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Stromal upregulation of SOX2 promotes tumorigenesis through the generation of a SFRP1/2-expressing cancer-associated fibroblast population [ATAC-seq]

ABSTRACT: Although how CAFs impact the tumor epithelium is being progressively unveiled, transcriptional processes of lineage plasticity in fibroblasts govern the acquisition of the CAF phenotype are much less understood. Here we show that the upregulation of SOX2 is a critical step in this process, which is negatively regulated by the atypical protein kinase (aPKC) PKCz. We demonstrate that the loss of PKCz is essential for the acquisition of the CAF phenotype and for the induction of the desmoplastic and more aggressive phenotype of intestinal tumors in a SOX2-dependent manner. Furthermore, we show here that the loss of PKCz drives the reprogramming of colon stromal fibroblasts into two different subpopulations that express either the Wnt regulators Sfrp1/2 or osteopontin, both ligands positively impinging into the mesenchymal and stem cell activation programs.

ORGANISM(S): Mus musculus

PROVIDER: GSE154857 | GEO | 2020/11/17

REPOSITORIES: GEO

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Stromal upregulation of SOX2 promotes tumorigenesis through the generation of a SFRP1/2-expressing cancer-associated fibroblast population [scRNA-seq]

Project description:Although how CAFs impact the tumor epithelium is being progressively unveiled, transcriptional processes of lineage plasticity in fibroblasts govern the acquisition of the CAF phenotype are much less understood. Here we show that the upregulation of SOX2 is a critical step in this process, which is negatively regulated by the atypical protein kinase (aPKC) PKCz. We demonstrate that the loss of PKCz is essential for the acquisition of the CAF phenotype and for the induction of the desmoplastic and more aggressive phenotype of intestinal tumors in a SOX2-dependent manner. Furthermore, we show here that the loss of PKCz drives the reprogramming of colon stromal fibroblasts into two different subpopulations that express either the Wnt regulators Sfrp1/2 or osteopontin, both ligands positively impinging into the mesenchymal and stem cell activation programs.

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Stromal upregulation of SOX2 promotes tumorigenesis through the generation of a SFRP1/2-expressing cancer-associated fibroblast population [Quant-seq]

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Stromal upregulation of SOX2 promotes tumorigenesis through the generation of a SFRP1/2-expressing cancer-associated fibroblast population [RNA-seq]

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Autocrine Sfrp1 inhibits lung fibroblast invasion during transition to injury induced myofibroblasts

Project description:Fibroblast to myofibroblast conversion is a major driver of tissue remodeling in organ fibrosis. Several distinct lineages of fibroblasts support homeostatic tissue niche functions, yet, specific activation states and phenotypic trajectories of fibroblasts during injury repair have remained unclear. Here, we combined spatial transcriptomics, longitudinal single-cell RNA-seq and genetic lineage tracing to study fibroblast fates during mouse lung regeneration. We discovered a transitional fibroblast state characterized by high Sfrp1 expression, derived from both Tcf21-Cre lineage positive and negative cells. Sfrp1+ cells appeared early after injury in peribronchiolar, adventitial and alveolar locations and preceded the emergence of myofibroblasts. We identified lineage specific paracrine signals and inferred converging transcriptional trajectories towards Sfrp1+ transitional fibroblasts and Cthrc1+ myofibroblasts. Tgfβ1 downregulated Sfrp1 in non-invasive transitional cells and induced their switch to an invasive Cthrc1+ myofibroblast identity. Finally, using loss of function experiments we show that autocrine Sfrp1 directly inhibits fibroblast invasion by regulating the RhoA pathway. In summary, our study reveals the convergence of spatially and transcriptionally distinct fibroblast lineages into transcriptionally uniform myofibroblasts and identifies Sfrp1 as an autocrine inhibitor of fibroblast invasion during early stages of fibrogenesis.

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Fibroblast-derived extracellular vesicles contain SFRP1 and mediate pulmonary fibrosis

Project description:Idiopathic pulmonary fibrosis (IPF) is a lethal chronic lung disease characterized by aberrant intercellular communication, extracellular matrix deposition and destruction of functional lung tissue. While extracellular vesicles (EVs) accumulate in the IPF lung, their cargo and biological effects remain unclear. We interrogated the proteome of EV and non-EV fractions during pulmonary fibrosis and characterize their contribution to fibrosis. EVs accumulated 14 days post-bleomycin challenge, correlating with decreased lung function and initiated fibrogenesis in healthy precision-cut lung slices. Label-free proteomics of broncho-alveolar lavage fluid (BALF)-EVs collected from mice challenged with bleomycin or control identified 107 proteins enriched in fibrotic vesicles. Multiomic analysis revealed fibroblasts as a major cellular source of BALF-EV cargo, which was enriched in Secreted Frizzled Related Protein 1 (SFRP1). Sfrp1 deficiency inhibited the activity of fibroblast-derived EVs to potentiate lung fibrosis in vivo. SFRP1 led to increased transitional cell markers, such as Krt8, and WNT/β-catenin signaling in primary alveolar type 2 cells. SFRP1 is expressed within the IPF lung and localized at the surface of EVs from patient-derived fibroblasts and BALF. Our work reveals altered EV protein cargo in fibrotic EVs promoting fibrogenesis and identifies fibroblast derived vesicular SFRP1 as fibrotic mediator and potential therapeutic target for IPF.

2024-11-05 | GSE272679 | GEO

Autocrine Sfrp1 inhibits fibroblast invasion during transition to injury induced myofibroblasts - Tcf21 labeled mice

Project description:Fibroblast to myofibroblast conversion is a major driver of tissue remodeling in organ fibrosis. Here, we combined spatial transcriptomics, longitudinal single-cell RNA-seq and genetic lineage tracing to study fibroblast fates during mouse lung regeneration. We discovered a transitional fibroblast state characterized by high Sfrp1 expression, derived from both Tcf21-Cre lineage positive and negative cells. Sfrp1+ cells appeared early after injury in peribronchiolar, adventitial and alveolar locations and preceded the emergence of myofibroblasts. We identified lineage specific paracrine signals and inferred converging transcriptional trajectories towards Sfrp1+ transitional fibroblasts and Cthrc1+ myofibroblasts. Tgfβ1 downregulated Sfrp1 in non-invasive transitional cells and induced their switch to an invasive Cthrc1+ myofibroblast identity. Our study reveals the convergence of spatially and transcriptionally distinct fibroblast lineages into transcriptionally uniform myofibroblasts and identifies Sfrp1 as an autocrine inhibitor of fibroblast invasion during early stages of fibrogenesis.

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SFRP1-regulated gene expression in premalignant breast lesions

Project description:• Atypical hyperplasias (AH) provide insights into early changes that may predispose breast epithelial cells to oncogenic transformation. • Of genes associated with premalignancy in prior studies, only mRNA levels of ESR1 and SFRP1 were detected in the present study. • Transcriptional profiling defined signatures distinguishing atypical hyperplasias. The patterns of expression were similar among hyperplastic lesions of lobular and ductal phenotype suggesting a common set of alterations underlying both lesions. Pathway analyses identified elevated expression of estrogen receptor alpha, androgen receptor and EGFR receptors and Rho signaling as central events nodes in the pathways altered in AH. • A set of 43 genes were identified as common targets using 2 different algorithms to detect signatures associated with AH. Knockdown of SFRP1 in a TERT immortalized breast epithelial cell line resulted in 14 genes from this signature being either up-regulated or down-regulated as observed in the expression profiles from AH. • The results demonstrate a signature of genes representing alterations that are common to the development of hyperplasias in both ductal and lobular epithelium. Loss of SFRP1 expression is a key player underlying the transcriptional changes in AH that directs a module of genes that can be used to improve reproducibility of diagnosis of AH.

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MicroRNA expression in prostate cancer cells stimulated with cancer associated fibroblasts

Project description:Tumor microenvironment is a strong determinant for the acquisition of metastatic potential of cancer cells. It has been demonstrated (Giannoni E et al., Cancer Res 2010) that cancer associated fibroblasts (CAF) elicit an epithelial-mesenchymal transition (EMT) in prostate cancer (PCa) cells, leading to enhanced tumor cell aggressiveness. Here, we investigated the involvement of microRNAs (miRNA) in such malignant tumor-stroma interplay, to identify possible tools to counteract metastasis dissemination. To verify whether specific miRNAs are involved in CAF-induced EMT in PCa cells, PC-3 cells were subjected to a variety of stimuli, known to induce or not the acquisition of a mesenchymal phenotype (Giannoni E et al., Cancer Res 2010; Giannoni E et al., Antioxid Redox Signal 2011) , and profiled for miRNA expression on a microarray platform. miRNA expression profiles successfully distinguished cells that underwent EMT following the stimulation with activated fibroblasts (here referred to as “mesenchymal”) from cells that did not (“epithelial”).

2013-09-01 | E-GEOD-42699 | biostudies-arrayexpress

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