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Multiomic analysis reveals conservation of cancer associated fibroblast phenotypes across species and tissue of origin [scATAC-seq]

ABSTRACT: Cancer associated fibroblasts (CAFs) are integral to the solid tumor microenvironment. Once thought to be a relatively uniform population of matrix-producing cells, the arrival of single cell RNA sequencing has revealed diverse CAF phenotypes. Here, we further probe CAF heterogeneity with a comprehensive multiome approach. Using paired, same-cell chromatin accessibility and transcriptome analysis, we provide an integrated analysis of CAF subpopulations over a complex spatial transcriptomic and proteomic landscape to identify three superclusters – steady state-like (SSL), mechanoresponsive (MR) and immunomodulatory (IM) CAFs. These superclusters are recapitulated across multiple tissue types and species. Selective disruption of underlying mechanical force or immune checkpoint inhibition therapy results in shifts in CAF subpopulation distributions and impacts tumor growth. As such, the balance among CAF superclusters may have considerable translational implications. Collectively, this research expands our understanding of CAF biology, identifying regulatory pathways in CAF differentiation and elucidating novel therapeutic targets in a species- and tumor-agnostic manner.

ORGANISM(S): Mus musculus

PROVIDER: GSE212481 | GEO | 2022/10/21

REPOSITORIES: GEO

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Multiomic analysis reveals conservation of cancer associated fibroblast phenotypes across species and tissue of origin [scRNA-seq]

Project description:Cancer associated fibroblasts (CAFs) are integral to the solid tumor microenvironment. Once thought to be a relatively uniform population of matrix-producing cells, the arrival of single cell RNA sequencing has revealed diverse CAF phenotypes. Here, we further probe CAF heterogeneity with a comprehensive multiome approach. Using paired, same-cell chromatin accessibility and transcriptome analysis, we provide an integrated analysis of CAF subpopulations over a complex spatial transcriptomic and proteomic landscape to identify three superclusters – steady state-like (SSL), mechanoresponsive (MR) and immunomodulatory (IM) CAFs. These superclusters are recapitulated across multiple tissue types and species. Selective disruption of underlying mechanical force or immune checkpoint inhibition therapy results in shifts in CAF subpopulation distributions and impacts tumor growth. As such, the balance among CAF superclusters may have considerable translational implications. Collectively, this research expands our understanding of CAF biology, identifying regulatory pathways in CAF differentiation and elucidating novel therapeutic targets in a species- and tumor-agnostic manner.

2022-10-21 | GSE212461 | GEO

Multiomic analysis reveals conservation of cancer associated fibroblast phenotypes across species and tissue of origin [scRNA-Seq]

2022-10-21 | GSE212708 | GEO

Multiomic analysis reveals conservation of cancer associated fibroblast phenotypes across species and tissue of origin [multiome]

2022-10-21 | GSE212707 | GEO

Multiomic analysis reveals conservation of cancer associated fibroblast phenotypes across species and tissue of origin [spatial trascriptomics]

2022-10-21 | GSE212706 | GEO

Cancer-associated fibroblasts recapitulate phenotypes and functions across tumor types and species

Project description:Cancer-associated fibroblasts (CAFs) are among the most abundant cell types in desmoplastic tumors. However, CAFs are not yet a treatment target in mainstream cancer therapy likely because CAF heterogeneity and their roles in solid tumors remain incompletely understood. Here, we explored CAF heterogeneity via single-cell gene expression and chromatin accessibility in conjunction with spatial transcriptomics. We found that CAF heterogeneity is recapitulated across solid tumor types and species, and CAF subpopulations fall into two functional categories: mechano-responsive and immuno-modulatory. These categories are spatially-distinct and governed by specific changes in chromatin accessibility. Selective disruption of underlying mechanical force or immune signaling results in predictable shifts in subpopulation distributions and impacts tumor growth. Collectively, this research elucidates the spatial dynamics of CAF biology, delineates CAF subpopulation functions, identifies CAF-specific treatment factors, and provides a multimodal -omics framework for understanding the tumor stromal niche.

2023-02-01 | GSE179705 | GEO

Differential proteomic profiling between Cancer Associated Fibroblasts and KRAS mutated cancer cell lines

Project description:Purpose Cancer-associated fibroblasts (CAFs) are a key component of tumors. We aimed to profile the proteome of cancer cell lines representing three common cancer types (lung, colorectal and pancreatic) and a representative CAF cell line from each tumor type to gain insight into CAF function and identify new CAF biomarkers. Experimental Design We used isobaric labeling, liquid chromatography and mass spectrometry to evaluate the proteome of 9 cancer and 3 CAF cell lines. Functions of selected differentially expressed proteins in CAF cell lines were further investigated using siRNA and the expression levels of candidate novel CAF biomarkers were evaluated by immunohistochemistry in 30 human tumor specimens. Results Of the 9460 proteins evaluated, functional enrichment analysis revealed N-glycan biosynthesis and extracellular membrane proteins to be upregulated in CAFs and not in cancer cells. 85 proteins had 16-fold higher expression in CAFs compared to cancer cells. These included previously known CAF markers like ACTA2, FAP and SDC2. Novel biomarkers overexpressed in CAFs were noted, including HSPB6 and PTGS1. SiRNA knockdown of these genes encoding these proteins did not reduce contractility in lung CAFs, suggesting they were not crucial to this function despite high expression. Immunohistochemical analysis of 30 tumor samples (10 lung, 10 colorectal and 10 pancreatic) showed HSPB6 and PTGS1 expression were restricted to the stroma. Conclusions An unbiased analysis of the differences in the proteome of cancer cells compared to CAFs revealed increased expression of HSPB6 and PTGS1 in CAFs.

2023-08-21 | PXD040360 | Pride

Functional heterogeneity of cancer-associated fibroblasts from human colon tumors shows specific prognostic gene expression signature

Project description:Tumor growth and metastasis is controlled by paracrine signaling between cells of the tumor microenvironment and malignant cells. Cancer-associated fibroblasts (CAFs), are functionally important components of the tumor microenvironment. Although some steps involved in the cross-talk between these cells are known, there is still a lot that is not clear. Thus, the addition of, the consideration of microenvironment in the development of the disease, to the clinical and pathological procedures (currently admitted as the consistent value cancer treatments) could lay the foundations for the development of new treatment strategies to control the disease. Primary CAF cultures from 15 primary human colon tumors were established Their purity was evaluated by the expression of various epithelial and myofibroblast specific markers Co-culture assays of primary CAFs with different colon tumor cells were performed to evaluate pro-migratory CAF-derived effects on cancer cells CAF gene expression profiles were analyzed by microarray to identify deregulated genes in different pro-migratory CAFs

2013-10-30 | E-GEOD-51257 | biostudies-arrayexpress

Hypoxia-induced proteomic remodeling of human mammary cancer associated fibroblast

Project description:Intratumoral hypoxia causes the formation of dysfunctional blood vessels which contribute to tumor metastasis. Blood vessels are embedded in the tumor stroma where cancer-associated fibroblasts (CAFs) constitute the most prominent cellular component. We found that hypoxic human mammary CAFs promote blood vessel growth in CAF-endothelial cell co-cultures in vitro. Mass spectrometry-based proteomic analysis of CAF secretome unravels how hypoxic CAFs contribute to blood vessel abnormalities by altering the secretion of a multitude of pro- and anti-angiogenic factors. Hypoxia induces pronounced remodeling of the CAF proteome, including proteins that have not been previously related to this process. Our study provides a map of unprecedented depth of hypoxia-induced molecular alterations in mammary CAFs that can be exploited to identify novel mechanisms that control hypoxic CAF functions.

2019-02-15 | PXD006535 | Pride

Comparative single-cell genomics uncovers evolutionarily conserved features and therapeutic targets in triple-negative breast cancer fibroblasts

Project description:We performed scRNA-seq analysis of fibroblasts from murine and human TNBCs. We observed three CAF subtypes in mouse TNBC: two transcriptionally distinct CAFs that were found intermingled and adjacent to tumor cells, and distal CAFs that were located further away from tumor cells. All three CAFs appear to evolve from normal resident fibroblasts/pericytes by activation of Pdgf and Tgfb receptors in fibroblasts in parallel with reciprocal upregulation of ligands in tumor cells and other tumor microenvironment cells. Additionally, extracellular matrix, glycolytic and mitochondrial respiratory genes were strongly upregulated in all three CAFs. Murine pancreatic CAFs displayed matching subtypes. Human TNBCs displayed three analogous CAF subtypes, although only a subset of marker genes are conserved. Finally, the upregulation of specific extracellular matrix genes in different CAF subtypes provides a basis for developing selective CAF-targeted therapeutics.

2022-09-01 | GSE199515 | GEO

Hypoxia-induced proteomic remodeling of human mammary cancer associated fibroblast - siRNA NCBP2-AS2

Project description:Intratumoral hypoxia causes the formation of dysfunctional blood vessels which contribute to tumor metastasis. Blood vessels are embedded in the tumor stroma where cancer-associated fibroblasts (CAFs) constitute the most prominent cellular component. We found that hypoxic human mammary CAFs promote blood vessel growth in CAF-endothelial cell co-cultures in vitro. Mass spectrometry-based proteomic analysis of CAF secretome unravels how hypoxic CAFs contribute to blood vessel abnormalities by altering the secretion of a multitude of pro- and anti-angiogenic factors. Hypoxia induces pronounced remodeling of the CAF proteome, including proteins that have not been previously related to this process. Amongst those, the uncharacterized antisense gene protein NCBP2-AS2 is one of the most transcriptionally upregulated proteins in the proteome and secretome of hypoxic CAFs. Silencing of NCBP2-AS2 abrogates the pro-angiogenic function acquired by hypoxic CAFs through decreasing VEGF expression levels to the levels found in normoxic CAFs.

2019-02-15 | PXD006539 | Pride

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