Inhibition of Notch pathway arrests PTEN-deficient advanced prostate cancer by triggering p27-driven cellular senescence
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE76822 | GEO | 2017/01/03
SECONDARY ACCESSION(S): PRJNA308659
REPOSITORIES: GEO
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Project description:Activation of NOTCH signalling is associated with advanced prostate cancer and treatment resistance in prostate cancer patients. However, the mechanism that drives NOTCH activation in prostate cancer remains still elusive. Moreover, preclinical evidence of the therapeutic efficacy of NOTCH inhibitors in prostate cancer is lacking. Here, we provide evidence that PTEN loss in prostate tumours upregulates the expression of ADAM17, thereby activating NOTCH signalling. Using prostate conditional inactivation of both Pten and Notch1 along with preclinical trials carried out in Pten-null prostate conditional mouse models, we demonstrate that Pten-deficient prostate tumours are addicted to the NOTCH signalling. Importantly, we find that pharmacological inhibition of γ-secretase promotes growth arrest in both Pten-null and Pten/Trp53-null prostate tumours by triggering cellular senescence. Altogether, our findings describe a novel pro-tumorigenic network that links PTEN loss to ADAM17 and NOTCH signalling, thus providing the rational for the use of γ-secretase inhibitors in advanced prostate cancer patients.
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Project description:Establishment of a functional vascular network is rate-limiting in embryonic development, tissue repair and engineering. During blood vessel formation, newly generated endothelial cells rapidly expand into primitive plexi that undergo vascular remodeling into circulatory networks, requiring coordinated growth inhibition and arterial-venous specification. Whether the mechanisms controlling endothelial cell cycle arrest and acquisition of specialized phenotypes are interdependent is unknown. Here we demonstrate that fluid shear stress, at arterial flow magnitudes, maximally activates NOTCH signaling, which upregulates GJA4 (commonly, Cx37) and downstream cell cycle inhibitor CDKN1B (p27). Blockade of any of these steps causes hyperproliferation and loss of arterial specification. Re-expression of GJA4 or CDKN1B, or chemical cell cycle inhibition, restores endothelial growth control and arterial gene expression. Thus, we elucidate a mechanochemical pathway in which arterial shear activates a NOTCH-GJA4-CDKN1B axis that promotes endothelial cell cycle arrest to enable arterial gene expression. These insights will guide vascular regeneration and engineering.
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Project description:Notch signalling mediates secondary senescence
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Project description:This randomized phase I/II clinical trial is studying the side effects and best dose of gamma-secretase/notch signalling pathway inhibitor RO4929097 when given together with vismodegib and to see how well they work in treating patients with advanced or metastatic sarcoma. Vismodegib may slow the growth of tumor cells. Gamma-secretase/notch signalling pathway inhibitor RO4929097 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving vismodegib together with gamma-secretase/notch signalling pathway inhibitor RO4929097 may be an effective treatment for sarcoma.
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Project description:Oncogene induced senescence (OIS) is a tumour suppressive response to oncogene activation that can be transmitted to neighbouring cells through secreted factors of the senescence associated secretory phenotype (SASP). Using single-cell transcriptomics we observed two distinct endpoints, a primary marked by Ras and a secondary by Notch. We find that secondary senescence in vitro and in vivo requires Notch, rather than SASP alone as previously thought. Currently, primary and secondary senescent cells are not thought of as functionally distinct endpoints. A blunted SASP response and the induction of fibrillar collagens in secondary senescence compared to OIS point towards a functional diversification.
2019-04-23 | GSE115301 | GEO
Project description:As the unique cell type in articular cartilage, chondrocyte senescence is a crucial cellular event contributing to osteoarthritis development. Here we show that clathrin-mediated endocytosis and activation of Notch signaling promotes chondrocyte senescence and osteoarthritis development, which is negatively regulated by myosin light chain 3. Myosin light chain 3 (MYL3) protein levels decline sharply in senescent chondrocytes of cartilages from model mice and osteoarthritis (OA) patients. Conditional deletion of Myl3 in chondrocytes significantly promoted, whereas intra-articular injection of adeno-associated virus overexpressing MYL3 delayed, OA progression in male mice. MYL3 deficiency led to enhanced clathrin-mediated endocytosis by promoting the interaction between myosin VI and clathrin, further inducing the internalization of Notch and resulting in activation of Notch signaling in chondrocytes. Pharmacologic blockade of clathrin-mediated endocytosis-Notch signaling prevented MYL3 loss-induced chondrocyte senescence and alleviated OA progression in mice. Our results establish a previously unknown mechanism essential for cellular senescence and provide a potential therapeutic direction for OA.
2023-09-07 | PXD044684 | Pride
Project description:Soft tissue sarcomas (STS) are a heterogeneous group of tumors associated with poor clinical outcome. While a subset of STS are characterized by simple karyotypes and recurrent chromosomal translocations, the mechanisms driving cytogenetically complex sarcomas are largely unknown. Clinical evidence led us to partially inactivate Pten and p53 in the smooth muscle lineage of mice, which developed high-grade undifferentiated pleomorphic sarcomas (HGUPS), leiomyosarcomas (LMS) and carcinosarcomas (CS) that widely recapitulate the human disease, including the aberrant karyotype and metastatic behavior. Pten was found haploinsufficient whereas the wild-type allele of p53 invariably gained point mutations. Gene expression profile showed upregulated Notch signaling in PtenM-bM-^HM-^F/+p53M-bM-^HM-^F/+ tumors compared to Pten+/+p53M-bM-^HM-^F/+. Consistently, Pten silencing exacerbated the clonogenic and invasive potential of p53-deficient bone marrow-derived mouse mesenchymal stem cells and tumor cells, while activating the Notch pathway. Moreover, the increased oncogenic behavior of PtenM-bM-^HM-^F/+p53M-bM-^HM-^F/+ and shPten-transduced Pten+/+p53M-bM-^HM-^F/+ tumor cells was counteracted by treatment with a gamma secretase inhibitor (GSI), suggesting that the aggressiveness of those tumors can be attributed, at least in part, to enhanced Notch signaling. This study demonstrates a cooperative role for Pten and p53 suppression in complex karyotype sarcomas while establishing Notch as an important functional player in the crosstalk of these pathways during tumor progression. Our results highlight the importance of molecularly subclassifying high-grade sarcoma patients for targeted treatments. Compare PtenM-bM-^HM-^F/+p53M-bM-^HM-^F/+ to Pten+/+p53M-bM-^HM-^F/+ high-grade undifferentiated pleomorphic sarcomas (HGUPS) 4 PtenM-bM-^HM-^F/+p53M-bM-^HM-^F/+ were compared to 5 Pten+/+p53M-bM-^HM-^F/+ Keywords: Differential gene expression.
2013-01-01 | E-GEOD-42103 | biostudies-arrayexpress
Project description:Soft tissue sarcomas (STS) are a heterogeneous group of tumors associated with poor clinical outcome. While a subset of STS are characterized by simple karyotypes and recurrent chromosomal translocations, the mechanisms driving cytogenetically complex sarcomas are largely unknown. Clinical evidence led us to partially inactivate Pten and p53 in the smooth muscle lineage of mice, which developed high-grade undifferentiated pleomorphic sarcomas (HGUPS), leiomyosarcomas (LMS) and carcinosarcomas (CS) that widely recapitulate the human disease, including the aberrant karyotype and metastatic behavior. Pten was found haploinsufficient whereas the wild-type allele of p53 invariably gained point mutations. Gene expression profile showed upregulated Notch signaling in Pten∆/+p53∆/+ tumors compared to Pten+/+p53∆/+. Consistently, Pten silencing exacerbated the clonogenic and invasive potential of p53-deficient bone marrow-derived mouse mesenchymal stem cells and tumor cells, while activating the Notch pathway. Moreover, the increased oncogenic behavior of Pten∆/+p53∆/+ and shPten-transduced Pten+/+p53∆/+ tumor cells was counteracted by treatment with a gamma secretase inhibitor (GSI), suggesting that the aggressiveness of those tumors can be attributed, at least in part, to enhanced Notch signaling. This study demonstrates a cooperative role for Pten and p53 suppression in complex karyotype sarcomas while establishing Notch as an important functional player in the crosstalk of these pathways during tumor progression. Our results highlight the importance of molecularly subclassifying high-grade sarcoma patients for targeted treatments. Compare Pten∆/+p53∆/+ to Pten+/+p53∆/+ high-grade undifferentiated pleomorphic sarcomas (HGUPS)
2013-01-01 | GSE42103 | GEO
Project description:To further investigate the mechanism how the decline in Notch signaling induces premature senescence in endothelial cells, we performed microarray analysis and identified Id1 nd DUSP1 as the downstream molecules of Notch pathway. In quantitative PCR and western blot analyses, the expression level of Id1 and DUSP1 increased in Notch1 over-expressing endothelial cells and decreased in knockdown similar to the result of microarray. The gene expression of human unbilical endothelial vein cells (HUVEC) infected with retroviral vectors encoding Jagged1, Jagged1-shRNA, or Notch1-shRNA. HUVEC infected with empty vector was used as a control. In each genotypes, three independent lines at passage 8 were performed.
2012-08-28 | E-GEOD-40403 | biostudies-arrayexpress