IntroductionPancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy characterised by dismal prognosis due to early metastasis and chemoresistance. However, the molecular basis underlying these features remains poorly understood. SOX9 is a developmental transcription factor that regulates the stem cell biology in the embryo and also in mature organs, including the pancreas. As SOX9 is required for the maintenance of the pancreatic ductal identity and is involved in the initiation of pancreatic cancer, we aimed at investigating its putative roles in pancreatic tumour cell plasticity, dissemination and resistance to therapies.Material and methodsTo address our objectives we have analysed human PDAC samples, patient-derived xenografts (PDXs) and animal models, and we have performed functional studies of gain and loss of SOX9 function in human PDAC cell lines.Results and discussionsSOX9 expression was analysed in 198 cases of human PDAC and also in 24 PDXs. Our results revealed that SOX9 protein was highly expressed in pancreatic cancer, being the expression particularly high in metastatic cases. SOX9 expression was correlated with high vimentin expression (p=0.0006) and low E-cadherin expression (p=0.003), reflecting a process of epithelial–mesenchymal transition (EMT). Gain and loss of SOX9 analysis in primary and metastatic PDAC cells, respectively, determined that SOX9 induction increases migration, invasion and metastatic dissemination of primary tumour cells, whilst SOX9 silencing in metastatic cells impaired the metastatic colonisation potential, along with a reversion to epithelial features and loss of self-renewal and tumour maintenance ability. Additionally, we determined that high SOX9 expression confers resistance to gemcitabine. Mechanistically, we identified that the transcriptional repressor BMI-1 is a mediator in the oncogenic activity exerted by SOX9 in PDAC.ConclusionWe conclude that in PDAC SOX9 is critical for tumour maintenance, dissemination and metastatic colonisation through its action on EMT, self-renewal and proliferation.