Single-cell Sequencing Highlights Heterogeneity and Malignant Progression in Actinic Keratosis and Cutaneous Squamous Cell Carcinoma
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ABSTRACT:
PROVIDER: PRJNA795772 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17514602_1.fastq.gz | Fastqsanger.gz | |||
| SRR17514602_2.fastq.gz | Fastqsanger.gz | |||
| SRR17514603_1.fastq.gz | Fastqsanger.gz | |||
| SRR17514603_2.fastq.gz | Fastqsanger.gz | |||
| SRR17514604_1.fastq.gz | Fastqsanger.gz |
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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
Project description:normal skin (no), actinic keratosis (ak), and squamous cell carcinoma (scc) of the skin were examined:; BACKGROUND: Carcinogenesis is a multi-step process indicated by several genes up- or down-regulated during tumor progression. This study examined and identified differentially expressed genes in cutaneous squamous cell carcinoma (SCC). RESULTS: Three different biopsies of 5 immunosuppressed organ-transplanted recipients each normal skin (all were pooled), actinic keratosis (AK) (two were pooled), and invasive SCC and additionally 5 normal skin tissues from immunocompetent patients were analyzed. Thus, total RNA of 15 specimens were used for hybridization with Affymetrix HG-U133A microarray technology containing 22,283 genes. Data analyses were performed by prediction analysis of microarrays using nearest shrunken centroids with the threshold 3.5 and ANOVA analysis was independently performed in order to identify differentially expressed genes (p < 0.05). Verification of 13 up- or down-regulated genes was performed by quantitative real-time reverse transcription (RT)-PCR and genes were additionally confirmed by sequencing. Broad coherent patterns in normal skin vs. AK and SCC were observed for 118 genes. CONCLUSION: The majority of identified differentially expressed genes in cutaneous SCC were previously not described.
2007-10-02 | E-GEOD-2503 | biostudies-arrayexpress
Project description:Squamous cell carcinoma is the second most common skin cancer and frequently progress from an intraepithelial actinic keratosis. The role of microRNAs during the progression from actinic keratosis to cutaneous squamous cell carcinoma (cSCC) remains to be elicited. By using an Agilent microRNA expression microarray we found the expression of miR-204 to be markedly downregulated in cSCC when compared to actinic keratoses. DNA methylation of the TRPM3 promoter region upstream of miR-204-5p was identified as one of the repressive mechanisms that accounts for miR-204 silencing in cSCC. Functional studies on HaCaT cells revealed that this microRNA downregulates the Signal Transducer and Activator of Transcription 3 (STAT3) pathway and favours the MAPK signaling pathway, likely acting through PTPN11, a tyrosine phosphatase that is a direct miR-204 target. We found that activated STAT3, as detected by pY705-STAT3 immunofluorescence, is retained in the membrane and cytoplasm compartment in AK, whereas cSCC displayed STAT3 in the nuclei. Taken together, our data indicates that MiR-204 may act as a “rheostat” that controls the signaling towards the MAPK pathway or the STAT3 pathway.
2016-12-31 | GSE71953 | GEO
Project description:Actinic keratosis is a common skin disease that may progress to invasive squamous cell carcinoma. Ingenol mebutate has demonstrated efficacy in field treatment of actinic keratosis. However, molecular mechanisms on ingenol mebutate response are not yet fully understood.
2020-05-18 | GSE142108 | GEO
Project description:Single cell transcriptomes of genetic landscape from actinic keratosis to cutaneous squamous cell carcinoma
| PRJNA824113 | ENA
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
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 sequencing (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 matched 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 (DEGs) analysis screened out multiple key driver genes including transcription factors 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.
| S-EPMC10783873 | biostudies-literature
Project description:Genome wide DNA methylation profiling in cutaneous squamous cell carcinoma. The Infinium MethylationEPIC BeadChips 850K has been used to interrogate DNA methylation changes. The cohort included 23 patients in total, with precursors of squamous cell carcinoma (actinic keratosis group) and with cSCC at different stages.
2019-12-12 | E-MTAB-8542 | biostudies-arrayexpress
Project description:The goal of the study is to compare the transcriptomic profile of patient-derived skin samples, Actinic Keratosis, Intraepidermal Carcinoma and Squamous Cell Carcinoma samples using next generation RNA Sequencing. We aim to identify perturbed pathways and similarities between the 4 conditions. Please note that detailed patients' information, such as gender and age, was withheld from this submission to protect the patients' identity.
2017-05-16 | E-MTAB-5678 | biostudies-arrayexpress
Project description:Skin carcinogenesis is known to be a multi-step process with several stages along its malignant evolution. We hypothesized that transformation of normal epidermis to cutaneous squamous cell carcinoma (cSCC) is causally linked to alterations in miRNA expression. For this end we decided to evaluate their alterations in the pathologic states ending in cSCC. Total RNA was extracted from FFPE biopsies of five stages along the malignant evolution of keratinocytes towards cSCC: Normal epidermis, severe solar elastosis (SE), actinic keratosis (KIN1-2), advanced actinic keratosis, (KIN3) and well differentiated cSCC. Next generation small RNA sequencing was performed. We found that 18 miRNAs are over expressed and 28 miRNAs are under expressed in cSCC compared to normal epidermis. miR-424, miR-320, miR- 222 and miR-15a showed the highest fold change among the over expressed miRNAs. And miR-100, miR-101 and miR-497 showed the highest fold change among the under expressed miRNAs. Heat map of hierarchical clustering analysis of significantly changed miRNAs and principle component analysis disclosed that the most prominent change in miRNAs expression occurred in the switch from “early” stages; normal epidermis, solar elastosis and early actinic keratosis to the “late” stages of epidermal carcinogenesis; late actinic keratosis and cSCC. We found several miRNAs with "stage specific" alterations while others display a clear “gradual”, either progressive increase or decrease in expression along the malignant evolution of keratinocytes. The observed alterations focused in miRNAs involved in the regulation of AKT/mTOR or in those involved in epithelial to mesenchymal transition. We chose to concentrate on the evaluation of the molecular role of miR- 497. We found that it induces reversion of epithelial to mesenchymal transition. We proved that SERPINE-1 is its biochemical target. The present study allows us to further study the pathways which are regulated by miRNAs along the malignant evolution of keratinocytes towards cSCC.
2017-12-31 | GSE101192 | GEO