Oncogenic K-Ras upregulates ITGA6-expression via FOSL1 to induce anoikis resistance and synergizes with αV-class integrins to promote EMT
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ABSTRACT:
PROVIDER: PRJEB19401 | ENA |
REPOSITORIES: ENA
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Project description: Not available
| S-EPMC5658677 | biostudies-literature
Project description:We have established that human cytomegalovirus (HCMV) infection modulates the biology of target primary blood monocytes, allowing HCMV to use monocytes as 'vehicles' for its systemic spread. HCMV infection of monocytes results in rapid induction of PI(3)K and NF-kB activity. Integrins, which are upstream of the PI(3)K and NF-kB pathways, were shown to be involved in HCMV binding to and entry into fibroblasts, suggesting that receptor-ligand-mediated signaling following viral binding to integrins on monocytes could trigger the functional changes seen in infected monocytes. We now show that integrin engagement and the activation of the integrin/Src-signaling pathway is essential for the induction of HCMV-infected monocyte motility. To investigate how integrin engagement by HCMV triggers monocyte motility, we examined the infected monocyte transcriptome and found that the integrin/Src-signaling pathway regulates the expression of paxillin, which is an important signal transducer in the regulation of actin rearrangement during cell adhesion and movement. Functionally, we observed that paxillin is activated via the integrin/Src-signaling pathway and is required for monocyte motility. Because motility is intimately connected to cellular cytoskeletal organization, a process that is also important in viral entry, we investigated the role paxillin regulation plays in the process of viral entry of monocytes. New results confirmed that HCMV`s ability to enter target monocytes is significantly inhibited in cells deficient in paxillin expression or that had their integrin/Src/paxillin signaling pathway blocked. From our data, HCMV-cell interactions emerge as an essential trigger for the cellular changes that allow for HCMV entry and hematogenous dissemination. Monocytes were mock-infected, HCMV-infected, or pretreated with PP2 inhibitor prior to HCMV infection. There were three samples analyzed per individual replicate. Three replicates are included. comparative studies with a use of the specific Src kinase activity inhibitor
2010-10-31 | E-GEOD-24238 | biostudies-arrayexpress
Project description:Integrin dimers a3/b1, a6/b1 and a6/b4 are the receptors of mammary epithelial cells for Laminin, major component of the mammary basement membrane. Antibodies against a6 and a3 integrin chains serve to isolate stem cell enriched populations from mammary epithelium, however, role of integrin dimers comprising these chains in the control of mammary stem cell activity are not known. To investigate the role of Laminin-binding integrins in the control of mammary stem cell function, a3 and a6 chains were deleted from mammary basal cells in vitro using Cre-recombinase carrying adenovirus. We found that deletion of single integrin chain (either a3, or a6) did not significantly affect stem cell potential as evaluated by transplantation and mammosphere assays, whereas basal cells depleted of both a3 and a6 integrin chains (a3a6KO) presented severely diminished stem cell activity. In this study the transcriptional profiles of a3a6KO were analysed and compared to those of control cells.
2019-04-23 | GSE117120 | GEO
Project description:We have established that human cytomegalovirus (HCMV) infection modulates the biology of target primary blood monocytes, allowing HCMV to use monocytes as “vehicles” for its systemic spread. HCMV infection of monocytes results in rapid induction of PI(3)K and NF-κB activity. Integrins, which are upstream of the PI(3)K and NF-κB pathways, were shown to be involved in HCMV binding to and entry into fibroblasts, suggesting that receptor-ligand-mediated signaling following viral binding to integrins on monocytes could trigger the functional changes seen in infected monocytes. We now show that integrin engagement and the activation of the integrin/Src-signaling pathway is essential for the induction of HCMV-infected monocyte motility. To investigate how integrin engagement by HCMV triggers monocyte motility, we examined the infected monocyte transcriptome and found that the integrin/Src-signaling pathway regulates the expression of paxillin, which is an important signal transducer in the regulation of actin rearrangement during cell adhesion and movement. Functionally, we observed that paxillin is activated via the integrin/Src-signaling pathway and is required for monocyte motility. Because motility is intimately connected to cellular cytoskeletal organization, a process that is also important in viral entry, we investigated the role paxillin regulation plays in the process of viral entry of monocytes. New results confirmed that HCMV`s ability to enter target monocytes is significantly inhibited in cells deficient in paxillin expression or that had their integrin/Src/paxillin signaling pathway blocked. From our data, HCMV-cell interactions emerge as an essential trigger for the cellular changes that allow for HCMV entry and hematogenous dissemination.
2010-10-31 | GSE24238 | GEO
Project description:Stephen Paget first proposed, in 1889, that organ distribution of metastases is a non-random event, yet metastatic organotropism remains one of the greatest mysteries in cancer biology. Here, we demonstrate that exosomes released by lung-, liver- and brain-tropic tumor cells fuse preferentially with resident cells at their predicted destination, such as fibroblasts and epithelial cells in the lung, Kupffer cells in the liver, and endothelial cells in the brain. We found that exosome homing to organ-specific cell types prepares the pre-metastatic niche and that treatment with exosomes derived from lung tropic models can redirect metastasis to the lung. Proteomic profiling of exosomes revealed distinct integrin expression patterns associated with each organ-specific metastasis. Whereas exosomal integrins α6β4 and α6β1 were associated with lung metastasis, exosomal integrins αvβ5 and αvβ3 were linked with liver and brain metastases, respectively. Targeting α6β4 and αvβ5 integrins decreased exosome uptake and metastasis in the lung and liver, respectively. Importantly, we demonstrate that exosome uptake activates a cell-specific subset of S100 family genes, known to support cell migration and niche formation. Finally, our clinical data indicate that integrin-expression profiles in circulating plasma exosomes from cancer patients could be used to predict organ-specific metastasis. Education of human von Kupffer cells in vitro with human pancreatic cancer exosomes
2015-06-17 | E-GEOD-68919 | biostudies-arrayexpress
Project description:Stephen Paget first proposed, in 1889, that organ distribution of metastases is a non-random event, yet metastatic organotropism remains one of the greatest mysteries in cancer biology. Here, we demonstrate that exosomes released by lung-, liver- and brain-tropic tumor cells fuse preferentially with resident cells at their predicted destination, such as fibroblasts and epithelial cells in the lung, Kupffer cells in the liver, and endothelial cells in the brain. We found that exosome homing to organ-specific cell types prepares the pre-metastatic niche and that treatment with exosomes derived from lung tropic models can redirect metastasis to the lung. Proteomic profiling of exosomes revealed distinct integrin expression patterns associated with each organ-specific metastasis. Whereas exosomal integrins α6β4 and α6β1 were associated with lung metastasis, exosomal integrins αvβ5 and αvβ3 were linked with liver and brain metastases, respectively. Targeting α6β4 and αvβ5 integrins decreased exosome uptake and metastasis in the lung and liver, respectively. Importantly, we demonstrate that exosome uptake activates a cell-specific subset of S100 family genes, known to support cell migration and niche formation. Finally, our clinical data indicate that integrin-expression profiles in circulating plasma exosomes from cancer patients could be used to predict organ-specific metastasis.
2015-06-17 | GSE68919 | GEO
Project description:Interactions with the extracellular matrix (ECM) through integrin adhesion receptors provide cancer cells with physical and chemical cues that act in concert with growth factors to support survival and proliferation. Preclinical studies testing beta1 integrin antagonists in (breast) cancer models have shown inhibition of tumor growth and sensitization to radio- or chemotherapy and these strategies are currently evaluated in clinical trials. Here, we show that disruption of beta1 integrin-mediated ECM adhesion attenuates breast tumor growth but dissemination to the lungs from such small tumors can be markedly enhanced. beta1 integrin downregulation induces compensatory upregulation of beta3 integrins, but increased beta3 expression does not lead to enhanced lung metastasis. Instead, beta1 integrin downregulation in human and mouse triple negative, E-cadherin positive breast cancer cells elicits a switch from collective invasion to individual cell migration in 3D ECM. This involves alterations in the TGFbeta-BMP signaling network shifting the balance between miR-200 and ZEB, which causes a block in E-cadherin transcription. The switch is fully reversible: restored beta1 expression reinstates E-cadherin expression and cell cohesion. Moreover, restoring the network at the level of TGFbetaR, ZEB/miR-200 balance, or E-cadherin, restores cohesion and prevents the induction of lung metastasis without affecting tumor growth. These findings reveal that integrin-mediated ECM-attachments regulate a signaling network in control of epithelial characteristics that suppress metastatic spread. This raises concerns with respect to the use of beta1 integrins as cancer drug targets
2014-02-11 | E-MTAB-2185 | biostudies-arrayexpress
Project description:The diversity of cell-cell interactions in different regions of a tumor reflects the functional heterogeneity of cancer, which poses challenges in early diagnosis, selection of treatment strategies, and prognosis of breast cancer. Cancer cells interact with each other to form different morphological structures in the tumor and stromal host cells via integrins. The objective of this study was to characterize the morphological and spatial heterogeneity of primary breast tumors in the context of expression profiles of integrins and their ligands. We studied spatial transcriptomics using the 10X Visium approach and the NICHES algorithm to map ligand-receptor signaling pathways and visualize the heterogeneity of signaling archetypes in tumor clusters. Cluster analysis of the expression profiles of tumor spots from the samples indicated pronounced inter-tumoral heterogeneity. Integrin-ligand functional clusters were associated with intratumoral heterogeneity, which was manifested by the presence of several morphological loci as observed in histological tumor samples. Inter-tumoral heterogeneity was manifested by a different number of functional clusters, ranging from 2 to 9 for each tumor sample. The main characteristic of these clusters was the significant predominance of non-complementary integrin subunits. Of the 42 functional integrin-ligand pairs in 21 clusters of five samples, 41 pairs occurred only once. The exception was the LAMA5-ITGB4 pair, which was detected in two clusters of different samples. The spatial heterogeneity of integrin-ligand expression clusters in breast cancer contributes significantly to the functional heterogeneity of the tumor, which sets the stage for many scenarios of parenchymatous-stromal relationships, some of which may be effective in the emergence of metastasizing tumor seed cells. The intra- and inter-tumoral spatio-functional heterogeneity of the tumor tissue that we discovered may largely explain why it is difficult to achieve success in most patients with breast cancer using any therapeutic strategy targeting one molecule of the vast array, regardless of the importance of its pathogenetic significance.
2023-09-08 | GSE242311 | GEO
Project description: Not available
| S-EPMC5290147 | biostudies-literature
Project description:Integrin dimers α3/β1, α6/β1 and α6/β4 are the mammary epithelial cell receptors for laminins, which are major components of the basement membrane, a specialized extracellular matrix surrounding the mammary epithelium. The roles of specific basement membrane components and their integrin receptors in the regulation of functional gland development have not been analyzed in detail. To investigate the functions of laminin-binding integrins, we obtained mutant mice with mammary luminal cell-specific deficiencies of the α3 and α6 integrin chains generated by the Cre-Lox approach. During pregnancy, mutant mice displayed low levels of luminal progenitor activity and retarded lobulo-alveolar development, whereas their mammary glands seemed to be functional at the onset of lactation. Myoepithelial cell morphology was markedly altered in mutant glands, suggesting cellular compensation mechanisms involving cytoskeleton reorganization. However, lactation was not sustained in mutant mice, and the glands underwent precocious involution. Inactivation of the p53 gene rescued the growth defects but did not restore lactogenesis in mutant mice. This study reveals an essential role for laminin-binding integrins in functional mammary gland development.
2020-02-04 | GSE132281 | GEO