Differential Activity of MAPK signalling Defines Fibroblast Subtypes in Pancreatic Cancer
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PROVIDER: PRJNA1032959 | ENA |
REPOSITORIES: ENA
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Project description:Differential Activity of MAPK signalling Defines Fibroblast Subtypes in Pancreatic Cancer (scRNA-Seq)
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Project description:Differential Activity of MAPK signalling Defines Fibroblast Subtypes in Pancreatic Cancer (Spatial Transcriptomics)
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Project description:Differential Activity of MAPK signalling Defines Fibroblast Subtypes in Pancreatic Cancer (RNA-Seq)
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Project description:Fibroblast heterogeneity is increasingly recognised across cancer conditions. Given their important contribution to disease progression, mapping fibroblasts’ heterogeneity is critical to devise effective anti-cancer therapies. Cancer-associated fibroblasts (CAFs) represent the most abundant cell population in pancreatic ductal adenocarcinoma (PDAC). Whether CAF phenotypes are differently specified by PDAC cell lineages remains to be elucidated. Here, we reveal an important role for the MAPK signalling pathway in defining PDAC CAF phenotypes. We show that epithelial MAPK activity promotes the myofibroblastic differentiation of CAFs by sustaining the expression and secretion of TGF-β1. We integrate single-cell profiling of post-perturbation transcriptional responses from mouse models with cellular and spatial profiles of human tissues to define a MAPKhigh CAF (mapCAF) phenotype. We show that this phenotype associates with basal-like tumour cells and reduced frequency of CD8+ T cells. In addition to elevated MAPK activity, this mapCAF phenotype is characterized by TGF-b signalling, hypoxia responsive signatures, and immunoregulatory gene programs. Furthermore, the mapCAF signature is enriched in myofibroblastic CAFs from various cancer conditions and correlates with reduced response to immune checkpoint inhibition in melanoma Altogether, our data expand our knowledge on CAF phenotype heterogeneity and reveal a potential strategy for targeting of myofibroblastic CAFs in vivo.
2024-12-05 | GSE246458 | GEO
Project description:Fibroblast heterogeneity is increasingly recognised across cancer conditions. Given their important contribution to disease progression, mapping fibroblasts’ heterogeneity is critical to devise effective anti-cancer therapies. Cancer-associated fibroblasts (CAFs) represent the most abundant cell population in pancreatic ductal adenocarcinoma (PDAC). Whether CAF phenotypes are differently specified by PDAC cell lineages remains to be elucidated. Here, we reveal an important role for the MAPK signalling pathway in defining PDAC CAF phenotypes. We show that epithelial MAPK activity promotes the myofibroblastic differentiation of CAFs by sustaining the expression and secretion of TGF-β1. We integrate single-cell profiling of post-perturbation transcriptional responses from mouse models with cellular and spatial profiles of human tissues to define a MAPKhigh CAF (mapCAF) phenotype. We show that this phenotype associates with basal-like tumour cells and reduced frequency of CD8+ T cells. In addition to elevated MAPK activity, this mapCAF phenotype is characterized by TGF-b signalling, hypoxia responsive signatures, and immunoregulatory gene programs. Furthermore, the mapCAF signature is enriched in myofibroblastic CAFs from various cancer conditions and correlates with reduced response to immune checkpoint inhibition in melanoma Altogether, our data expand our knowledge on CAF phenotype heterogeneity and reveal a potential strategy for targeting of myofibroblastic CAFs in vivo.
2024-12-05 | GSE274665 | GEO
Project description:Fibroblast heterogeneity is increasingly recognised across cancer conditions. Given their important contribution to disease progression, mapping fibroblasts’ heterogeneity is critical to devise effective anti-cancer therapies. Cancer-associated fibroblasts (CAFs) represent the most abundant cell population in pancreatic ductal adenocarcinoma (PDAC). Whether CAF phenotypes are differently specified by PDAC cell lineages remains to be elucidated. Here, we reveal an important role for the MAPK signalling pathway in defining PDAC CAF phenotypes. We show that epithelial MAPK activity promotes the myofibroblastic differentiation of CAFs by sustaining the expression and secretion of TGF-β1. We integrate single-cell profiling of post-perturbation transcriptional responses from mouse models with cellular and spatial profiles of human tissues to define a MAPKhigh CAF (mapCAF) phenotype. We show that this phenotype associates with basal-like tumour cells and reduced frequency of CD8+ T cells. In addition to elevated MAPK activity, this mapCAF phenotype is characterized by TGF-b signalling, hypoxia responsive signatures, and immunoregulatory gene programs. Furthermore, the mapCAF signature is enriched in myofibroblastic CAFs from various cancer conditions and correlates with reduced response to immune checkpoint inhibition in melanoma Altogether, our data expand our knowledge on CAF phenotype heterogeneity and reveal a potential strategy for targeting of myofibroblastic CAFs in vivo.
2024-12-05 | GSE246457 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2024-12-05 | GSE246459 | GEO
Project description:Molecular Profiling Defines Three Subtypes of Synovial Sarcoma
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Project description:We investigated changes to murine pancreatic fibroblast gene expression in response to co-culture with 8 murine pancreatic tumour cell sub-populations. Tumours are complex ecosystems where phenotypically diverse tumour cells are embedded in a heterocellular environment. Using an in vitro model of intra-tumoral heterogeneity, we show that clonal tumour cell populations establish distinct interactions with stromal fibroblasts to expand phenotypic diversity across tumour and stromal cell populations. Heterocellular interactions drive differential engagement of tumour cell reciprocal signalling pathways, resulting in normalisation of cell-autonomous differences in MAPK signalling but diversification of AKT signalling. Consequently, tumour cell clones display differential cell-autonomous and non-cell autonomous dependencies. These results demonstrate that tumour-stroma interactions amplify tumour cell autonomous diversity and that our existing perspective on tumour cell heterogeneity underestimates functional diversity.
2019-09-30 | GSE135434 | GEO
Project description:Fibroblasts are functionally heterogeneous cells, capable of promoting and suppressing tumour progression. Across cancer types, the extent and cause of this phenotypic diversity remains unknown. We used single-cell RNA sequencing and multiplexed immunohistochemistry to examine fibroblast heterogeneity in human lung and non-small cell lung cancer (NSCLC) samples. This identified seven fibroblast subpopulations: including inflammatory fibroblasts and myofibroblasts (representing terminal differentiation states), quiescent fibroblasts, proto-myofibroblasts (x2) and proto-inflammatory fibroblasts (x2). Fibroblast subpopulations were variably distributed throughout tissues but accumulated at discrete niches associated with differentiation status. Bioinformatics analyses suggested TGF-β1 and IL-1 as key regulators of myofibroblastic and inflammatory differentiation respectively. However, in vitro analyses showed that whilst TGF-β1 stimulation in combination with increased tissue tension could induce myofibroblast marker expression, it failed to fully re-capitulate ex-vivo phenotypes. Similarly, IL-1β treatment only induced upregulation of a subset of inflammatory fibroblast marker genes. In silico modelling of ligand-receptor signalling identified additional pathways and cell interactions likely to be involved in fibroblast activation, This highlighted a potential role for IL-11 and IL-6 (among other ligands) in myofibroblast and inflammatory fibroblast activation respectively. This analysis provides valuable insight into fibroblast subtypes and differentiation mechanisms in NSCLC.
2020-06-24 | GSE153032 | GEO