Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA343474 | ENA |
REPOSITORIES: ENA
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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
Project description:Epithelial ovarian cancer (EOC) is the main subtype of ovarian cancer. In this study, we found that Ependymin-related 1 (EPDR1) was significantly downregulated in EOC tissues and low EPDR1 expression was associated with International Federation of Gynecology and Obstetrics (FIGO) stage, metastasis and poor prognosis. We confirmed that EPDR1 overexpression dramatically inhibited EOC cells proliferation, migration and invasion in vitro and in vivo. Mechanistically, EPDR1 suppressed EOC tumorigenesis and progression, at least in part, through inhibiting PI3K/AKT pathway. Furthermore, the expression and function were regulated by miR-429, as demonstrated by luciferase reporter assays and rescue experiments. In conclusion, our study demonstrated that EPDR1, negatively regulated by miR-429, played an important role in EOC development via PI3K/AKT pathway. The miR-429/EPDR1 axis might provide promising therapeutic targets for individualized treatment of EOC patients in future.
2021-11-18 | GSE188918 | GEO
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2020-11-24 | GSE142719 | GEO
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.
2021-08-25 | GSE173214 | GEO
Project description:LPA is a natural bioactive lipid with growth factor-like functions due to activation of series of six G protein-coupled receptors (LPA1-6). In this study we determine the LPA induced early-gene expression profile in three unrelated human cancer cell lines (MDA-MB-231, MCF7, PC3) with an objective to identify potential biomarker/s specifically upregulated through the activation of LPA receptor type 1 (LPA1)
2014-05-16 | GSE56265 | GEO
Project description:LPA is a natural bioactive lipid with growth factor-like functions due to activation of series of six G protein-coupled receptors (LPA1-6). In this study we determine the LPA induced early-gene expression profile in three unrelated human cancer cell lines (MDA-MB-231, MCF7, PC3) with an objective to identify potential biomarker/s specifically upregulated through the activation of LPA receptor type 1 (LPA1) MDA-MB-231, MCF7, PC3 cells were serum starved for 24h and then stimulated with LPA (1µM) for 45min. The controls were the serum starved unstimulated cells. Two replicates for each sample were included in this study. Microarray analysis was performed using a high-density oligonucleotide array (GeneChip Human Genome U133 plus 2.0 array, Affymetrix)
2014-05-16 | E-GEOD-56265 | biostudies-arrayexpress
Project description:Elevated levels of lysophosphatidic acid (LPA) species accumulate in the ascites of ovarian high grade serous cancer (HGSC) and are associated with a short relapse-free survival. LPA is known to support the metastatic spread of cancer cells by activating a multitude of signaling pathways through G-protein-coupled receptors of the LPAR family. Systematic unbiased analyses of the LPA-regulated signal transduction network in ovarian cancer cells have, however, not been reported to date. Methods: LPA-induced signaling pathways were identified by phosphoproteomics of both patient-derived cells and the HGSC cell line OVCAR8, RNA sequencing, pharmacological inhibition, measurements of intracellular Ca2+ and cAMP levels as well as cell imaging. The function of LPARs and downstream signaling components in migration and the formation of entotic cell-in-cell structures was analyzed by applying selective pharmacological inhibitors and RNA interference. Results: Transcriptional signaling by LPA is mainly mediated by LPAR1 to target genes promoting cell motility and migration via multiple cooperating pathways, including PKC, PKD1 and ERK1/2, as demonstrated for IL6 and THBS1 genes. Likewise, cytoplasmic signaling targeting actomyosin is mediated by interconnected phosphorylation-driven pathways triggered prominently by LPAR1. A central component of these signaling pathways is the protein phosphatase 1 regulatory subunit MYPT1, which is a negative regulator of myosin light chain 2 (MYL2). MYPT1 is negatively regulated by PKC- and ERK-mediated phosphorylation in response to LPA, and is indispensable for LPA-induced actomyosin-dependent cell migration and entosis (cell-in-cell invasion). We further show a novel LPAR2-DOCK7 pathway to be essential for the induction of entosis. Conclusion: The LPAR1-ERK/PKC-MYPT1 axis is a critical pathway of LPA-triggered cytoskeletal changes, cell migration and entotic cell-in-cell invasion, pointing to MYPT1 as a promising candidate for therapeutic intervention.
For phosphoproteomic analyses cells were treated with LPA, antagonists or solvent at least in triplicate as described above and lysed in 100 mM Tris pH 7.6, 4% SDS, PhosSTOP (Roche, #4906845001), Protease Inhibitor Cocktail (Sigma, P8340). Analysis of OCMI91s lysates were performed as described [PMID: 19029910]. The protocol was modified to use 12 ug of peptide per channel for TMT labeling, resulting in 500 ug multiplexed samples. LC-MS2 analysis was performed on 50% of the corresponding sample material rehydrated in 0.1% formic acid as published [PMID: 19029910]. Detailed information on instrumentation parametrization was extracted and summarized using MARMoSET [PMID: 310976732] and is included in the repository-deposited data set.
Peptide/spectrum matching as well as TMT quantitation was performed using the MaxQuant suit of algorithms (versions 1.6.8.0, [PMID: 19029910]) against the human canonical and isoforms Uniprot database (downloaded 20190819, 173199 entries). Mass spectrometric raw data along with documentation of instrumentation parameters governing its acquisition as well as MaxQuant parameters employed are deposited. Data were filtered for rows containing no zero values, and analyzed by paired Student's t-test (blocking on replicate set / phosphoproteome analysis chip). Thresholds were set according to the dynamic range of the assay to FC >1.2x or <0.83x and p <0.1.
2023-01-25 | MSV000091146 | MassIVE
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2014-12-19 | E-GEOD-64302 | biostudies-arrayexpress
Project description:Platelets play a crucial role in cancer and thrombosis. The receptor-ligand repertoire mediating prostate cancer (PCa) cell-platelet interactions have not been fully elucidated. Microvilli emanating from the plasma membrane of PCa cell lines (RC77 T/E, MDA PCa 2b) directly contacted individual platelets and platelet aggregates, thereby stimulating calcium mobilization in platelets and promoting translocation of P-selectin and integrin aIIbb3 onto the platelet surface. Platelets in turn dose-dependently stimulated PCa cell invasion and apoptotic resistance. PCa cells were exceedingly sensitive to activation by platelets, occurring at platelet:PCa cell ratios ~20,000-fold lower than normally encountered in blood. Candidate platelet-PCa cell signaling axis partners responsible for these cellular events were identified by RNA-Seq and could be broadly divided into 4 categories: i) integrin-ligand, ii) EPH receptor-ephrin, iii) immune checkpoint receptor-ligand, and iv) miscellaneous receptor-ligand interactions. PCa cell-stimulated calcium mobilization was mediated by a fibronectin1 (FN1; PCa side)-aIIbb3 (platelet side) axis. Reciprocally, platelet-stimulated PCa cell invasion was facilitated by a CD55 (platelet side)-adhesion G-protein coupled receptor E5 (ADGRE5; PCa side) axis, with contribution from platelet cytokines CCL3L1 and IL32. Platelet-stimulated PCa cell apoptotic resistance relied on ephrin-EPH receptor and lysophosphatidic acid (LPA)-LPA receptor (LPAR) signaling. Of the participating partners, FN1 and LPAR3 overexpression was observed in PCa specimens compared to normal prostate, while high expression of CCR1 (CCL3L1 receptor), EPHA1 and LPAR5 in PCa was associated with poor patient survival. These findings emphasize that non-overlapping receptor-ligand pairs participate in oncogenesis and thrombosis, highlighting the complexity of any contemplated clinical intervention strategy.
2022-11-05 | GSE216942 | GEO
Project description:Myeloid-derived suppressor cells (MDSCs) suppress antitumor immune activities and facilitate cancer progression. Although the concept of immunosuppressive MDSCs is well established, the mechanism that MDSCs regulate non-small cell lung cancer (NSCLC) progression through the paracrine signals is still lacking. Here, we reported that the infiltration of MDSCs within NSCLC tissues were associated with the progression of cancer status, and were positively correlated with the Patient-derived xenograft (PDX) model establishment, and poor patient prognosis. Intratumoral MDSCs directly promoted NSCLC metastasis and highly expressed chemokines that promote NSCLC cells invasion, including CCL11. CCL11 was capable of activating the AKT and ERK signaling pathways to promote NSCLC metastasis through the epithelial-mesenchymal transition (EMT) process. Moreover, high expression of CCL11 was associated with a poor prognosis in lung cancer as well as other types of cancer. Our findings underscore that MDSCs produce CCL11 to promote NSCLC metastasis via activation of ERK and AKT signaling and induction of EMT, suggesting that the MDSCs-CCL11-ERK/AKT-EMT axis contains potential targets for NSCLC metastasis treatment.
2021-01-17 | GSE136949 | GEO