Project description:Background: Cutaneous squamous cell carcinomas (cSCC) are among the most common and highly mutated human malignancies, with rising incidence rates. There are limited treatment options for advanced and metastatic cSCC and particularly high-risk groups, such as organ transplant recipients, are in urgent need for strategies to treat aggressive cSCC. We have previously developed a preclinical murine model for cSCC, with remarkably similar histopathology and genetics to human cSCC. Understanding the impact of DNA methylation in cSCC may provide avenues to develop new treatment or prevention strategies. Here, we perform reduced-representation bisulfite sequencing based DNA methylation analysis of a murine cSCC model (6 tumors, 6 controls, 2 independent healthy skin samples) and compare results with publicly available human cSCC methylation data for two cSCC subtypes, stem-cell like and keratinocyte like tumors. Results: Contrasting most cancers, general DNA hypermethylation was previously reported for high-risk human cSCC. Similarly, we found significantly increased average methylation in mouse cSCC as well as in stem-cell like, but not keratinocyte like, human cSCC. Locus specific methylation changes in mouse cSCC often occurred in regions of potential regulatory function, including enhancers and promoters. One differentially methylated region was located in a potential enhancer of the tumor suppressor gene Filip1l and expression of this gene was significantly reduced in mouse tumors and human cSCC cell lines. Furthermore, comparison of differentially methylated genes revealed remarkable similarities between human and mouse cSCC. Conclusion: Our data suggest that, in addition to mutations, deregulation of DNA methylation is an important feature of murine and human cSCC. DNA methylation likely contributes to silencing of tumor suppressor genes, as shown for the Filip1l gene. The similarities between mouse and human cSCC, particularly stem-cell like, highlight the clinical relevance of our model and presents unique opportunities to identify new treatment strategies.
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.
Project description:To determine the differentially expressed miRNAs in human cutaneous squamous cell carcinoma biopsies versus normal skin samples using microarray analysis.
Project description:Identification of the expression pattern of miRNAs at different stages of skin cancer progression in a panel of murine skin cancer cell lines miR-203 and miR-205 were differentially expressed in this panel, and were evaluated as biomarkers of prognosis in human cutaneous squamous cell carcinoma Three main tumor phenotypes: (i) Squamous non-malignant: Five non-malignant cell lines: three of them immortalized keratinocyte cell lines, and of them two papilloma cell lines. (ii) Three malignant squamous cell lines. (iii) Five malignant spindle cell lines. One replicate per array, except A5 that was done in duplicate as control
Project description:Identification of the expression pattern of miRNAs at different stages of skin cancer progression in a panel of murine skin cancer cell lines miR-203 and miR-205 were differentially expressed in this panel, and were evaluated as biomarkers of prognosis in human cutaneous squamous cell carcinoma
Project description:Interactions between cells and the extracellular matrix, mediated by integrin adhesion complexes (IACs), play key roles in cancer progression and metastasis. We report here systems-level changes in the adhesome during progression of a patient-derived cutaneous squamous cell carcinoma (cSCC). We found that the actin regulatory protein Mena is enriched in IACs in metastatic cSCC cells and is connected within a subnetwork of actin-binding proteins to the LINC complex component nesprin-2.