The secret origins and surprising fates of pancreas tumors

Abstract

Pancreatic ductal adenocarcinoma (PDA) is especially deadly due to its recalcitrance to current therapies. One of the unique qualities of PDA that may contribute to this resistance is a striking plasticity of differentiation states starting at tumor formation and continuing throughout tumor progression, including metastasis. Here, we explore the earliest steps of tumor formation and neoplastic progression and how this results in a fascinating cellular heterogeneity that is probably critical for tumor survival and progression. We hypothesize that reinforcing differentiation pathways run awry or targeting morphologically and molecularly distinct tumor stem-like cells may hold promise for future treatments of this deadly disease.

Fig. 1.

A model depicting the importance of acinar cell differentiation in pancreas tumorigenesis. The differentiation of acinar cells is actively maintained by factors such as Mist1 and Nr5a2, among others. Acinar cell differentiation can be counteracted by expression of Sox17 or activation of the EGFR or Notch pathways, driving transdifferentiation into the tuft-cell-containing (shown in green) metaplastic duct. If a transdifferentiated tuft cell should acquire or have a pre-existing oncogenic mutation in Kras, it can act as a tumor-initiating cell and seed the formation of PanIN, a precancerous lesion that can progress to PDA. Illustration used with permission of the Mayo Foundation for Medical Education and Research.