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TGFb-blockade uncovers stromal plasticity in tumors by revealing the existence of a novel subset of interferon-licensed fibroblasts [human]

ABSTRACT: TGFb-blockade uncovers stromal plasticity in tumors by revealing the existence of a novel subset of interferon-licensed fibroblasts [human]

PROVIDER: PRJNA673940 | ENA |

REPOSITORIES: ENA

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TGFb-blockade uncovers stromal plasticity in tumors by revealing the existence of a novel subset of interferon-licensed fibroblasts

Project description:TGFb-blockade uncovers stromal plasticity in tumors by revealing the existence of a novel subset of interferon-licensed fibroblasts

| PRJNA673933 | ENA

TGFb-blockade uncovers stromal plasticity in tumors by revealing the existence of a novel subset of interferon-licensed fibroblasts [mouse]

Project description:TGFb-blockade uncovers stromal plasticity in tumors by revealing the existence of a novel subset of interferon-licensed fibroblasts [mouse]

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TGFb-blockade uncovers stromal plasticity in tumors by revealing the existence of a novel subset of interferon-licensed fibroblasts [human]

Project description:Despite the increasing interest in targeting stromal elements of the tumor microenvironment, we still face tremendous challenges in developing adequate therapeutics to modify the tumor stromal landscape. A major obstacle to this is our poor understanding of the phenotypic and functional heterogeneity of stromal cells in tumors. Herein, we performed an unbiased interrogation of tumor mesenchymal cells, delineating the co-existence of distinct subsets of cancer-associated fibroblasts in the microenvironment of murine carcinomas, each endowed with unique phenotypic features and functions. Furthermore, our study shows that neutralization of TGFβ in vivo led to a profound remodeling of CAF dynamics, greatly reducing the frequency and activity of the myofibroblast subset, while promoting the formation of a novel fibroblast population characterized by strong response to interferon and heightened immunomodulatory properties. These changes correlated with the development of productive anti-tumor immunity and greater efficacy of PD1 immunotherapy. Along with providing the scientific rationale for the evaluation of TGFβ and PD1 co-blockade in the clinical settings, this study also supports the concept of plasticity of the stromal cell landscape in tumors, laying the foundation for future investigations aimed at defining pathways and molecules to program CAF composition for cancer therapy.

2020-11-03 | GSE160686 | GEO

TGFb-blockade uncovers stromal plasticity in tumors by revealing the existence of a novel subset of interferon-licensed fibroblasts [mouse]

2020-10-25 | GSE160052 | GEO

TGFb-blockade uncovers stromal plasticity in tumors by revealing the existence of a novel subset of interferon-licensed fibroblasts

Project description:This SuperSeries is composed of the SubSeries listed below.

2020-11-03 | GSE160687 | GEO

TGF?-blockade uncovers stromal plasticity in tumors by revealing the existence of a subset of interferon-licensed fibroblasts.

Project description:Despite the increasing interest in targeting stromal elements of the tumor microenvironment, we still face tremendous challenges in developing adequate therapeutics to modify the tumor stromal landscape. A major obstacle to this is our poor understanding of the phenotypic and functional heterogeneity of stromal cells in tumors. Herein, we perform an unbiased interrogation of tumor mesenchymal cells, delineating the co-existence of distinct subsets of cancer-associated fibroblasts (CAFs) in the microenvironment of murine carcinomas, each endowed with unique phenotypic features and functions. Furthermore, our study shows that neutralization of TGF? in vivo leads to remodeling of CAF dynamics, greatly reducing the frequency and activity of the myofibroblast subset, while promoting the formation of a fibroblast population characterized by strong response to interferon and heightened immunomodulatory properties. These changes correlate with the development of productive anti-tumor immunity and greater efficacy of PD1 immunotherapy. Along with providing the scientific rationale for the evaluation of TGF? and PD1 co-blockade in the clinical setting, this study also supports the concept of plasticity of the stromal cell landscape in tumors, laying the foundation for future investigations aimed at defining pathways and molecules to program CAF composition for cancer therapy.

| S-EPMC7725805 | biostudies-literature

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High-dose oncogenic PIK3CA drives constitutive cellular stemness through increased NODAL/TGFb signaling

Project description:Oncogenic PIK3CA mutations activate phosphoinositide 3-kinase (PI3K) and are among the commonest somatic mutations in cancer and mosaic, developmental overgrowth disorders. We recently demonstrated that the ‘hotspot’ variant PIK3CAH1047R exerts striking allele dose-dependent effects on stemness in human induced pluripotent stem cells (iPSCs), and moreover demonstrated multiple oncogenic PIK3CA copies in a substantial subset of human cancers. To identify the molecular mechanism underpinning PIK3CAH1047R allele dose-dependent stemness, we profiled isogenic wild-type, PIK3CAWT/H1047R and PIK3CAH1047R/H1047R iPSCs by high-depth transcriptomics, proteomics and reverse-phase protein arrays (RPPA). PIK3CAH1047R/H1047R iPSCs exhibited altered expression of 5644 genes and 248 proteins, whereas heterozygous hPSCs showed 492 and 54 differentially-expressed genes and proteins, respectively, confirming a nearly deterministic phenotypic effect of homozygosity for PIK3CAH1047R. Pathway and network-based analyses predicted a strong association between self-sustained TGFb/NODAL signaling and the ‘locked’ stemness phenotype induced by homozygosity for PIK3CAH1047R. This stemness gene signature was maintained without exogenous NODAL in PIK3CAH1047R/H1047R iPSCs and was reversed by pharmacological inhibition of TGFb/NODAL signaling but not by PIK3CA-specific inhibition. Analysis of PIK3CA-associated human breast cancers revealed increased expression of the stemness markers NODAL and POU5F1 as a function of disease stage and PIK3CAH1047R allele dosage. Together with emerging realization of the link between NODAL re-expression and aggressive cancer behavior, our data suggest that TGFb/NODAL inhibitors warrant testing in advanced breast tumors with multiple oncogenic PIK3CA copies.

2021-03-03 | PXD014719 | Pride

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