CAF-S3 subset in human breast and ovarian cancers
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ABSTRACT:
PROVIDER: EGAS00001003344 | EGA |
REPOSITORIES: EGA
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Project description:Carcinoma-associated fibroblasts (CAF) are key players in the tumor microenvironment. Here, by combining 6 well-known stromal markers, we identify four CAF subsets (CAF-S1 to CAF-S4) in human breast cancer (BC) that exhibit distinct activation patterns and accumulate differently in BC subtypes.
| EGAS00001002508 | EGA
Project description:The major cause of death among breast cancer patients is metastatic dissemination, suggesting that understanding the mechanisms driving this process remains an unmet medical need. Here, by concomitantly using 5 markers, we identify 4 Carcinoma-Associated Fibroblasts (CAF) subsets in primary tumors and corresponding metastatic lymph nodes (LN). Two CAF subsets, called CAF-S1 and CAF-S4, correlate with the proportion of cancer cells in invaded LN and exert distinct functions in tumor cell spread. CAF-S1 promote cancer cell migration and initiates an epithelial to mesenchymal transition through a CXCL12 / TGFb positive loop. For their part, the highly contractile CAF-S4 foster cancer cell motility and invasion in 3-dimensional matrix via Notch pathway activation. Finally, CAF-S1 and CAF-S4 accumulation in LN is a new prognostic factor at diagnostic, independent of breast cancer subtypes and LN status, strengthening the validity of our findings in human breast cancer pathophysiology.
| EGAS00001003238 | EGA
Project description:High-grade serous epithelial ovarian cancer (HGSOC) has been recently subdivided into molecular subgroups, including the mesenchymal HGSOC associated with partial tumor-debulking surgery and poor patient survival. Consistent with stromal-related genes signatures defining mesenchymal HGSOC, we show here that stroma plays a key function in this HGSOC molecular subtype. We first highlight stromal heterogeneity in HGSOC by identifying 4 subsets of Carcinoma-Associated Fibroblast (CAF-S1-4). Mesenchymal HGSOC significantly accumulate the activated CAF-S1 subset, which exhibits immunosuppressive functions by promoting attraction, survival and activation of regulatory T-lymphocytes. The CXCL12β chemokine reliably characterizes mesenchymal HGSOC and specifically accumulates in the CAF-S1 subset through a regulation mediated by the miR-141/200a. CXCL12β promotes attraction of T-lymphocytes and is thus a key actor in CAF-S1-mediated immunosuppressive functions. In conclusion, we highlight here for the first time stromal heterogeneity and immunosuppression in mesenchymal HGSOC that could participate in the poor patient prognosis.
| EGAS00001002184 | EGA
Project description:RNA-seq data from iCAF (sorted) and myCAF cluster 0 (spread) CAF-S1 fibroblasts maintained in culture
| EGAS00001004031 | EGA
Project description:A subset of Cancer-Associated Fibroblasts (CAF-S1) mediates immunosuppression in breast cancers (BC), but its heterogeneity and its impact on immunotherapy response remain unknown. Here, we identify 8 CAF-S1 clusters by analyzing more than 18000 single CAF-S1 fibroblasts from BC. We validate the 5 most abundant clusters by flow cytometry and in silico analyses in other cancer types, highlighting their relevance. Myofibroblasts from clusters 0 and 3, characterized by extra-cellular matrix proteins and TGF signaling respectively, are indicative of primary resistance to immunotherapies. Cluster 0 up-regulates PD-1 and CTLA-4 protein levels in regulatory T lymphocytes (Tregs), which in turn increases CAF-S1 cluster 3 cellular content. Thus, our study highlights a positive feedback loop between specific CAF-S1 clusters and Tregs and uncovers their role in immunotherapy resistance.
| EGAS00001004030 | EGA
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
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.
2020-10-25 | GSE160052 | GEO
Project description:Senescence of stromal fibroblasts has been linked to establishment of cancer associated fibroblasts (CAF) and aging-associated increase of tumors. However, in clinically occurring carcinomas, density and proliferation of CAFs are frequently increased rather than decreased. We previously showed that genetic deletion or down-modulation of the canonical Notch effector CSL/RBP-J? in skin dermal fibroblasts is sufficient for CAF activation with consequent development of multifocal keratinocyte tumors. We now show that CSL deletion or knockdown induces senescence of primary fibroblasts derived from dermis, oral mucosa, breast and lung. CSL functions in these cells as a constitutive direct repressor of multiple senescence- and CAF-effector genes. At the same time, it physically interacts with p53, repressing its activity, and p53 activation provides a failsafe mechanism against compromised CSL function. Concomitant loss of CSL and p53 overcomes fibroblast senescence, enhances expression of CAF effector genes and, in vivo, promotes tumour and stromal cell expansion. Together, the findings support a CAF activation/stromal evolution model under convergent CSL/p53 control. Examination of genome-wide CSL binding sites in primary human dermal fibroblasts usinf two different antibodies against CSL
2015-08-24 | E-GEOD-59942 | biostudies-arrayexpress
Project description:Senescence of stromal fibroblasts has been linked to establishment of cancer associated fibroblasts (CAF) and aging-associated increase of tumors. However, in clinically occurring carcinomas, density and proliferation of CAFs are frequently increased rather than decreased. We previously showed that genetic deletion or down-modulation of the canonical Notch effector CSL/RBP-Jκ in skin dermal fibroblasts is sufficient for CAF activation with consequent development of multifocal keratinocyte tumors. We now show that CSL deletion or knockdown induces senescence of primary fibroblasts derived from dermis, oral mucosa, breast and lung. CSL functions in these cells as a constitutive direct repressor of multiple senescence- and CAF-effector genes. At the same time, it physically interacts with p53, repressing its activity, and p53 activation provides a failsafe mechanism against compromised CSL function. Concomitant loss of CSL and p53 overcomes fibroblast senescence, enhances expression of CAF effector genes and, in vivo, promotes tumour and stromal cell expansion. Together, the findings support a CAF activation/stromal evolution model under convergent CSL/p53 control. Human Dermal Fibroblasts were transfected with two different siRNA against CSL in parallel with a control siRNA. Total RNA was extracted 3 days post-transfection, followed by RNA-Seq analysis.
2015-08-24 | E-GEOD-65473 | biostudies-arrayexpress
Project description:DNA methylation profiling in epiRIL344 BC1-S1 to BC1-S6 aerial part (epiRIL344_BC1-S1 - epiRIL344_BC1-S2 - epiRIL344_BC1-S3 - epiRIL344_BC1-S4 - epiRIL344_BC1-S5 - epiRIL344_BC1-S6) Keywords: Genome binding/occupancy profiling by genome tiling array
2012-09-03 | GSE37285 | GEO