NOTCH1 gene amplification promotes expansion of Cancer Associated Fibroblast populations in human skin
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ABSTRACT:
PROVIDER: PRJNA453141 | ENA |
REPOSITORIES: ENA
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Project description:Cancer associated fibroblasts (CAFs) represent a key component of the tumor microenvironment. Possible genomic alterations in these cells remain a point of contention. The skin is constantly exposed to clastogenic insults, such as UVA light that can target directly the stromal compartment, therefore representing a relevant model to study. Here we report that CAFs from skin Squamous Cell Carcinoma (SCC) lesions display chromosomal alterations, with heterogeneous levels of NOTCH1 gene amplification that also occur, to a lesser extent, in dermal fibroblasts of apparently unaffected skin. The fraction of the latter cells harboring NOTCH1 gene amplification is expanded by chronic UVA exposure, which induces a DNA damage response (DDR) to which CAFs are resistant. The selective advantage conferred by NOTCH1 gene amplification and over-expression can be explained by NOTCH1 ability to block DDR-mediated growth arrest through competitive suppression of ATM-FOXO3a association and downstream signaling cascade. These findings are of translational significance as, in an orthotopic model of skin SCC, genetic or pharmacological inhibition of NOTCH1 activity suppresses cancer / stromal cells expansion. Thus, NOTCH1 amplification and increased expression contribute to CAFs evolution and are an attractive target for preventing cancer / stromal cell expansion.
2020-08-25 | GSE113577 | GEO
Project description:Cancer associated fibroblasts (CAFs) are a key component of the tumor microenvironment. Genomic alterations in these cells remain a point of contention. We report that CAFs from skin squamous cell carcinomas (SCCs) display chromosomal alterations, with heterogeneous NOTCH1 gene amplification and overexpression that also occur, to a lesser extent, in dermal fibroblasts of apparently unaffected skin. The fraction of the latter cells harboring NOTCH1 amplification is expanded by chronic UVA exposure, to which CAFs are resistant. The advantage conferred by NOTCH1 amplification and overexpression can be explained by NOTCH1 ability to block the DNA damage response (DDR) and ensuing growth arrest through suppression of ATM-FOXO3a association and downstream signaling cascade. In an orthotopic model of skin SCC, genetic or pharmacological inhibition of NOTCH1 activity suppresses cancer/stromal cells expansion. Here we show that NOTCH1 gene amplification and increased expression in CAFs are an attractive target for stroma-focused anti-cancer intervention.
| S-EPMC7550609 | biostudies-literature
Project description:Genomic instability is a hallmark of cancer. Whether or not it also occurs in cancer-associated fibroblasts (CAFs) is a question of importance for the cancer/stromal cell co-evolution process. We find that DNA damage, telomere shortening and chromosome fusions occur at early times of CAF activation, as triggered by silencing of the CSL/RBP-J-κ gene in primary human dermal fibroblasts (HDFs) from multiple individuals. Similar alterations occur in skin Squamous Cell Carcinoma (SCC) - derived CAFs, in which CSL is down-modulated, versus HDFs from unaffected skin of the same patients. Mechanistically, CSL is part of a telomere protective complex with UPF1, KU70, and KU80 proteins, which fail to bind to telomeres in the absence of CSL. In CAFs, persistent genomic instability is associated with frequent amplification and overexpression of NOTCH1 gene, which is required to suppress DNA damage-induced ATM/P53 activation and growth arrest. These findings are of translational significance as, in an orthotopic model of skin SCC, genetic or pharmacological suppression of NOTCH1 activity suppresses cancer/stromal cell proliferation and expansion.
2019-09-11 | GSE113542 | GEO
Project description:Dual role of CSL (RBP-Jk) and NOTCH1 in cancer-associated fibroblast genome stability and expansion [RNA-seq]
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Project description:The regulation of multipotent cardiac progenitor cell (CPC) expansion and subsequent differentiation into cardiomyocytes, smooth muscle, or endothelial cells is a fundamental aspect of basic cardiovascular biology and cardiac regenerative medicine. However, the mechanisms governing these decisions remain unclear. Here, we show that Wnt/β-Catenin signaling, which promotes expansion of CPCs, is negatively regulated by Notch1-mediated control of phosphorylated β-Catenin accumulation within CPCs, and that Notch1 activity in CPCs is required for their differentiation. Notch1 positively, and β-Catenin negatively, regulated expression of the cardiac transcription factors, Isl1, Myocd and Smyd1. Surprisingly, disruption of Isl1, normally expressed transiently in CPCs prior to their differentiation, resulted in expansion of CPCs in vivo and in an embryonic stem (ES) cell system. Furthermore, Isl1 was required for CPC differentiation into cardiomyocyte and smooth muscle cells, but not endothelial cells. These findings reveal a regulatory network controlling CPC expansion and cell fate that involve unanticipated functions of β-Catenin, Notch1 and Isl1 that may be leveraged for regenerative approaches involving CPCs. YFP+ cells marking precardiac mesoderm (Isl1-cre domain) were FACS-sorted (w/wo stabilized Beta-catenin). Their total RNA was amplified with the WT-Ovation Pico RNA Amplification System, fragmented and labeled with the FL-Ovation cDNA Biotin Module V2 (Nugen). The hybridization, staining and scanning of the Affymetrix GeneChips were performed in the Gladstone Genomics Core Lab. Raw data generated from at least three independent experiments were further analyzed by the group of Dr. Ru-Fang Yeh at the Center for Informatics and Molecular Biostatistics, UCSF.
2009-05-13 | E-GEOD-15232 | biostudies-arrayexpress
Project description:The study design involves the proteomics characterization of primary skin fibroblast cell lines derived from skin biopsies from patients affected by either amyotrophic lateral sclerosis (ALS) or frontotemporal dementia (FTD). Patients enrolled were divided in three groups: 1) ALS patients carrying the C9ORF72 repeat expansion as main genetic mutation (c9orf72 pos; n=6), 2) sporadic ALS patients, carrying mutations other than the C9ORF72 repeat expansion (c9orf72 neg; n=8), 3) FTD patients carrying the C9ORF72 repeat expansion (FTD; n=2). Total protein extracts were obtained from primary skin fibroblasts cultures and trypsin digested. Shotgun proteomics by LC-MS/MS (two technical replicates per sample) and systems biology analyses were performed as follows
2021-11-02 | PXD023866 | Pride
Project description:Human-specific gene ARHGAP11B promotes basal progenitor amplification and neocortex expansion
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Project description:Functional studies to investigate gene mutations recurrent in B cell lymphoma have been hampered by the inability to genetically manipulate primary cells, attributed to low transduction efficacy and procedure-associated toxicity. Alternative approaches utilize cell lines and mouse models, which often only poorly represent the genomic complexity and biology of the primary malignancy. To overcome these limitations, we have developed a method to retrovirally transfer genes into primary malignant B cells with high transduction efficacy and minimal toxicity. Using this method, we investigated the functions of NOTCH1, the most commonly mutated gene in CLL, by generating isogenic primary tumor cells from patients with Chronic Lymphocytic Leukemia (CLL) and Mantle Cell Lymphoma (MCL), differing only in their expression of NOTCH1. Our data demonstrate that NOTCH1 facilitates immune escape of malignant B cells by up-regulating PD-L1, partly dependent on autocrine interferon-g signaling. In addition, NOTCH1 causes silencing of the entire HLA-class II locus via suppression of the transcriptional co-activator CIITA. These NOTCH1-mediated immune escape mechanisms are associated with the expansion of CD4+ T cells in vivo, further contributing to the poor clinical outcome of NOTCH1-mutated CLL and MCL
2022-08-26 | PXD024112 | Pride
Project description:The evolutionary expansion of the human neocortex reflects increased amplification of basal progenitors in the subventricular zone, producing more neurons during fetal corticogenesis. Here, we analyze the transcriptomes of distinct progenitor subpopulations isolated by a novel approach from developing mouse and human neocortex. We identify 56 genes preferentially expressed in human apical and basal radial glia that lack mouse orthologs. Among these, ARHGAP11B has the highest degree of radial glia-specific expression. ARHGAP11B arose from partial duplication of the Rho GTPase-activating-protein–encoding ARHGAP11A on the human lineage after separation from the chimpanzee lineage. Expression of ARHGAP11B in embryonic mouse neocortex promotes basal progenitor generation and self-renewal, and can increase cortical plate area and induce gyrification. Hence, ARHGAP11B may have contributed to evolutionary expansion of human neocortex.
2015-03-02 | GSE65000 | GEO
Project description:The evolutionary expansion of the human neocortex reflects increased amplification of basal progenitors in the subventricular zone, producing more neurons during fetal corticogenesis. Here, we analyze the transcriptomes of distinct progenitor subpopulations isolated by a novel approach from developing mouse and human neocortex. We identify 56 genes preferentially expressed in human apical and basal radial glia that lack mouse orthologs. Among these, ARHGAP11B has the highest degree of radial glia-specific expression. ARHGAP11B arose from partial duplication of the Rho GTPase-activating-protein–encoding ARHGAP11A on the human lineage after separation from the chimpanzee lineage. Expression of ARHGAP11B in embryonic mouse neocortex promotes basal progenitor generation and self-renewal, and can increase cortical plate area and induce gyrification. Hence, ARHGAP11B may have contributed to evolutionary expansion of human neocortex. Gene expression profiles of mouse and human purified neocortical progenitor types and neurons were generated by RNA-seq and analyzed including inter- and intra-species comparison.
2015-03-02 | E-GEOD-65000 | biostudies-arrayexpress