Deregulation of Transcription Factor Networks Driving Cell Plasticity and Metastasis in Pancreatic Cancer

Abstract

Pancreatic cancer is a very aggressive disease with 5-year survival rates of less than 10%. The constantly increasing incidence and stagnant patient outcomes despite changes in treatment regimens emphasize the requirement of a better understanding of the disease mechanisms. Challenges in treating pancreatic cancer include diagnosis at already progressed disease states due to the lack of early detection methods, rapid acquisition of therapy resistance, and high metastatic competence. Pancreatic ductal adenocarcinoma, the most prevalent type of pancreatic cancer, frequently shows dominant-active mutations in KRAS and TP53 as well as inactivation of genes involved in differentiation and cell-cycle regulation (e.g. SMAD4 and CDKN2A). Besides somatic mutations, deregulated transcription factor activities strongly contribute to disease progression. Specifically, transcriptional regulatory networks essential for proper lineage specification and differentiation during pancreas development are reactivated or become deregulated in the context of cancer and exacerbate progression towards an aggressive phenotype. This review summarizes the recent literature on transcription factor networks and epigenetic gene regulation that play a crucial role during tumorigenesis.

Deciphering the roadmap of in vivo reprogramming toward pluripotency

“…scRNA-seq of reprogrammed pancreas suggests that pancreatic cell types are not equally affected by OSKM activation, with acinar cells being the most susceptible ones to reprogramming. This probably reflects the known plasticity of acinar cells, which can rapidly dedifferentiate upon inflammatory or oncogenic damages ( van Roey et al., 2021 ). Also, expression of OSKM in acinar cells results in a general shut down of enhancers and dedifferentiation ( Shibata et al., 2018 ).…”

Deciphering the roadmap of in vivo reprogramming towards pluripotency

“…Single cell RNA sequencing of reprogrammed pancreas suggests that pancreatic cell types are not equally affected by OSKM activation, with acinar cells being the most susceptible to reprogramming. This probably reflects the known plasticity of acinar cells, which can rapidly dedifferentiate upon inflammatory or oncogenic damages (van Roey et al, 2021). Also, expression of OSKM in acinar cells results in a general shut down of enhancers, and dedifferentiation (Shibata et al, 2018).…”

Epithelial to Mesenchymal Transition as Mechanism of Progression of Pancreatic Cancer: From Mice to Men

“…While perfecting this model, some of the authors initially involved in its drawing acknowledged that the waves of clonal expansions from early to advanced carcinoma and then to metastasis were not associated with known genetic alterations [ 1 ]. Since then, several transgenic mouse models and clinical observations underpinned that disseminated neoplastic cells do not invariably develop distant metastasis [ 2 , 3 , 4 , 5 , 6 , 7 ].…”

“…Several master transcription factors (TFs) can activate the EMT [ 7 , 15 ]. Among these, TWIST1 plays an essential role both in normal development and cancer metastasis [ 61 ].…”