A decision point between transdifferentiation and programmed cell death priming controls

The involvement of cell death pathways in the early stage of pancreatic ductal adenocarcinoma (PDAC) development, especially KRAS-dependent acinar-to-ductal metaplasia (ADM), remains to be investigated. Here, we show that TAK1 mediates cell survival during ADM transdifferentiation through suppression of Caspase-8/3-dependent apoptosis and RIPK3-MLKL-dependent necroptosis, which could be targeted for prevention and treatment of PDAC. Given that mutations are a driving force of PDAC development and TAK1 might modulate chromosomal stability and the mutational spectrum of PDAC via NF-κB, we performed an array comparative genomic hybridization (aCGH) analysis on pancreatic tissue of five KRASG12D TAK1/CASP8ΔAc RIPK3-/- mice and five KRASG12D mice. Interestingly, both genotypes showed distinct chromosomal abnormalities with gain or loss of genetic regions. Further analysis of these chromosomal regions showed they contained genes known to be involved in the pathogenesis of human PDAC, such as Trp53, Cdkn2a, Smad4, Rnf43 and Arid1a. However, we did not observe a consistent pattern of chromosomal/gene alterations in the majority of samples/tumors between KRASG12D single transgenic mice and KRASG12D TAK1/CASP8ΔAc RIPK3-/- mice, arguing against the hypothesis that TAK1 deficiency mediated late stages of tumor promotion through changes in chromosomal stability. the genomic DNA of pancreatic tissue from 5 KRAS mutant mice (KRASG12D) and 5 mice which were KRAS mutant (KRASG12D), TAK1/CASP8 deficient and RIPK3-/- knockout was hybridized against the genomic DNA from a pooled normal DNA reference from the same mouse strain and the resulting copy number profiles compared to each other.