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Divergent regulation and function of Wnt/β-catenin signaling and TCF transcription factors in pancreatic cancer

  • Author(s): Kershaw, Kathleen
  • Advisor(s): Dawson, David W
  • et al.
Abstract

With steadily increasing incidence and an 8-9% 5-year survival rate, pancreatic ductal adenocarcinoma (PDA) treatment represents an urgent, unmet clinical need. Hindered by long asymptomatic growth, methods of early detection are not yet available, resulting in frequent late-stage patient presentation at which point treatment options are extremely limited. Current standards of care offer only modest increases in survival, and molecular targeted therapies have underperformed in the clinic, likely due in part to the high degree of genetic heterogeneity within PDA. Increased efforts to sequence large numbers of tumors have revealed a short list of highly mutated pathways within that heterogeneity, including the Wnt/β-catenin signaling pathway. A highly detailed understanding of the regulation and function of Wnt/β-catenin signaling in PDA however, is lacking. Here we use an unbiased approach to uncover the existence of discrete patterns of expression for T-cell factor/lymphoid enhancer factor (TCF/LEF) family members that are linked to divergent Wnt activity and function in PDA. Importantly, these distinct patterns were also observed in resected patient tumors where they are correlated with survival outcomes. TCF expression was found to define distinct subtypes of PDA with differential phenotypic responses to similar stimuli. Furthermore, patterns of TCF expression corresponded to differing Wnt niche growth requirements. The predictive power of TCFs may serve as a more sensitive biomarker for stratifying patients into relevant groups for targeted clinical therapies. Additionally, the effect of Wnt manipulation on TCF-mediated control of particular gene programs reveals vulnerabilities that could be targeted by novel therapeutics alongside Wnt, pushing PDA treatment one step closer to effective, personalized medicine.

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