GSE134235
Mutant Kras co-opts a progenitor-derived enhancer network to initiate pancreatic tumorigenesis [RNA-seq]
Oncogenes are highly specific in the cells they can transform, although the molecular basis for this is poorly understood. Inflammation often promotes tumorigenesis, and in the pancreas it promotes cellular plasticity and accelerates Kras-driven neoplasia. We demonstrate that plasticity is coupled to the emergence of transient progenitor cells that are readily transformed by KrasG12D. The progenitor state is linked to coordinate upregulation of proliferation genes through chromatin opening at nearby lineage-specific enhancers. Mutant Kras taps into this program by co-opting the normally transient enhancer elements, making them permanent and Kras-dependent in cancer. Mechanistically, co-option occurs through cooperation of Kras-driven transcription factors with the existing landscape of pancreatic lineage transcription factors, which are recruited to play a central role in driving the mutant Kras-dependent transcriptional program. These observations suggest that proliferation is controlled by tissue-specific enhancer networks that are tapped into by oncogenes, helping explain the lineage specificity of cancer drivers. Overall design: Examination of transcriptome of [1] mCherry-positive cells on day0,day,day7 after CAE injection. [2] eGFP-positive cells from pancreas after knocking out Kras,Junb,Fosl1,Klf5,Foxa2,Rosa.injection and the PDA. [3] mCherry-positive cells from Tamoxifen induced KrasG12D on day7 after CAE injection and the PDA.