Towards a Synthesis of the Non-Genetic and Genetic Views of Cancer in Understanding Pancreatic Ductal Adenocarcinoma Initiation and Prevention

SIMPLE SUMMARY: Cancer initiation and progression has been studied in purely genetic terms for decades. Implicit in this view is that all cells in a tissue are phenotypically identical until a single cell acquires a set of mutations that will eventually lead to malignancy. This model does not fully account for numerous clinical and epidemiological findings about cancer incidence and progression. Here, we summarize recent mathematical and biological insights that demonstrate how cells in a tissue can switch between dramatically different phenotypes independent of mutations. We explore how these insights, combined with our detailed understanding of oncogenic mutations, may answer key unexplained aspects of pancreatic ductal adenocarcinoma initiation. Importantly, such a combined model allows for a more nuanced understanding of pre-malignancy, and points the way towards early detection and intervention approaches in high-risk patients. ABSTRACT: While much of the research in oncogenesis and cancer therapy has focused on mutations in key cancer driver genes, more recent work suggests a complementary non-genetic paradigm. This paradigm focuses on how transcriptional and phenotypic heterogeneity, even in clonally derived cells, can create sub-populations associated with oncogenesis, metastasis, and therapy resistance. We discuss this complementary paradigm in the context of pancreatic ductal adenocarcinoma. A better understanding of cellular transcriptional heterogeneity and its association with oncogenesis can lead to more effective therapies that prevent tumor initiation and slow progression.