Hnf4a regulated transcriptome in murine PDAC autochthonous tumors [FFPE tumors]

Pancreatic ductal adenocarcinoma is an aggressive disease with a dismal five-year survival of 5%. Gene expression profiling has been instrumental for subtype classification in cancer, highlighting fundamental differences in tumors at the molecular level. Over the last years, multiple genomics studies have led to the classification of PDAC into two major subtypes: classical and basal-type. The classical subtype expresses higher levels of endodermal lineage specifiers, including HNF4A, GATA6, FOXA2, FOXA3 than the basal-type. The basal-type confers a worse prognosis, raising the possibility that loss of these lineage specifiers might enhance the malignant potential of PDAC. We found that the lineage specifier HNF4a plays a key role in maintaining a transcriptional network that characterizes the classical subtype, restraining growth in different PDAC models. Additionally, we demonstrated that HNF4a controls PDAC cell identity and proliferation, and represses the expression of SIX family members, two mesodermal lineage specifiers highly expressed in basal-type. Overall design: The study was designed to compare the expression profiles of Hnf4a-positive pancreatic ductal adenocarcinomas with tumors in which Hnf4a was deleted at the time of initiation. RNA was isolated from aniline blue-stained FFPE sections of micro-dissected autochthonous tumors.