cells stimulated with PBS, LPA and LPA in combination with IFNt. LPA, one of the signaling molecule, is locally produced and released from the bovine endometrium during estrous cycle and early pregnancy. The highest concentration of LPA and expression of its active receptor (LPAR1) were detected in bovine endometrium at the time of maternal recognition of pregnancy, when the conceptus announces its presence by increased IFNt production. Using transcriptomic approach we compared the influence of LPA and LPA together with IFNt on the gene expression profiles in bovine endometrial cells. A total of nine normally cycling Holstein/Polish Black and White (75/25% respectively) cows were used in this study. Global transcriptional profiling was performed using co-cultured stromal and epithelial cells (ratio - 3:1) isolated from bovine endometrium. Three experimental conditions (control (PBS), LPA and LPA plus IFNt) with three replicates per condition were prepared. Total RNAs were extracted from 9 pooled samples (n=3 for each sample) amplified and hybridized onto Affymetrix microarrays.

2014-01-10 | E-GEOD-53457 | biostudies-arrayexpress

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2014-05-12 | E-GEOD-57496 | biostudies-arrayexpress

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