Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1304172 | ENA |
REPOSITORIES: ENA
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Project description:Anaplastic thyroid cancer (ATC) is a highly lethal malignancy characterized by rapid progression and therapeutic resistance. This study uncovers the pivotal role of extracellular matrix (ECM) stiffness in driving ATC aggressiveness through mechanotransduction mediated by the Integrin α6β4/Focal Adhesion Kinase (FAK) axis. By engineering collagen-coated polyacrylamide hydrogels with tunable rigidity, we demonstrated that high ECM stiffness (60 kPa) markedly enhanced ATC cell proliferation, clonogenicity, migration, and invasion. Mechanistically, stiff matrices induced cytoskeletal reorganization, activated RhoA/Rac1/Cdc42 signaling, and upregulated Integrin α6β4-FAK pathway components, as validated by transcriptomic, proteomic, and functional assays. Pharmacological inhibition of FAK reversed stiffness-dependent tumor-promoting effects in vitro. In vivo, mice implanted with high-stiffness ECM-mimicking hydrogels exhibited accelerated subcutaneous tumor growth and increased lung metastatic burden, which were significantly attenuated by FAK-targeted therapy. These findings establish ECM stiffness as a biomechanical determinant of ATC progression and metastasis, offering novel insights into microenvironment-driven malignancy and highlighting FAK as a promising therapeutic target to disrupt mechanosignaling in ATC.
2025-08-07 | PXD067033 |
Project description:Fibrosis is a pathological process characterized by persistent fibroblast activation and excessive extracellular matrix (ECM) accumulation. Aortic carboxypeptidase-like protein (ACLP), an ECM-associated protein that binds fibrillar collagen, is upregulated in fibrotic tissues and promotes fibroblast differentiation through canonical TGFβ receptor I signaling. We hypothesized that when presented within the collagen matrix, ACLP engages mechanically driven signaling pathway that contribute to fibroblast activation. Here, we identified a previously unrecognized mechanism through which collagen-bound ACLP activates fibroblasts via β1 integrin-mediated signaling. Collagen-bound ACLP induced rapid fibroblast spreading, increased β1 integrin activation, and promoted focal adhesion maturation. These early adhesion events were followed by elevated activation of the GTPases RhoA and Rac1, with enhanced F-actin assembly and nuclear accumulation of myocardin-related transcription factor A (MRTFA), a key regulator of activated fibroblast gene expression. Transcriptomic profiling revealed enrichment of focal adhesion, ECM–receptor interaction, and actin cytoskeletal gene pathways in response to collagen-bound ACLP. These findings establish collagen-bound ACLP as an ECM-derived cue that links matrix composition to fibroblast activation pathways.
2026-03-31 | GSE312027 | GEO
Project description:Fibrosis is a pathological process characterized by persistent fibroblast activation and excessive extracellular matrix (ECM) accumulation. Aortic carboxypeptidase-like protein (ACLP), an ECM-associated protein that binds fibrillar collagen, is upregulated in fibrotic tissues and promotes fibroblast differentiation through canonical TGFβ receptor I signaling. We hypothesized that when presented within the collagen matrix, ACLP engages mechanically driven signaling pathway that contribute to fibroblast activation. Here, we identified a previously unrecognized mechanism through which collagen-bound ACLP activates primary stromal cells towards a myofibroblast phenotype via β1 integrin-mediated signaling. Collagen-bound ACLP induced rapid fibroblast spreading, increased β1 integrin activation, and promoted focal adhesion maturation. These early adhesion events were followed by elevated activation of the GTPases RhoA and Rac1, with enhanced F-actin assembly and nuclear accumulation of myocardin-related transcription factor A (MRTFA), a key regulator of activated fibroblast gene expression. Transcriptomic profiling revealed enrichment of focal adhesion, ECM–receptor interaction, and actin cytoskeletal gene pathways in response to collagen-bound ACLP. These findings establish collagen-bound ACLP as an ECM-derived cue that links matrix composition to fibroblast activation pathways.
2026-03-31 | GSE324887 | GEO
Project description:Aim of this work is to verify if pericytes (Pc) residing in ischemic failing human hearts display altered mechano-transduction properties and to assess which alterations of the mechano-sensing machinery are associated with the observed impaired response to mechanical cues. Results: microvascular rarefaction and defects of YAP/TAZ activation characterize failing human hearts. Although both donor (D-) and explanted (E-) heart derived cardiac pericytes (CPc) support angiogenesis, D-CPc exert this effect significantly better than E-CPc. The latter are characterized by reduced focal adhesion density, decreased activation of the focal adhesion kinase (FAK)/ Crk-associated substrate(CAS) pathway, low expression of caveolin-1, and defective transduction of extracellular stiffness into cytoskeletal stiffening, together with an impaired response to both fibronectin and lysophosphatidic acid. Importantly, Mitogen-activated protein kinase kinase inhibition restores YAP/TAZ nuclear translocation.
2020-11-16 | GSE157205 | GEO
Project description:Integrins, the principal extracellular matrix (ECM) receptors of the cell, promote cell adhesion, migration, and proliferation, which are key events for cancer growth and metastasis. To date, most integrin-targeted cancer therapeutics have disrupted integrin-ECM interactions, which are viewed as critical for integrin functions. However, such agents have failed to improve cancer patient outcomes. We show that integrin b1, a highly expressed subunit in lung epithelium, is required for lung adenocarcinoma development in a carcinogen-induced mouse model. Likewise, human lung adenocarcinoma cell lines with integrin b1 deletion failed to form colonies in soft agar and tumors in mice. Mechanistically, we demonstrate that these effects do not require integrin b1-mediated adhesion to ECM but are dependent on integrin b1 cytoplasmic tail-mediated activation of focal adhesion kinase (FAK). Together, these studies support a critical role for integrin b1 in lung tumorigenesis that is mediated through constitutive, ECM-binding independent signaling involving the cytoplasmic tail.
2022-08-01 | GSE175687 | GEO
Project description:The composition and stiffness of the extracellular matrix (ECM) environment that surrounds Multipotent mesenchymal stem cells (MSCs) stem cells dictates transcriptional programming, thereby affecting stem cell lineage decision-making. Cells sense force between themselves and their microenvironment controlling the capability of MSCs to differentiate into adipocytes, osteocytes and chondrocytes. Force sensing is transmitted by integrin receptors and their associated adhesion signalling complexes. To identify regulators of MSC force sensing we sought to catalogue MSC adhesion complex composition. Therefore we isolated integrin-associated adhesion complexes formed in MSCs plated on the ECM ligand fibronectin. We identifed proteins using mass spectrometry that define a MSC specific subset of adhesion complex proteins consisting of key linkages to the actin cytoskeleton together with integrin signalling and force sensing components.
2016-07-20 | MSV000079956 | MassIVE
Project description:Introduction Metastatic potential and rising incidence make cutaneous melanoma a major health concern worldwide. Although the therapies currently in use have proven effective, their use is limited by side effects arising and development of drug resistance. For this reason, research for new therapeutic targets and predictive biomarkers is crucial. Semaphorin 5A (SEMA5A) is a member of the Semaphorin family with involvement in cancer biology and neural development. We previously demonstrated that this protein promotes different in vitro melanoma aggressive features. In this work we further investigated the role and the mechanism of action of SEMA5A in melanoma formation and progression. Methods We performed proteomic analysis of stable knockdown SEMA5A human melanoma cells, and in silico analysis to identify cellular pathways modulated by SEMA5A. In vitro clonogenic assay and cell viability assay under different substrate conditions were conducted by using both human and murine melanoma SEMA5A knockdown clones. Western blotting analysis and immunofluorescence have been employed to investigate focal adhesion pathway regulation and lamellipodia formation after SEMA5A depletion. Nocodazole assay was used to evaluate focal adhesion dynamic. Xenograft mouse model of melanoma was used to investigate the effect of SEMA5A depletion in tumor formation and growth. Results Ingenuity pathway analysis showed that SEMA5A effects several different cellular pathways essential for cell viability, cell proliferation, and cytoskeletal dynamics, including focal adhesion and lamellipodia formation. We demonstrated that SEMA5A depletion reduced clonogenic properties and cell viability of cells in both low and high stiffness condition of culture. SEMA5A affected Focal adhesion kinase and Paxillin phosphorylation, integrin beta 1 activation, thus regulating focal adhesion dynamics, and lamellipodia formation, regulating Arp3 nucleation and expression. Delay of tumor formation and reduced tumor growth was observed in mice bearing tumor expressing low level of SEMA5A. Conclusions These findings demonstrate that SEMA5A is a novel player of melanoma aggressiveness and progression, being involved in modulating cell viability, focal adhesion signaling and lamellipodia in vitro and tumor growth in vivo.
2025-12-01 | PXD065661 | Pride
Project description:Soluble VEGFR-1 (sVEGFR-1) acts both as a decoy receptor for VEGFs and as an extracellular matrix protein for α5β1 integrin. A sVEGFR-1-derived peptide that interacts with α5β1 integrin promotes angiogenesis. However, canonical signal downstream integrin activation is not induced, resulting into lack of focal adhesion maturation. We performed a gene expression profile of endothelial cells adhering on sVEGFR-1 compared to that of cells adhering on fibronectin, the principal α5β1 integrin ligand. Three protein kinase-C substrates, adducin, MARCKS, and radixin were differently modulated. Adducin and MARCKS were less phosphorylated whereas radixin was higher phosphorylated in sVEGFR-1 adhering cells, the latter leading to prolonged small GTPase Rac1 activation and induction of a pathway involving the heterotrimeric G protein α13. Altogether, our data indicated endothelial cell acquisition of an highly motile phenotype when adherent on sVEGFR-1. Finally, we indicated radixin as accountable for the angiogenic effect of α5β1 integrin interaction with sVEGFR-1 that in turn depends on an active VEGF-A/VEGFR-2 signaling. Endothelial cells were let adhere in Petri dishes coated with fibronectin or sVEGFR-1 before RNA extraction and hybridization on Affymetrix microarrays. Endothelial cells plated on BSA-treated Petri dishes were used as non-adhesion control. Each hybridization was performed in triplicate.
2014-01-20 | E-GEOD-32560 | biostudies-arrayexpress
Project description:The protein tyrosine phosphatase PRL-1 (Gene Symbol: PTP4A1) has been identified as an important oncogene with roles in promoting cell proliferation, survival, migration, invasion, and metastasis. However, little is currently known about the signaling pathways through which it mediates its effects. Studies have shown a relationship between PRL-1 and the expression or activity levels of various molecules involved in integrin-mediated cell signaling. These integrin-responsive players can promote re-arrangements in the actin cytoskeleton that are central to cell motility, invasion, and metastasis. Therefore, to investigate the effects of PRL-1 overexpression in human embryonic kidney 293 (HEK293) cells, we used qRT-PCR to examine the expression levels of 184 genes which either were identified by microarray and proteomic analysis to be differentially expressed in response to PRL-1 or have known associations to integrin-mediated signaling, cytoskeletal remodeling, and/or cell motility. Total RNA was extracted from duplicate cultures of HEK293 cells stably overexpressing PRL-1 (HEK293-PRL-1) and HEK293 cells stably transfected with empty pcDNA4 vector (HEK293-Vector). Samples were analyzed using custom TaqMan Array 96-well Plates to examine the expression of 184 genes with known involvement in or association with signaling pathways related to integrin-mediated cell adhesion, cytoskeletal remodeling, and/or cell motility.
2013-07-30 | E-GEOD-42587 | biostudies-arrayexpress