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Functionally distinct cancer-associated fibroblast subpopulations establish a tumor-promoting environment in squamous cell carcinoma

ABSTRACT: Cutaneous squamous cell carcinoma (cSCC) is a serious public health problem due to its high incidence and metastatic potential. It may progress from actinic keratosis (AK), a precancerous lesion, or the in situ carcinoma Bowen's disease (BD). During this progression, malignant keratinocytes activate dermal fibroblasts into tumor-promoting cancer-associated fibroblasts (CAFs), whose origin and emergence remain largely unknown. Here, we generate and analyze >115,000 single-cell transcriptomes from healthy skin, BD and cSCC of male donors. Our results reveal immunoregulatory and matrix-remodeling CAF subtypes that might derive from pro-inflammatory and mesenchymal fibroblasts, respectively. These CAF subtypes are largely absent in AK and interact with different cell types to establish a pro-tumorigenic microenvironment. These findings are cSCC-specific and could not be recapitulated in basal cell carcinomas. Our study provides important insights into the functionalities of dermal CAFs that will be highly beneficial for the specific targeting of the cSCC microenvironment.

ORGANISM(S): Homo sapiens

PROVIDER: GSE218170 | GEO | 2023/08/09

REPOSITORIES: GEO

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Differential proteomic analysis of actinic keratosis, Bowen's disease and cutaneous squamous cell carcinoma by label-free LC-MS/MS

Project description:BACKGROUND: The boundaries between actinic keratosis (AK), Bowen's disease (BD), and cutaneous squamous cell carcinoma (cSCC) are sometimes not clear. Large-scale proteomic profiling studies of these lesions are also non-existent. OBJECTIVE: To evaluate proteomic changes between normal epidermis, AK, BD and cSCC that could support a molecular classification and improve our understanding of disease progression. METHODS: Microdissected formalin-fixed paraffin embedded samples of normal epidermis (n = 4, pooled), AK (n = 10), BD (n = 10) and cSCC (n = 10) were analyzed by mass spectrometry. Following normalization and multiple testing adjustments, differential abundance analysis was performed using Linear Models for Microarray data. Proteins were filtered for significance (adjusted p-value ≤ 0.05) and fold change of at least ±1.5. Comparative bioinformatics analysis was performed using Ingenuity Pathway Analysis (IPA) software. Proteomic findings were subsequently substantiated using immunohistochemistry. RESULTS: 2073 unique proteins were identified. cSCC had the highest number of differentially abundant proteins (63 proteins) followed by BD (58 proteins) and AK (46 proteins). Six proteins (APOA1, ALB, SERPINA1, HLA-B, HP and TXNDC5) were differentially abundant in cSCC compared to AK. Immunohistochemical analysis corroborated changes in MIF, RPL37A and TXNDC5. IPA analysis predicted that cell proliferation, angiogenesis and inflammatory reactions were significantly activated in cSCC compared to BD and AK. Cell death and DNA damage were predicted to be inhibited in BD. CONCLUSION: Our study supports the concept that AK and BD are precursors of cSCC. The identification of proteome changes indicates disruption of repair, pro-apoptotic, and tumor promoting pathways. Our findings will help select targets for classification and treatment.

2018-11-21 | PXD011609 | Pride

Single-cell Sequencing Highlights Heterogeneity and Malignant Progression in Actinic Keratosis and Cutaneous Squamous Cell Carcinoma

Project description:Cutaneous squamous cell carcinoma (cSCC) is the second most frequent of the keratinocyte-derived malignancies with actinic keratosis (AK) as a precancerous lesion. To comprehensively delineate the underlying mechanisms for the whole progression from normal skin to AK to invasive cSCC, we performed single-cell RNA-seq (scRNA-seq) to acquire the transcriptomes of 138,982 cells from 13 samples of six patients including AK, squamous cell carcinoma in situ (SCCIS), cSCC and their normal tissues, covering comprehensive clinical courses of cSCC. We identified diverse cell types, including important subtypes with different gene expression profiles and functions in major keratinocytes. In SCCIS, we discovered the malignant subtypes of basal cells with differential proliferative and migration potential. Differentially expressed genes (DEG) analysis screened out multiple key driver genes including transcription factors (TFs) along AK to cSCC progression. Immunohistochemistry (IHC) / immunofluorescence (IF) experiments and single-cell ATAC sequencing (scATAC-seq) data verified the expression changes of these genes. The functional experiments confirmed the important roles of these genes in regulating cell proliferation, apoptosis, migration and invasion in cSCC tumor. Furthermore, we comprehensively described the tumor microenvironment (TME) landscape and potential keratinocyte-TME crosstalk in cSCC providing theoretical basis for immunotherapy. Together, our findings provide a valuable resource for deciphering the progression from AK to cSCC and identifying potential targets for anticancer treatment of cSCC.

2023-01-12 | GSE193304 | GEO

Methylation profiling identifies two subclasses of squamous cell carcinoma related to distinct cell types of origin

Project description:Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer type and arises from keratinocytes. Most cSCC progress from a UV-induced precancerous lesion termed actinic keratosis (AK). Despite various efforts to characterize these lesions molecularly, the etiology of AK and its progression to cSCC remain only partially understood. Here we have used Infinium MethylationEPIC BeadChips to interrogate the DNA methylation status of about 850.000 CpGs in epidermal preparations from healthy skin, AK and cSCC. Importantly, we found that the premalignant AK samples displayed classical features of cancer methylomes and were highly similar to cSCC methylomes. Further analysis identified typical features of stem cell methylomes, such as a reduced DNA methylation age, non-CpG methylation and stem cell-related keratin and enhancer methylation patterns. Interestingly, this signature was detected only in one half of the AK and cSCC samples, while the other half showed methylation patterns that were more closely related to the control epidermis. These findings suggest the existence of two distinct subclasses of AK and cSCC that originate from distinct keratinocyte differentiation stages.

2017-12-19 | E-MTAB-5738 | biostudies-arrayexpress

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

Distinct fibroblast functional states drive clinical outcomes in ovarian cancer and are regulated by TCF21

Project description:Recent studies indicate that cancer-associated fibroblasts (CAFs) are phenotypically and functionally heterogeneous. However, little is known about CAF subtypes and the roles they play in cancer progression. Here we identify and characterize two CAF subtypes that coexist within high grade serous ovarian cancers: Fibroblast activation protein (FAP)-high (FH) CAFs resemble the classical myofibroblast-type CAF, whereas FAP-low (FL) CAFs possesses a preadipocyte-like molecular signature.

2020-05-01 | GSE126132 | GEO

Distinct fibroblast functional states drive clinical outcomes in ovarian cancer and are regulated by TCF21

2020-05-01 | GSE126131 | GEO

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

Androgen receptor functions as transcriptional repressor of Cancer Associated Fibroblast (CAF) activation [ChIP-seq]

Project description:The age-associated increase of cancer risk has been linked with stromal fibroblast senescence and early steps of Cancer Associated Fibroblast (CAF) activation. Surprisingly little is known about the role of androgen receptor (AR) signalling in this context. We show that AR expression is down-modulated in stromal fibroblasts underlying premalignant skin cancer lesions (actinic keratoses, AK) as well as in CAFs from the three major skin cancer types, squamous (SCC) and basal cell (BCC) carcinomas and melanomas. Decreased AR expression is linked to the concomitant down-modulation of CSL, key effector of canonical Notch signalling and global modulator of chromatin configuration, and it can be counteracted by treatment with BET inhibitors, which reverse CAF activation. Functionally, AR gene silencing in dermal fibroblasts results in p53-dependent senescence and induction of key CAF-effector genes, with AR physically converging with CSL in negative control of these genes. The findings are of functional significance as, in an orthotopic model of skin cancer, dermal fibroblasts with AR loss enhance significantly tumorigenicity of SCC and melanoma cells. As such, the findings establish AR as a novel potential target for stroma-focused cancer prevention and treatment.

2018-08-28 | GSE107320 | GEO

Androgen receptor functions as transcriptional repressor of Cancer Associated Fibroblast (CAF) activation [RNA-seq]

2018-08-28 | GSE107319 | GEO

Single cell transcriptomes of genetic landscape from actinic keratosis to cutaneous squamous cell carcinoma

Project description:Here, we performed scRNA-seq to compare the transcriptomes of individual cells from three groups: (1) healthy sun-exposed skin; (2) AK samples; (3) cSCC samples. A total of 81792 cells from 8 AK samples, 3 cSCC samples and 3 control skin tissue were characterized, which comprising representatives from each of the major dermal cell types. Our results demonstrate the heterogeneity within tissues/patients and corroborated the effect of the tumor environment during carcinogenesis, especially immune cell populations. Additionally, we identified a list of gene expression changes that affected several known cancerous pathways, with potential evolution trajectory from a subset of AK premalignant cells to cSCC cells. Our findings will improve current understanding about the mechanism of AK-cSCC progression, and are potentially valuable in providing novel precautionary/ therapeutic markers.

2024-03-01 | GSE200334 | GEO

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