GATA3 Promotes Ferroptosis Resistance by Repressing Integrin β1 Signaling
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PROVIDER: PRJNA1287559 | ENA |
REPOSITORIES: ENA
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Project description:Understanding mechanisms that determine the response of cells to ferroptotic stress is a timely issue that has significant ramifications for biology and pathology. We investigated these mechanisms in the context of breast cancer where tumors are comprised of diverse populations of cancer cells that differ in their ferroptosis sensitivity. Using single-cell RNA-sequencing, we determined that cancer cell populations with luminal differentiation are more resistant to ferroptosis than other cells within a heterogeneous tumor. Subsequent bioinformatic analysis and experimentation revealed that GATA3, a transcription factor that promotes luminal differentiation, has a causal role in ferroptosis resistance in luminal breast cancer cells. In pursuit of the mechanism involved, we found that GATA3 represses the expression of integrin β1 and its downstream signaling cascade. This observation led us to demonstrate that integrin β1 signaling is necessary for sensitivity to ferroptosis in basal breast cancer cells because it regulates a FAK/ROCK pathway that sustains the expression of ACSL4, a lipid-modifying enzyme that is essential for ferroptosis. The repression of integrin β1 by GATA3 inhibits this signaling pathway rendering cells ferroptosis resistant. Together, these data provide insight into mechanisms of ferroptosis sensitivity and resistance that are linked to the cell biology and signaling pathways of the diverse types of cells present in breast tumors.
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Project description:Cell states are governed by cell-intrinsic properties and external cues that regulate cell shape and signaling via cell-cell junctions or adhesions. Integrin β1-mediated adhesion is dispensable in early mouse embryogenesis at pre-implantation but becomes indispensable post-implantation. This implies distinct roles for β1-integrins in the naïve pre-implantation and primed post-implantation pluripotent stem cells (PSC). These, however, remain poorly understood. We investigated integrin β1 control of naïve-like and primed human induced PSC (hiPSC) states. We find that integrin β1 is active in naïve and primed hiPSCs and the degree of activity varies in vitro on different extracellular matrices (ECMs). Integrin β1 inhibition in primed hiPSCs induces naïve-like colony features, reduces actomyosin contraction and ERK activity and alters gene expression, indicative of more naïve-like features. Reverting the primed state of pluripotency to naïve involves dramatic reorganization of colony morphology, actin and adhesions. Importantly, functional and single-cell transcriptomics analyses demonstrate that integrin β1 inhibition attenuates colony morphology transitions in cells exiting naïve pluripotency. These data reveal unprecedented integrin-dependent regulation of PSC states and demonstrate how integrin inhibitors may help to fine-tune hiPSC function and properties in vitro.
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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.
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Project description:Aortic carboxypeptidase-like protein activates fibroblasts through β1 integrin signaling
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Project description:H3K9 Trimethylation Dictates Neuronal Ferroptosis through repressing Tfr1
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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.
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Project description:β1-integrin is the major β-integrin subunit expressed in both lens epithelial and fiber cells. Our previous research indicated that β1-integrin is essential for the maintenance of lens epithelial integrity and survival in late embryonic lens development (Simirskii et al, 2009). Lack of β1-integrin in the lens will lead to severe micropthalmia and lack of lens in adult mice. In order to study the mechanisms involved, high throughput RNA sequencing (RNAseq) was performed to determine the genes that are differentially expressed between E15.5 wild type (WT) lenses and lenses that lack β1-integrin expression due to the action of MLR10 CRE (β1-cKO). The methodology used here is similar to the other RNAseq experiments that were previously performed in our lab (Manthey et al., 2014a and Audette et al, 2015) (Geo accession: GSE 49949 and GSE69940) . Meanwhile, the filtering criteria and processing procedures were also published (Manthey et al., 2014b). Compared to WT, 120 genes were found to be differentially expressed in β1-cKO lenses. Moreover, bioinformatics tools (DAVID (the database for Annotation, Visulization and Integrated Discovery), and PANTHER (Protein Analysis through Evolutionary Relationship) classification system) as well as manual literature searching was applied for further data analysis. It showed that genes involved in EMT and stress-responses were differentially expressed in β1-cKO compared to that of WT. Description of filtering criteria: To identify the differentially expressed genes, pair-wise qCML method exact tests with a Benjamini Hochberg false discovery rate correction greater than the threshold of P<0.05 was applied, which identified 5120 genes. As previously described (Manthey et al., 2014b), most of the genes differentially expressed between inbred C57Bl/6 <har> and mice with a mixed background were below a threshold of 2.5 fold change. Therefore, all differentially expressed genes with a less than 2.5 fold change were filtered out. Further, genes whose expression level were not high enough to be biologically significant were also filtered out, based on the RPMK (Reads per Kilobase per million reads) value. Any gene in the final list has RPKM greater that 2 in either WT or β1-cKO samples, a value that corresponds to approximately 1 mRNA molecule per cell. By applying a combination of these filtering criteria, 120 differentially expressed genes were found, which could potentially elucidate the molecular connections between conditional deletion of β1-intergrin from the lens and the observed phenotypic abnormalities. Manthey, A. L., Lachke, S. A., FitzGerald, P. G., Mason, R. W., Scheiblin, D. A., McDonald, J. H. and Duncan, M. K. (2014a) 'Loss of Sip1 leads to migration defects and retention of ectodermal markers during lens development', Mech Dev 131: 86-110. Manthey, A. L., Terrell, A. M., Lachke, S. A., Polson, S. W. and Duncan, M. K. (2014b) 'Development of novel filtering criteria to analyze RNA-sequencing data obtained from the murine ocular lens during embryogenesis', Genom Data 2: 369-374.
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Project description:Aortic carboxypeptidase-like protein activates primary stromal cells through β1 integrin signaling
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