AbstractObjectiveMolecular taxonomy of tumors is the foundation of personalized medicine and is becoming of paramount importance for therapeutic purposes. Four transcriptomics-based classification systems of pancreatic ductal adenocarcinoma (PDAC) exist, which consistently identified a subtype of highly aggressive PDACs with basal-like features, including ΔNp63 expression and loss of the epithelial master regulator GATA6. We investigated the precise molecular events driving PDAC progression and the emergence of the basal program.DesignWe combined the analysis of patient-derived transcriptomics datasets and tissue samples with mechanistic experiments using a novel dual-recombinase mouse model for Gata6 deletion at late stages of KRasG12D-driven pancreatic tumorigenesis (Gata6LateKO).ResultsThis comprehensive human-to-mouse approach allowed us to show that GATA6 loss is necessary, but not sufficient, for the expression of a basal program in patients and in mice. The concomitant loss of HNF1A and HNF4A, likely through epigenetic silencing, is required for the full phenotype switch. Moreover, Gata6 deletion in mice dramatically increased the metastatic rate, with a propensity for lung metastases. Through RNA-Seq analysis of primary cells isolated from mouse tumors, we show that Gata6 inhibits tumor cell plasticity and immune evasion, suggesting that it works as a barrier for acquiring the fully developed basal and metastatic phenotype.ConclusionsOur work provides both a mechanistic molecular link between the basal phenotype and metastasis and a valuable preclinical tool to investigate the most aggressive subtype of PDAC. These data, therefore, are important for understanding the pathobiological features underlying the heterogeneity of pancreatic cancer in both mice and human.What is already known about this subject?Multiple transcriptomics-based studies have identified a basal-like subtype of pancreatic ductal adenocarcinoma (PDAC) with especially poor prognosis.Loss of GATA6 in PDAC cells is associated with altered differentiation, including ectopic expression of basal markers such as KRT14.Aberrant expression of the ΔNp63 transcription factor can drive the expression of the basal transcriptional program.What are the new findings?Loss of GATA6 expression is necessary but not sufficient for the expression of ΔNp63 and the basal phenotype.Concomitant silencing of HNF4A and HNF1A, possibly through epigenetic mechanisms, is required for the full-blown phenotype.Gata6 deletion in established murine tumors favors the basal and metastatic phenotype, with a lung tropism, in a next-generation model of KRasG12D-driven PDAC.Loss of GATA6 expression is associated with features of immune escape in mouse and human PDAC cells.How might it impact on clinical practice in the foreseeable future?The combined analysis of GATA6, HNFs, and TP63 expression in patient-derived samples will provide a more precise classification of PDAC.Restoration of the classical PDAC phenotype may not only reduce metastatic potential but also increase immune recognition of tumor cells.
The Genetic Basis of Transcriptional and Spatial Heterogeneity of Squamous Features in Pancreatic Ductal Adenocarcinoma
