Integrin-b4 identifies cancer stem cell-enriched populations of partially mesenchymal carcinoma cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE95540 | GEO | 2017/03/06
SECONDARY ACCESSION(S): PRJNA377346
REPOSITORIES: GEO
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Project description:Tumor heterogeneity and cisplatin resistance are major causes of tumor relapse and poor survival. Here, we show that in lung cancer, interaction between paxillin (PXN) and integrin b4 (ITGB4), components of the focal adhesion (FA) complex, contributes to cisplatin resistance. Knocking down PXN and ITGB4 attenuated cell growth and improved cisplatin sensitivity, both in 2D and 3D cultures. PXN and ITGB4 independently regulated expression of several genes. In addition, they also regulated expression of common genes including USP1 and VDAC1 that are required for maintaining genomic stability and mitochondrial function, respectively. Mathematical modelling suggested that bistability could lead to stochastic phenotypic switching between cisplatin-sensitive and resistant states in these cells. Consistently, purified subpopulations of sensitive and resistant cells recreated the mixed parental population when cultured separately. Altogether, these data point to an unexpected role of the FA complex in cisplatin resistance, and highlight a novel non-genetic mechanism.
2020-08-04 | GSE155605 | GEO
Project description:Analysis of gene expression profiles of matrix-detached cells with and without expression of ITGB4, in clustering and non-clustering conditions. The experiment tested the hypothesis that the integrin beta 4 (ITGB4) mediates a significant amount of pro-survival signaling in matrix-detached conditions. Expression of ITGB4 in cancer is correlated with poor patient survival and is impliated in increased metastatic spread. Survival in matrix-deprived conditions is essential to metastasis and targeting signaling downstream of the integrin beta 4 may help curtail metasasis.
2019-04-16 | GSE115059 | GEO
Project description:Neoplastic cells within individual carcinomas often exhibit considerable phenotypic heterogeneity in their epithelial versus mesenchymal-like cell states. Because carcinoma cells with mesenchymal features are often more resistant to therapy and may serve as a source of relapse, we sought to determine whether such cells could be further stratified into functionally distinct subtypes. Indeed, we find that a basal epithelial marker, integrin-β4 (ITGB4), can be used to enable stratification of mesenchymal-like triple-negative breast cancer (TNBC) cells that differ from one another in their relative tumorigenic abilities. Notably, we demonstrate that ITGB4+ cancer stem cell (CSC)-enriched mesenchymal cells reside in an intermediate epithelial/mesenchymal phenotypic state. Among patients with TNBC who received chemotherapy, elevated ITGB4 expression was associated with a worse 5-year probability of relapse-free survival. Mechanistically, we find that the ZEB1 (zinc finger E-box binding homeobox 1) transcription factor activity in highly mesenchymal SUM159 TNBC cells can repress expression of the epithelial transcription factor TAp63α (tumor protein 63 isoform 1), a protein that promotes ITGB4 expression. In addition, we demonstrate that ZEB1 and ITGB4 are important in modulating the histopathological phenotypes of tumors derived from mesenchymal TNBC cells. Hence, mesenchymal carcinoma cell populations are internally heterogeneous, and ITGB4 is a mechanistically driven prognostic biomarker that can be used to identify the more aggressive subtypes of mesenchymal carcinoma cells in TNBC. The ability to rapidly isolate and mechanistically interrogate the CSC-enriched, partially mesenchymal carcinoma cells should further enable identification of novel therapeutic opportunities to improve the prognosis for high-risk patients with TNBC.
| S-EPMC5373369 | biostudies-literature
Project description:HMLER cells (Ras-transformed version of HMLE cells) were FACS sorted as two subpopulation using CD24 and ITGB4 antibodies. Cells which are negative for CD24 and ITGB4 were mesenchymal in morphology, while cells which are psotive for CD24 and ITGB4 were epithelial. We performed RNA sequencing and expression of several epithelial and mesenchymal phenotype associated proteins were consistent with their mrphology. In addition to the EMT related genes, these two population expressed some unique set of genes.
2022-01-12 | GSE115058 | GEO
Project description:Integrins are extracellular matrix receptors comprised of an a and b subunit that connect and mediate signaling between cells and the surrounding matrix. In organogenesis of epithelial tissues, the b1 integrin subunit regulates essential epithelial cell functions, but the role of b1 integrin in epithelial repair is poorly understood. To define the role of b1 integrin during alveolar repair, we challenged b1 integrin deficient mice with intratracheal lipopolysaccharide, resulting in increased mortality with emphysematous lungs 21 days following injury. The alveolar barrier was repopulated with an overabundance of type 2 alveolar epithelial cells, with reduced numbers of elongated alveolar type 1 cells, suggesting b1 integrin is required for type 2 to type 1 epithelial transition. Consistent with this finding, b1 deficient type 2 epithelial cells proliferated at increased rates throughout repair, lacked actin-rich cellular protrusions necessary for lateral cellular extension, and exhibited transcriptomic dysregulation of adherens junction and actin polymerization pathways. Finally, we show that b1 integrin balances actin polymerization versus stabilization through GTPase activation. Taken together, these data support a novel role for b1 integrin in re-establishing the alveolar niche after injury through modulation of type 2 epithelial cell proliferation and cytoskeletal-dependent cell shape change.
2023-06-10 | GSE205882 | GEO
Project description:We used microfluidic single cell RNA-seq on adult isolated CC10-CreERT2 (negative) integrin beta4(pos) cells lung epithelial cells in order to determine the transcriptional profile of this putative progenitor population. CC10-CreERT2 / tdTomato (negative) integrin beta4(pos) cells were isolated by FACS, as were Krt5-CreERT2 / tdTomato (positive) cells. These cells were pooled and loaded onto the Fluidigm C1 device.
2014-11-17 | E-GEOD-61300 | biostudies-arrayexpress
Project description:Geier2011 - Integrin activation
Rule based model that integrates the available data to test the biololical hypotheses regarding the role of talin, Dok1 and PIPKI in integrin activation.
This model is described in the article:
A computational analysis of the dynamic roles of talin, Dok1, and PIPKI for integrin activation.
Geier F, Fengos G, Iber D.
PLoS One. 2011;6(11):e24808.
Abstract:
Integrin signaling regulates cell migration and plays a pivotal role in developmental processes and cancer metastasis. Integrin signaling has been studied extensively and much data is available on pathway components and interactions. Yet the data is fragmented and an integrated model is missing. We use a rule-based modeling approach to integrate available data and test biological hypotheses regarding the role of talin, Dok1 and PIPKI in integrin activation. The detailed biochemical characterization of integrin signaling provides us with measured values for most of the kinetics parameters. However, measurements are not fully accurate and the cellular concentrations of signaling proteins are largely unknown and expected to vary substantially across different cellular conditions. By sampling model behaviors over the physiologically realistic parameter range we find that the model exhibits only two different qualitative behaviors and these depend mainly on the relative protein concentrations, which offers a powerful point of control to the cell. Our study highlights the necessity to characterize model behavior not for a single parameter optimum, but to identify parameter sets that characterize different signaling modes.
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2014-03-05 | MODEL1208280001 | BioModels
Project description:Integrins facilitate intercellular movement and communication. Unlike the promiscuous activities of many integrins, β6 integrin is restricted to epithelia and partners exclusively with integrin αV to modulate acute lung injury (ALI). Given that ALI is a complication of respiratory infection, we used mice lacking β6 integrin (β6 KO) to probe the role of the epithelial layer in controlling the lung microenvironment during infection. We found β6 KO mice were protected from disease caused by influenza and Sendai virus infections. They were also protected from disease caused by Streptococcus pneumoniae infection alone and after prior influenza virus infection, the co-infection representing an often-lethal condition in humans. Resistance in the absence of epithelial β6 integrin was caused by intrinsic priming of the lung microenvironment by type I interferons through a mechanism involving transforming growth factor-β regulation. Expression of β6 on epithelia suppresses the production of interferons, providing an advantage to the pathogen. Acute inhibition of β6 function may therefore provide a means to improve outcomes in lung microbial infections. We used microarrays to explore the gene expression profiles differentially expressed in resident alveolar macrophage cells from wild-type and β6 integrin knockout mice. Cells were purified by sorting from lung digests. The comparison made was CD11c+, autofluorescent+ cells from wild-type controls to the dominant CD11c+, CD11b+, autofluorescent+ cells in the knockout. Note that conventional CD11c+ alveolar macrophages do not exist in the knockout mice.
2016-07-18 | E-GEOD-68802 | biostudies-arrayexpress
Project description:We used microfluidic single cell RNA-seq on adult isolated CC10-CreERT2 (negative) integrin beta4(pos) cells lung epithelial cells in order to determine the transcriptional profile of this putative progenitor population.
2014-11-17 | GSE61300 | GEO
Project description:Integrins facilitate intercellular movement and communication. Unlike the promiscuous activities of many integrins, β6 integrin is restricted to epithelia and partners exclusively with integrin αV to modulate acute lung injury (ALI). Given that ALI is a complication of respiratory infection, we used mice lacking β6 integrin (β6 KO) to probe the role of the epithelial layer in controlling the lung microenvironment during infection. We found β6 KO mice were protected from disease caused by influenza and Sendai virus infections. They were also protected from disease caused by Streptococcus pneumoniae infection alone and after prior influenza virus infection, the co-infection representing an often-lethal condition in humans. Resistance in the absence of epithelial β6 integrin was caused by intrinsic priming of the lung microenvironment by type I interferons through a mechanism involving transforming growth factor-β regulation. Expression of β6 on epithelia suppresses the production of interferons, providing an advantage to the pathogen. Acute inhibition of β6 function may therefore provide a means to improve outcomes in lung microbial infections.
2016-07-18 | GSE68802 | GEO