GSE138142
Hnf4a regulated transcriptome in organoid cultures derived from murine pancreas where HNnf4a is deleted after tumor initiation. [organoid]
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 transcriptome profiles between isogenic Hnf4a-positive and Hnf4a-negative murine pancreatic cancer organoid lines. Hnf4a was deleted by treating the 3D cultures with 4OH-Tamoxifen