Chromatin deregulation in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) has the lowest survival rate of all major cancers with a median survival of only six months. At the genetic level, it involves numerous mutations in genes such as Kras, Tp53, Cdkn2a and Smad4 as well as aberrations of the chromatin regulatory machinery.

Chromatin-associated genes are attractive drug targets as epigenetic alterations can be reversed. However, these genes have not been explored as therapeutic targets in PDAC.

Scientists on the EU-funded EPI-TARGETS IN PDAC (Systemic analysis of chromatin-regulatory genes in PDAC using advanced in vivo RNAi) project set out to delineate the role of chromatin-regulatory genes in PDAC onset and maintenance. In this context, they combined genetically engineered PDAC mouse models, multiplexed RNAi screening and advanced in vivo RNAi technologies.

Researchers generated a genetically engineered mouse that lacks Trp53, while it expresses constitutively active form of the oncogene Kras. Trp53 is the mouse homologue of the tumour suppressor Tp53. Following extensive characterisation of this PDAC mouse model, researchers went on to perform RNA interference screening in vitro using a library with short-hairpin RNA molecules that targeted different transcripts of the epigenetic machinery. Selected hits were subsequently validated in vitro and in vivo using cell proliferation and functional assays. The rationale behind this approach was to identify molecules that could reverse the PDAC phenotype of the transgenic mouse model.

Overall, the research work conducted during the EPI-TARGETS IN PDAC project provided invaluable mechanistic insight into the role of chromatin deregulation in PDAC. The identification of new target molecules implicated in cancer onset should help develop interventions that improve PDAC patient survival. Moreover, newly developed drugs could be tested using the in vitro and in vivo tools generated during this project.