Project description:To examine origin firing upon CDT1 overexpression, EdUseq-HU was performed in HCT116 cells with normal expression levels of CDT1 (OFF) and HCT116 cells with CDT1 overexpression (ON)
Project description:Colorectal adenomas are precursor lesions of colorectal cancers and represent clonal amplifications of single cells from colonic crypts. DNA methylation patterns specify cell-type identity during cellular differentiation and therefore provide novel opportunities for the molecular analysis of tumors. We have now analyzed DNA methylation patterns in colorectal adenomas and identified three biologically defined subclasses that describe different intestinal crypt differentiation stages. Importantly, colorectal carcinomas could be classified into the same methylation subtypes, reflecting their shared cell-types of origin with adenomas. Further data analysis also revealed significantly reduced overall survival for one of the subtypes. Our results establish a novel concept for understanding the methylation patterns observed in colorectal cancer and provide opportunities for tumor subclassification and patient stratification.
Project description:Ptch1 is a key regulator of embryonic development, acting through the sonic hedgehog (SHH) signaling pathway. Ptch1 is best known as a tumor suppressor, as germline or somatic mutations in Ptch1 lead to the formation of skin basal cell carcinomas. Here we show that Ptch1 also acts as a lineage-dependent oncogene, as overexpression of Ptch1 in adult skin in K14Ptch(FVB) transgenic mice synergizes with chemically induced Hras mutations to promote squamous carcinoma development. These effects were not because of aberrant activation of SHH signaling by the K14Ptch(FVB) transgene, as developmental defects in the highest expressing transgenic lines were consistent with the inhibition of this pathway. Carcinomas from K14Ptch(FVB) transgenic mice had only a small number of nonproliferative Ptch1 transgene-positive cells, suggesting that the Ptch1 transgene is not required for tumor maintenance, but may have a critical role in cell-fate determination at the initiation stage.