FOXA 2 controls the cis ‐regulatory networks of pancreatic cancer cells in a differentiation grade‐specific manner

Abstract

Differentiation of normal and tumor cells is controlled by regulatory networks enforced by lineage‐determining transcription factors (TFs). Among them, TFs such as FOXA1/2 bind naïve chromatin and induce its accessibility, thus establishing new gene regulatory networks. Pancreatic ductal adenocarcinoma (PDAC) is characterized by the coexistence of well‐ and poorly differentiated cells at all stages of disease. How the transcriptional networks determining such massive cellular heterogeneity are established remains to be determined. We found that FOXA2, a TF controlling pancreas specification, broadly contributed to the cis‐regulatory networks of PDACs. Despite being expressed in both well‐ and poorly differentiated PDAC cells, FOXA2 displayed extensively different genomic distributions and controlled distinct gene expression programs. Grade‐specific functions of FOXA2 depended on its partnership with TFs whose expression varied depending on the differentiation grade. These data suggest that FOXA2 contributes to the regulatory networks of heterogeneous PDAC cells via interactions with alternative partner TFs.

Tumor cell heterogeneity and its transcriptional bases in pancreatic cancer: a tale of two cell types and their many variants

“…When considering human PDAC, FOXA2 is broadly expressed in tumor cells irrespective of their differentiation grade, both in vivo and in vitro , a finding that is consistent with the role of FOXA2 at early stages of endodermal development (Milan et al, 2019). In spite of such broad expression, FOXA2 displays a profoundly different genomic distribution in well‐ and poorly differentiated PDAC cells and impacts on different gene expression programs and biological properties.…”

“…In spite of such broad expression, FOXA2 displays a profoundly different genomic distribution in well‐ and poorly differentiated PDAC cells and impacts on different gene expression programs and biological properties. These grade‐specific functions of FOXA2 are dependent on its partnership with distinct TFs, such as HNF1β (discussed below) that are expressed in a grade‐specific manner and that thus enable FOXA2 recruitment to grade‐specific subsets of cis ‐regulatory elements (Milan et al, 2019).…”

Human Papillomavirus Infection in Head and Neck Squamous Cell Carcinomas: Transcriptional Triggers and Changed Disease Patterns

“…In uterine cancer, FOXA2 is frequently mutated and act as a pathogenic driver gene in the etiology of this cancer ( Le Gallo et al, 2018 ). In pancreatic cancer, FOXA2 controls the cis -regulatory networks in a differentiation grade-specific manner ( Milan et al, 2019 ). FOXA2 is overexpressed in ovarian cancer stem cells and regulates its autophagy activity ( Peng et al, 2017 ).…”

Blocking the road to de‐differentiation: HNF 1A/ KDM 6A complex safeguards epithelial integrity in pancreatic cancer

“…Pancreatic ductal adenocarcinoma can arise from acinar cells undergoing acinar‐to‐ductal metaplasia (ADM), a process of plasticity and reprogramming of acinar cells to an embryonic ductal progenitor state, which further proceed to the carcinoma stage (Roy & Hebrok, ). Recent work demonstrates that this process and alterations of epithelial cell differentiation in established human PDAC are governed by cell‐type‐specific transcriptional regulatory networks (Diaferia et al , ; Martinelli et al , ; Milan et al , ). Transcription factors (TF) that control acinar fate and identity include FOXA family members , GATA6, NR5A2, and RBPJL.…”

“…Indeed, FOXA2 function depends on the availability of differentiation‐specific partner TFs regulating FOXA2 target site binding. In well‐differentiated tumor cells, FOXA2 interacts with HNF1B and AP‐1 maintaining epithelial differentiation, whereas the FOXA2 cistrome is regulated by HOXB8 in poorly differentiated PDAC cells (Milan et al , ). These data clearly show that rewiring of highly complex transcriptional regulatory circuits underlies and maintains the de‐differentiation and progression of human PDAC.…”