Role Of The Foxa Transcription Factors In Shaping Distinct Transcriptional Programs In Human Pancreatic Cancers

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest types of cancer and is characterized by a high intra-tumor heterogeneity, with the coexistence of well- and poorly-differentiated cells in virtually all the tumor cases. FOXA1/2 play a fundamental role in pancreas development and are believed to act as pioneer factors, namely to create accessible chromatin by displacing nucleosomes early in development and making genomic regulatory elements available to other transcriptional regulators. Therefore, we asked whether FOXA1/2 also control differentiation in human PDAC. Whereas FOXA1 showed a remarkable propensity to be expressed selectively by well-differentiated tumor areas and cell lines, FOXA2 showed a broad profile of expression throughout PDAC stages. Through the combination of genomic and functional assays we found that FOXA2 contributed to activate distinct transcriptional programs in tumor cells of different grades. Such complexity in FOXA2 activity specifically depended on its interaction with distinct transcription factors selectively expressed in high- or low-grade tumor cells. While in low-grade (well-differentiated) PDAC cells FOXA2 binding specificity relied on the interaction with the epithelial transcription factor HNF1beta, in high-grade cells it depended on the cooperation with HOXB8 and HOXB9. Knocking out these transcription factors was sufficient to abolish differential recruitment of FOXA2 to grade specific genomic sites. In summary, we found that FOXA2 is broadly express throughout PDAC stages and, through the interaction with different transcription factors, shapes the transcriptional program of the different tumor grades in pancreatic cancer. These findings help to shed light on the complexity of PDAC heterogeneity and on the circuitries that maintain PDAC differentiation and grading. Citation Format: Marta Milan, Gioacchino Natoli. Role of the FOXA transcription factors in shaping distinct transcriptional programs in human pancreatic cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-202.