P120-catenin differentially regulates cell migration by Rho-dependent intracellular and secreted signals
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE55019 | GEO | 2016/12/31
SECONDARY ACCESSION(S): PRJNA238248
REPOSITORIES: GEO
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Project description:Pancreatic cancer is one of the most deadly cancers with a 5 year survival rate of about 5%. Therapeutic options are limited, especially for patients that present with late state disease and metastasis. Although the metastatic burden of pancreatic cancer is usually high, little is known about the mechanisms that regulate delamination and dissemination of epithelial cells from preinvasive and malignant pancreatic lesions. Here, we used a preinvasive mouse model of pancreatic cancer to conditionally knockout p120 catenin (Ctnnd1). Mice with biallelic loss of p120 catenin progressively develop high grade PanIN lesions and neoplasia accompanied by prominent acute and chronic inflammatory processes. Loss of p120 catenin in the context of oncogenic Kras also promotes remarkable apical and basal epithelial cell extrusion. Abundant single epithelial cells exit PanIN epithelium basally, survive, and display features of malignancy. Similar extrusion defects are observed following p120 catenin knockdown in vitro, and these effects are completely abrogated by activation of S1P/S1P2 signaling. Our results establish p120 catenin and S1P/S1P2 signaling as novel regulators of non-EMT mediated epithelial cell invasion in pancreatic neoplasia. Transcriptomes of KCiMist1G; p120wt/wt and KCiMist1G; p120f/f pancreases were compared, with three replicates each, using microarray.
2016-07-25 | E-GEOD-68090 | biostudies-arrayexpress
Project description:Pancreatic cancer is one of the most deadly cancers with a 5 year survival rate of about 5%. Therapeutic options are limited, especially for patients that present with late state disease and metastasis. Although the metastatic burden of pancreatic cancer is usually high, little is known about the mechanisms that regulate delamination and dissemination of epithelial cells from preinvasive and malignant pancreatic lesions. Here, we used a preinvasive mouse model of pancreatic cancer to conditionally knockout p120 catenin (Ctnnd1). Mice with biallelic loss of p120 catenin progressively develop high grade PanIN lesions and neoplasia accompanied by prominent acute and chronic inflammatory processes. Loss of p120 catenin in the context of oncogenic Kras also promotes remarkable apical and basal epithelial cell extrusion. Abundant single epithelial cells exit PanIN epithelium basally, survive, and display features of malignancy. Similar extrusion defects are observed following p120 catenin knockdown in vitro, and these effects are completely abrogated by activation of S1P/S1P2 signaling. Our results establish p120 catenin and S1P/S1P2 signaling as novel regulators of non-EMT mediated epithelial cell invasion in pancreatic neoplasia.
2016-07-25 | GSE68090 | GEO
Project description:Background: Negative-pressure wound therapy has become widely available in modern chronic wound cares. Accelerated keratinocyte (HaCaT cell) movements and decreased E-cadherin expressions induced by the applied negative pressure gradient of 125 mmHg (NP) have been reported in previous studies. However, the molecular mechanism for E-cadherin regulations under NP remains unexplored. We highlighted the signal transduction involved in NP-induced E-cadherin regulation for keratinocytes in the study. Results: Microarray results showed that catenin 1 (CTNND1) gene, the gene encoding the p120-catenin (p120ctn) in cell-cell junctions, was significantly (p = 0.0005) upregulated in HaCaT cells under NP for 12 hours in comparison with those at ambient pressure (AP). Cell fractionations and immunoblotting data showed that NP increased p120ctn phosphorylation, and resulted in p120ctn translocation from the plasma membrane to the cytoplasm. Fluorescent stains suggested that NP diminished the co-localization of p120ctn and E-cadherin on the plasma membrane. Similar phenomenon was also observed in the cells with overexpressed p120ctn at NP. Interestingly, overexpression of dN- p120ctn, a deletion mutant of p120ctn without the N-terminal phosphorylation sites, restored the adherens junctions (AJ) at NP. Knockdown of p120ctn with lentiviral small hairpin RNA not only diminished E-cadherin expressions but also accelerated cell movement at AP. Conclusions: Phosphorylation of p120ctn is endowed to respond rapidly to NP and contributes to the AJ disassembly. This NP-induced E-cadherin downregulation can possibly accelerate wound-healing process. Conclusions: Phosphorylation of p120ctn is endowed to respond rapidly to NP and contributes to the AJ disassembly. This NP-induced E-cadherin downregulation can possibly accelerate wound-healing process. HaCaT cells under negative pressure (NP) gradient of 125 mmHg for 12 hours in comparison with those at ambient pressure (AP) were tested for RNA extraction and hybridization on Affymetrix microarrays. The experiments have been biological replicated three times. The differential expression gene between NP and AP were selected and validated with qPCR method.
2015-12-31 | E-GEOD-70512 | biostudies-arrayexpress
Project description:Background: Negative-pressure wound therapy has become widely available in modern chronic wound cares. Accelerated keratinocyte (HaCaT cell) movements and decreased E-cadherin expressions induced by the applied negative pressure gradient of 125 mmHg (NP) have been reported in previous studies. However, the molecular mechanism for E-cadherin regulations under NP remains unexplored. We highlighted the signal transduction involved in NP-induced E-cadherin regulation for keratinocytes in the study. Results: Microarray results showed that catenin 1 (CTNND1) gene, the gene encoding the p120-catenin (p120ctn) in cell-cell junctions, was significantly (p = 0.0005) upregulated in HaCaT cells under NP for 12 hours in comparison with those at ambient pressure (AP). Cell fractionations and immunoblotting data showed that NP increased p120ctn phosphorylation, and resulted in p120ctn translocation from the plasma membrane to the cytoplasm. Fluorescent stains suggested that NP diminished the co-localization of p120ctn and E-cadherin on the plasma membrane. Similar phenomenon was also observed in the cells with overexpressed p120ctn at NP. Interestingly, overexpression of dN- p120ctn, a deletion mutant of p120ctn without the N-terminal phosphorylation sites, restored the adherens junctions (AJ) at NP. Knockdown of p120ctn with lentiviral small hairpin RNA not only diminished E-cadherin expressions but also accelerated cell movement at AP. Conclusions: Phosphorylation of p120ctn is endowed to respond rapidly to NP and contributes to the AJ disassembly. This NP-induced E-cadherin downregulation can possibly accelerate wound-healing process. Conclusions: Phosphorylation of p120ctn is endowed to respond rapidly to NP and contributes to the AJ disassembly. This NP-induced E-cadherin downregulation can possibly accelerate wound-healing process.
2015-12-31 | GSE70512 | GEO
Project description:The poor prognosis of diffuse gliomas is the consequence of adaptive growth and survival programs coupled to their unsurmountable capacity to infiltrate the brain. Diffuse brain infiltration is a particularly detrimental hallmark of gliomas, however the underlying cellular and signaling mechanisms remain elusive. Histological analysis of glioma samples suggests brain invasion by individual glioma cells extending along blood vessels and nerve tracts, consistent with individual-cell growth and invasion programs. However, using thick 3D tissue sections, we here show that human diffuse gliomas consist of multicellular networks in both tumor center and invasion region. This was confirmed in three orthotopic human glioma xenograft models in mouse brain reflecting neuronal, proneural and mesenchymal subtypes. The connections between glioma cells are provided by either branched filamentous protrusions connecting cells across distance or epithelial-like linear adherens junctions between directly adjacent cells. These intercellular contacts showed dynamic turn-over kinetics, which enabled intercellularly synchronized calcium signaling waves, directionally persistent migration as network and network plasticity. Interference with the stability of adherens junction by downregulating p120-catenin causes irreversibly compromised cell-cell interaction, near-complete inhibition of diffuse brain infiltration and a severe growth defect and marginalized microlesions as outcome. Mining of human glioma cohorts revealed an inverse association of p120 with patient survival and, using next-generation RNA sequencing, profound cell reprogramming with perturbed cell adhesion and axonal guidance pathways was uncovered after p120 downregulation. In conclusion, reminiscent of neuronal and glial progenitor programs during morphogenesis and repair, diffuse gliomas progress as neuronal-like, collective network the subunits of which cooperate by complex cell-cell signaling to promote cell growth and detrimental brain infiltration. Targeting adherens junctions and cell-cell cooperation thus represent unanticipated therapeutic principles to prevent glioma progression.
2019-12-02 | GSE73999 | GEO
Project description:Dynamic interactions between RhoA and Rac1, members of the Rho small GTPase family, play a vital role in the control of cell migration. Using predictive mathematical modelling and experimental validation in MDA-MB-231 mesenchymal breast cancer cells, we show that Rac1 and RhoA interactions via the PAK-family kinases can produce bistable, switch-like responses to a graded PAK inhibition. Using a small chemical inhibitor of PAK we confirm the model conjecture demonstrating that cellular RhoA and Rac activation levels respond in a bistable manner to PAK inhibition where for a given inhibition level these levels are high or low depending on the history of the system. Consequently, we show that downstream signalling, actin dynamics and cell migration also behave in a bistable fashion, displaying abrupt switches and hysteresis in response to PAK inhibition. In summary, our results demonstrate that PAK is a critical component in the Rac1-RhoA inhibitory crosstalk that mediates bistable GTPase activity and cell migration switches.
2017-03-29 | MSV000080751 | MassIVE
Project description:ARHGAP35 encoding p190A RhoGAP (p190A) was identified by GWAS as a major human cancer gene. Our published studies have determined that p190A is a tumor suppressor that activates the canonical Hippo pathway. To elucidate how p190A signals in this context, we performed mass spectrometry to identify p190A binding proteins. Two interactors were identified significantly more frequently than others: p120 RasGAP (p120) and ZO-1. Originally p190A was cloned via its direct binding to p120, hence validating our approach. In addition, we found that p190A also binds to ZO-2. The interaction of p190A with ZO-2 is dependent on p120, thus suggesting formation of a ternary complex. Next, we determine that both p120 and ZO-2, but not ZO-1, are necessary for p190A to activate LATS kinases and suppress tumorigenesis in a xenograft mouse model. Moreover, the interactions with p120 and ZO-2 are essential for transcriptional modulation by p190A, including the CDH1 gene encoding E-cadherin, which we previously have demonstrated is essential for p190A signaling. Collectively, this work identifies a novel tumor suppressor interactome of p190A, which includes ZO-2, an established constituent of the Hippo pathway, and p120, which in spite of its strong association with Ras signaling, is essential for p190A to activate LATS kinases.
2023-04-15 | GSE212619 | GEO
Project description:Rho family small GTPases serve as molecular switches in the regulation of diverse cellular functions including actin cytoskeleton remodeling, cell migration, gene transcription, and cell proliferation. Importantly, Rho overexpression is frequently seen in many carcinomas. However, published studies have almost invariably utilized immortal or tumorigenic cell lines to study Rho GTPase functions and there are no studies on the potential of Rho small GTPase to overcome senescence checkpoints and induce preneoplastic transformation of human mammary epithelial cells (hMECs). We found that ectopic expression of wild-type RhoA as well as a constitutively-active RhoA mutant (G14V) in primary hMEC strains led to their immortalization and preneoplastic transformation. Significantly, RhoA-T37A mutant, known to be incapable of interacting with many well known Rho-effectors ,was also capable of immortalizing hMECs.Our results demonstrate that RhoA can induce the preneoplastic transformation of hMECs by altering multiple pathways linked cellular transformation and breast cancer. Through microarray analysis, we want to identify genes and pathways linked to RhoA induced hMECs immortalization. Experiment Overall Design: 4 samples, in triplicate analyses per sample.
2008-10-26 | E-GEOD-12917 | biostudies-arrayexpress
Project description:Dynamic interactions between RhoA and Rac1, members of the Rho small GTPase family, play a vital role in the control of cell migration. Using predictive mathematical modelling and experimental validation in MDA-MB-231 mesenchymal breast cancer cells, we show that Rac1 and RhoA interactions via the PAK-family kinases can produce bistable, switch-like responses to a graded PAK inhibition. Using a small chemical inhibitor of PAK we confirm the model conjecture demonstrating that cellular RhoA and Rac activation levels respond in a bistable manner to PAK inhibition where for a given inhibition level these levels are high or low depending on the history of the system. Consequently, we show that downstream signalling, actin dynamics and cell migration also behave in a bistable fashion, displaying abrupt switches and hysteresis in response to PAK inhibition. In summary, our results demonstrate that PAK is a critical component in the Rac1-RhoA inhibitory crosstalk that mediates bistable GTPase activity and cell migration switches.
2016-12-23 | PXD003213 | Pride
Project description:Rho family small GTPases serve as molecular switches in the regulation of diverse cellular functions including actin cytoskeleton remodeling, cell migration, gene transcription, and cell proliferation. Importantly, Rho overexpression is frequently seen in many carcinomas. However, published studies have almost invariably utilized immortal or tumorigenic cell lines to study Rho GTPase functions and there are no studies on the potential of Rho small GTPase to overcome senescence checkpoints and induce preneoplastic transformation of human mammary epithelial cells (hMECs). We found that ectopic expression of wild-type RhoA as well as a constitutively-active RhoA mutant (G14V) in primary hMEC strains led to their immortalization and preneoplastic transformation. Significantly, RhoA-T37A mutant, known to be incapable of interacting with many well known Rho-effectors ,was also capable of immortalizing hMECs.Our results demonstrate that RhoA can induce the preneoplastic transformation of hMECs by altering multiple pathways linked cellular transformation and breast cancer. Through microarray analysis, we want to identify genes and pathways linked to RhoA induced hMECs immortalization.
2008-09-26 | GSE12917 | GEO