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Analysis of exosome RNA from co-culture of cancer cell and stroma cell

ABSTRACT: How stroma communicates with cancer to influence treatment response is poorly understood. We show that stromal fibroblasts protect breast cancer (BrCa) against radiation and chemotherapy through an exosome-mediated anti-viral pathway and NOTCH3. Stroma increases RAB27B and transfers exosomes to BrCa. RNA within exosomes, comprised largely of non-coding transcripts and transposable elements, stimulates the pattern recognition receptor RIG-I through a 5’-triphosphate motif to activate STAT1. BrCa NOTCH3 is activated in parallel by stromal JAG1 and cooperates with STAT1 to enhance transcriptional responses of NOTCH target genes and to expand therapy resistant tumor-initiating cells. Computational modeling using primary human and mouse BrCa supports the interaction of anti-viral/NOTCH3 pathways in controlling NOTCH target genes and treatment resistance, particularly in basal subtype tumors. Gamma secretase inhibitors reverse stromal protection and abrogate radiation resistance in vivo. Thus, stroma orchestrates an intricate cross-talk with BrCa by utilizing exosomes to coax anti-viral signaling that expands therapy resistant cells through druggable pathways.

ORGANISM(S): Homo sapiens

PROVIDER: GSE60997 | GEO | 2014/10/24

SECONDARY ACCESSION(S): PRJNA260061

REPOSITORIES: GEO

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Analysis of exosome RNA from co-culture of cancer cell and stroma cell

Project description:How stroma communicates with cancer to influence treatment response is poorly understood. We show that stromal fibroblasts protect breast cancer (BrCa) against radiation and chemotherapy through an exosome-mediated anti-viral pathway and NOTCH3. Stroma increases RAB27B and transfers exosomes to BrCa. RNA within exosomes, comprised largely of non-coding transcripts and transposable elements, stimulates the pattern recognition receptor RIG-I through a 5M-bM-^@M-^Y-triphosphate motif to activate STAT1. BrCa NOTCH3 is activated in parallel by stromal JAG1 and cooperates with STAT1 to enhance transcriptional responses of NOTCH target genes and to expand therapy resistant tumor-initiating cells. Computational modeling using primary human and mouse BrCa supports the interaction of anti-viral/NOTCH3 pathways in controlling NOTCH target genes and treatment resistance, particularly in basal subtype tumors. Gamma secretase inhibitors reverse stromal protection and abrogate radiation resistance in vivo. Thus, stroma orchestrates an intricate cross-talk with BrCa by utilizing exosomes to coax anti-viral signaling that expands therapy resistant cells through druggable pathways. RNA profile of ceullar RNA and exosome of co-culture of breast caner cell line 1833 and stroma cell line MRC5.

2014-10-24 | E-GEOD-60997 | biostudies-arrayexpress

Exosome Transfer from Stromal to Breast Cancer Cells Regulates Therapy Resistance Pathways [set 2]

Project description:Stromal communication with cancer cells can influence treatment response. We show that stromal and breast cancer (BrCa) cells utilize paracrine and juxtacrine signaling to drive chemotherapy and radiation resistance. Upon heterotypic interaction, exosomes are transferred from stromal to BrCa cells. RNA within exosomes, which are largely non-coding transcripts and transposable elements, stimulates the pattern recognition receptor RIG-I to activate STAT1-dependent anti-viral signaling. In parallel, stromal cells also activate NOTCH3 on BrCa cells. The paracrine anti-viral and juxtacrine NOTCH3 pathways converge as STAT1 facilitates transcriptional responses to NOTCH3 and expands therapy resistant tumor-initiating cells. Primary human and/or mouse BrCa analysis support the role of anti-viral/NOTCH3 pathways in NOTCH signaling and stroma-mediated resistance, which is abrogated by combination therapy with gamma secretase inhibitors. Thus, stromal cells orchestrate an intricate cross-talk with BrCa cells by utilizing exosomes to instigate anti-viral signaling. This expands BrCa subpopulations adept at resisting therapy and re-initiating tumor growth. Breast cancer cells lines and MRC5 fibroblasts were mono-cultured or co-cultured together. Cell types were separated by FACS and gene expression changes were examined using the Affymetrix Human Gene 1.0ST arrays. The effect of tumor-stromal cell interaction on different breast cancer cell types was analyzed using biological replicates. Gene expression changes resulting from knockdown of STAT1 was also investigated.

2014-10-24 | E-GEOD-60995 | biostudies-arrayexpress

Exosome Transfer from Stromal to Breast Cancer Cells Regulates Therapy Resistance Pathways [set 1]

2014-10-24 | E-GEOD-60994 | biostudies-arrayexpress

Exosome Transfer from Stromal to Breast Cancer Cells Regulates Therapy Resistance Pathways [set 2]

2014-10-24 | GSE60995 | GEO

Exosome Transfer from Stromal to Breast Cancer Cells Regulates Therapy Resistance Pathways [set 1]

2014-10-24 | GSE60994 | GEO

Single-cell RNA sequencing identifies dysregulated NOTCH3 signaling in tumor stroma of lung adenocarcinoma

Project description:Cancer immunotherapy has revolutionized the treatment of lung adenocarcinoma (LUAD); however, a significant fraction of patients fails to respond. Recent studies to understand transcriptomic determinants of immunotherapy response have pinpointed stroma-mediated resistance mechanisms. To gain a better understanding of the stromal biology at the cellular and molecular levels in LUAD, we obtained the transcriptomes of 256,379 single cells with 13,857 mesenchymal cells from 9 treatment-naïve patients. Among the mesenchymal cells, we identify subsets of FAP+PDPN+ cancer-associated fibroblasts (CAFs) and ACTA2+MCAM+ pericytes, which enrich in tumors, differentiate from lung resident fibroblasts and possess a myofibroblast phenotype. By utilizing imaging-mass cytometry, we found that both subsets are topographically adjacent to the perivascular niche and have close spatial interaction with endothelial cells (ECs). Modelling of ligand and receptor interactomes between mesenchymal and ECs identifies that NOTCH3/NOTCH signaling drives the cell-cell interaction in tumors, with pericytes and CAFs as the signal receivers and arterial and PLVAPhigh immature neovascular ECs as the signal senders. Either pharmacologically blocking NOTCH signaling or tuning down NOTCH3 level in mesenchymal cells reduced collagen production and suppressed cell invasion. By evaluating the clinical relevance of NOTCH signaling using bulk-RNA sequencing data, we demonstrate that NOTCH3 correlates with poor survival in stroma-rich patients and that a T-cell inflammation gene signature predicts survival only in low-NOTCH3 expressing patients. Our study underscores the importance of NOTCH3 in regulating tumor stroma biology and may serve as a potential target for immunotherapy combination strategies.

2024-01-31 | GSE253013 | GEO

ECM deposition is driven by caveolin1-dependent regulation of exosomal biogenesis and cargo sorting

Project description:The composition and physical properties of the extracellular matrix (ECM) critically influence tumor progression, but the molecular mechanisms underlying ECM layering are poorly understood. Tumor-stroma interaction is critically dependent on cell-cell communication mediated by exosomes, small vesicles generated within multivesicular bodies (MVBs). Here, we show that caveolin-1 (Cav1) is a central modulator of both exosome biogenesis and exosomal protein cargo sorting through the regulation of cholesterol content at the endosomal compartment/MVBs. Quantitative proteomics profiling revealed that Cav1 is required for exosomal sorting of ECM protein cargo subsets including tenascin-C (TnC), and for fibroblast-derived exosomes to efficiently depose ECM and promote tumor cell invasiveness. Cav1-driven exosomal ECM deposition not only promotes local stromal remodeling, but also the generation of distant ECM-enriched stromal niches. These results support a model by which Cav1 is a central regulatory hub for tumor-stroma interactions through a novel exosome-dependent ECM deposition mechanism. Linked studies: <a href='https://www.ebi.ac.uk/metabolights/MTBLS1977' rel='noopener noreferrer' target='_blank'>MTBLS1977</a>

2020-10-07 | MTBLS1969 | MetaboLights

ECM deposition is driven by caveolin1-dependent regulation of exosomal biogenesis and cargo sorting

Project description:The composition and physical properties of the extracellular matrix (ECM) critically influence tumor progression, but the molecular mechanisms underlying ECM layering are poorly understood. Tumor-stroma interaction is critically dependent on cell-cell communication mediated by exosomes, small vesicles generated within multivesicular bodies (MVBs). Here, we show that caveolin-1 (Cav1) is a central modulator of both exosome biogenesis and exosomal protein cargo sorting through the regulation of cholesterol content at the endosomal compartment/MVBs. Quantitative proteomics profiling revealed that Cav1 is required for exosomal sorting of ECM protein cargo subsets including tenascin-C (TnC), and for fibroblast-derived exosomes to efficiently depose ECM and promote tumor cell invasiveness. Cav1-driven exosomal ECM deposition not only promotes local stromal remodeling, but also the generation of distant ECM-enriched stromal niches. These results support a model by which Cav1 is a central regulatory hub for tumor-stroma interactions through a novel exosome-dependent ECM deposition mechanism. Linked studies: <a href='https://www.ebi.ac.uk/metabolights/MTBLS1969' rel='noopener noreferrer' target='_blank'>MTBLS1969</a>

2020-10-07 | MTBLS1977 | MetaboLights

BRCA mutational status shapes the stromal microenvironment of pancreatic cancer linking CLU+ CAF expression with HSF1 signaling (PSC)

Project description:Cancer-associated fibroblasts (CAFs) give rise to desmoplastic stroma, which supports tumor progression and metastasis, and comprises up to 90% of the tumor mass in pancreatic cancer. Recent work by us and others has shown that CAFs are transcriptionally rewired by adjacent cancer cells to form heterogeneous subtypes. Whether this rewiring is differentially affected by different driver mutations in cancer cells is largely unknown. Here we address this question by dissecting and comparing the stromal landscape of BRCA-mutated and BRCA Wild-type (WT) pancreatic ductal adenocarcinoma (PDAC). We comprehensively analyze PDAC samples from a cohort of 42 patients by laser-capture microdissection, RNA-sequencing and multiplexed immunofluorescence, revealing different CAF subtype compositions in germline BRCA-mutated vs. BRCA-WT tumors. In particular, we detect an increase in a subset of Clusterin (CLU)-positive CAFs in BRCA-mutated tumors. Using cancer organoids, co-cultures and in-vivo models we show that loss of BRCA function in cancer cells leads to a transcriptional shift of pancreatic stellate cells from myofibroblastic into immune-regulatory CLU+ CAFs. This process is mediated through activation of heat-shock factor 1 (HSF1), the transcriptional regulator of Clu. Our findings unravel a new dimension of stromal heterogeneity, influenced by germline mutations in cancer cells, with direct translational implications for clinical research.

2022-10-10 | GSE200616 | GEO

BRCA mutational status shapes the stromal microenvironment of pancreatic cancer linking CLU+ CAF expression with HSF1 signaling (KPC)

2022-10-10 | GSE200615 | GEO

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