Identification of Pdx1-dependent circuits that reprogram cell identity and promote pancreatic carcinogenesis

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Loss of cell identity is an important prerequisite for the initiation and progression of the pancreatic ductal adenocarcinoma (PDAC). Malignant cell transformation is hallmarked by genetic alterations, but also by a broad transcriptional reprogramming, involving the down-regulation of cell differentiation programs and activation of developmental signaling pathways. The transcription factor Pdx1 was initially identified as the master regulator of all pancreatic cell lineages. Our lab recently unveiled its role as an important guardian of pancreatic acinar cell identity. Consequently, depletion of Pdx1 in differentiated acinar cells cooperated with the oncogene KrasG12D and induced rapid and widespread cell transformation, characterized by an erosion of acinar cell identity and the formation of PDAC precursor lesions and PDAC. However, the exact mechanisms behind the effect remain mostly elusive. Our preliminary data indicate that Pdx1 target genes involve important effectors of the Ras signaling cascade, such as Egfr. Ras activity levels are pivotal for PDAC development. Thus, by analyzing a mouse model with a concomitant loss of Pdx1 and Egfr, combined with single cell analysis to define the transcriptional landscape, I aim to determine how Pdx1 suppresses Ras pathway activity to counteract KrasG12D-driven malignant cell transformation. Elucidating the context between loss of acinar cell identity and oncogenic Kras signaling, will help to comprehend ways to revert malignant cell transformation. Tumor cell reprogramming towards a more aggressive phenotype and metastasis in late stage PDAC is accomplished by the down-regulation of a host of pancreatic transcription factors, including PDX1, due to epigenetic silencing mediated by DNA methylation. As indicated by our data, the sole knockdown of Pdx1 in pancreatic cancer cells leads to the reinforcement of tumor cell malignancy. Pdx1 knockdown cells are characterized by a temporary reduction in cell proliferation that is bypassed through an extensive transcriptional and metabolic reprogramming greatly affecting glutathione metabolism. Adaptations in glutathione biosynthesis can have profound effects on the epigenetic landscape by influencing the availability of methyl groups, needed for DNA and histone methylation. By applying drugs targeting glutathione biosynthesis, I will assess changes in DNA methylation levels, focusing on genes shown to be silenced during progression. I propose that identifying the mechanisms by which tumor cells compensate for Pdx1 loss, will contribute to uncover specific disease vulnerabilities and offer novel therapeutic strategies.