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Identification of transcriptomic drivers of squamous cell carcinoma development through a preneoplastic intermediate [mouse miRNA-Seq]

ABSTRACT: Cutaneous squamous cell carcinoma (cuSCC) comprises 15-20% of all skin cancers, accounting for over 700,000 cases in the U.S. annually. Most cuSCC arise in association with a distinct precancerous lesion, the actinic keratosis (AK). In order to identify potential targets for molecularly targeted chemoprevention, we performed integrated cross-species genomic analysis of cuSCC development through the preneoplastic AK stage using matched human samples and a solar UV-driven Hairless mouse model. We identified the major transcriptional drivers of this sequence showing that the key genomic changes in cuSCC development occur in the normal skin to AK transition. Our data validate the use of this UV-driven mouse cuSCC model for cross-species analysis and demonstrate that cuSCC bears deep molecular similarities to multiple carcinogen-driven SCCs from diverse sites, suggesting that cuSCC may serve as an effective, accessible model for multiple SCC types and that common treatment and prevention strategies may be feasible.

ORGANISM(S): Mus musculus

PROVIDER: GSE84192 | GEO | 2017/02/09

SECONDARY ACCESSION(S): PRJNA328262

REPOSITORIES: GEO

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Identification of transcriptomic drivers of squamous cell carcinoma development through a preneoplastic intermediate [human miRNA-Seq]

Project description:Cutaneous squamous cell carcinoma (cuSCC) comprises 15-20% of all skin cancers, accounting for over 700,000 cases in the U.S. annually. Most cuSCC arise in association with a distinct precancerous lesion, the actinic keratosis (AK). In order to identify potential targets for molecularly targeted chemoprevention, we performed integrated cross-species genomic analysis of cuSCC development through the preneoplastic AK stage using matched human samples and a solar UV-driven Hairless mouse model. We identified the major transcriptional drivers of this sequence showing that the key genomic changes in cuSCC development occur in the normal skin to AK transition. Our data validate the use of this UV-driven mouse cuSCC model for cross-species analysis and demonstrate that cuSCC bears deep molecular similarities to multiple carcinogen-driven SCCs from diverse sites, suggesting that cuSCC may serve as an effective, accessible model for multiple SCC types and that common treatment and prevention strategies may be feasible.

2017-02-09 | GSE84193 | GEO

Identification of transcriptomic drivers of squamous cell carcinoma development through a preneoplastic intermediate [mouse RNA-Seq]

2019-07-08 | GSE84292 | GEO

Identification of transcriptomic drivers of squamous cell carcinoma development through a preneoplastic intermediate [human RNA-Seq]

2017-02-09 | GSE84293 | 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

Transcription profiling of human normal skin, actinic keratosis and squamous cell carcinoma

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

Ingenol mebutate induces profound inflammatory and wound healing responses in uninvolved and actinic keratosis skin

Project description:We studied the transcriptomic profile of actinic keratosis (AK) skin compared to matched samples from uninvolved skin (US) before and after treatment with ingenol mebutate gel. We found that AK has a distinct mRNA profile that separates it from uninvolved skin. In particular, numerous genes associated with epidermal development and keratinocyte differentiation, such as LCE3D, SPRR1A, PI3 and several genes in the keratin family were highly expressed in AK0 skin, but not in US0, in line with the hyperkeratosis characteristic for AK. Topical application of ingenol mebutate had a profound effect on the gene expression profile, and interestingly, many more genes were affected in US than in AK. Enrichment analysis revealed that the main responses to ingenol mebutate treatment of both US and AK were inflammatory response, response to wounding, and wound healing. 30 skin biopsies were analysed; 5 from each of 6 AK patients. Before initiation of treatment, baseline biopsies were taken from one AK lesion (AK0) and from uninvolved skin (US0). A third biopsy was taken after day 1 application of ingenol mebutate from one AK lesion (AK1). The fourth and fifth biopsies were obtained one day after the second topical application with ingenol mebutate from an AK lesion (AK2) and from uninvolved skin (US2), respectively.

2016-03-31 | E-GEOD-63107 | biostudies-arrayexpress

Characterizing dermal transcriptional change in the progression from sun-protected skin to actinic keratosis. II[

Project description:Here we used a pan-cytokeratin antibody to differentiate the epidermal from dermal compartment and assayed over 18,000 RNA probes from multiple regions of interest (ROI) comparing sun protected skin, and two regions (edge and center) from AK/sun damaged skin. This allows for a trajectory from sun protected to sun damaged within an individual. Traditionally, cancer biology focusses on change within the tumor compartment for diagnosis and staging and current genetic profiling of actinic keratosis (the precursor lesion for cutaneous squamous cell carcinoma) has focused on analysis limited to whole skin or the epidermal compartment alone. Here we use spatial transcriptomics to compare and contrast the epidermal and stromal compartments from different regions of actinic keratosis and matched sun protected skin from six individuals. Our data show that the major changes in AK at the transcriptional level are evident in the dermal compartment. Sun protected skin (n=5-6 from 6 individuals for a total of 34 ROI), the center of an AK lesion (n=3 for a total of 18 ROI) and edge of the AK lesion (n=2-3 for a total of 17 ROI) representing sun-damaged skin, from six unrelated individuals, the center of an AK lesion (n=3 for a total of 18 ROI) and edge of the AK lesion (n=2-3 for a total of 17 ROI) representing sun-damaged skin, from six unrelated individuals.

2022-12-19 | GSE221000 | GEO

Characterizing dermal transcriptional change in the progression from sun-protected skin to actinic keratosis. [I]

2022-12-19 | GSE220998 | GEO

Ingenol mebutate induces profound inflammatory and wound healing responses in uninvolved and actinic keratosis skin

2016-03-31 | GSE63107 | GEO

Novel Molecular Markers for non-melanoma skin cancer

Project description:normal skin (no), actinic keratosis (ak), and squamous cell carcinoma (scc) of the skin were examined: Carcinogenesis is a multi-step process indicated by several genes up- or down-regulated during tumor progression. The type and number of genes involved in non-melanoma skin cancer (NMSC) are still unclear. This study examined and identified different expressed genes in NMSC. Fifteen snap-frozen biopsies of five immunosuppressed organ-transplanted recipients each normal skin, actinic keratosis (AK) and invasive squamous cell carcinoma (SCC) were analysed. Total RNA was extracted reverse transcribed and biotin-labeled cRNA was used for hybridization with Affymetrix HG-U133A gene expression cDNA-microarrays containing 22,283 known genes. Confocal scanner evaluated the signals twice and data analysis was performed by predicition analysis of microarrays (PAM) using nearest shrunken centroids with the threshold 3.5 to identify genes best characterizing normal skin and skin cancer. ANOVA analysis was performed as a second independent method to identify differentially expressed genes (p<0.05, and p<0.15). Quantitative verification of 13 up- or down-regulated genes was performed by real-time RT-PCR and genes were confirmed by sequencing. Broad coherent patterns in normal skin vs. AK and SCC were observed for 118 genes. Some of the genes (e.g. annexin, lamin, and metalloproteinases) up-regulated in carcinomas in our study have previously reported as over-expressed in NMSC. In total 42 genes were up-regulated and 76 genes were down-regulated in non-melanoma skin cancer. The majority of genes identified have not been previously reported different expressed during non-melanoma skin carcinogenesis. Keywords: ordered

2006-06-30 | GSE2503 | GEO

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