MNRR1 is a driver of ovarian cancer progression
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE218364 | GEO | 2023/01/15
REPOSITORIES: GEO
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Project description:Background: PIM1 is a constitutively active serine-threonine kinase regulating cell survival and proliferation. Increased PIM1 expression has been correlated with cancer metastasis by facilitating migration and anti-adhesion. Endothelial cells play a pivotal role in these processes by contributing a barrier to the blood stream. Here, we investigated whether PIM1 regulates mouse aortic endothelial cell (MAEC) monolayer integrity. Methods: Pim1-/-MAEC were isolated from Pim1 knockout mice and used in trypsinization-, wound closure assays, electrical cell-substrate sensing, immunostaining, cDNA transfection and as RNA source for microarray analysis. Results: Pim1-/-MAEC displayed decreased migration, slowed cell detachment and increased electrical resistance across the endothelial monolayer. Reintroduction of Pim1- cDNA into Pim1-/-MAEC significantly restored wildtype adhesive characteristics. Pim1-/--MAEC displayed enhanced focal adhesion and adherens junction structures containing vinculin and M-NM-2-catenin, respectively. Junctional molecules such as Cadherin 13 and matrix components such as Collagen 6a3 were highly upregulated in Pim1-/- cells. Intriguingly, extracellular matrix deposited by Pim1-/- cells alone was sufficient to induce the hyperadhesive phenotype in wildtype endothelial cells. Conclusion: Loss of Pim1 induces a strong adhesive phenotype by enhancing endothelial cell-cell and cell-matrix adhesion by the deposition of a specific extracellular matrix. Targeting PIM1 function therefore might be important to promote endothelial barrier integrity. Pim-1-/- mouse aortic endothelial cells were compared to wildtype cells
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Project description:Cell migration is key to tumor metastasis, the most challenging clinical problem in cancer treatment. Here we are investigating the role of DENND10/FAM45A, a recently described endosomal protein, in cancer cell migration via modulating the release of extracellular vesicles (EVs). Bioinformatics data mining showed that high DENND10 expression is significantly associated with poor prognosis in multiple cancer types. DENND10 knockout (DENND10-KO) resulted in defective cell spreading and migration, with impaired formation of stress fibers and focal adhesions. EV secretion was reduced in DENND10-KO cells. Importantly, wild-type conditioned medium or EVs restored the migratory ability and cytoskeletal organization of DENND10-KO cells. Quantitative mass spectrometry revealed that DENND10 depletion led to distinct EV compositional profiles with remodeled constituents of adhesion molecules and extracellular matrix. Together, our study unveiled DENND10 as an intrinsic coordinator between EV release and cell migration, which could be exploited for designing new anti-cancer strategies.
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