Summary Cancer progression and relapse remain the reality of current cancer therapy. Our work is aimed at understanding the root causes of this persistent problem. Since my lab’s inception we have probed the role of developmental signals in cancer initiation and propagation, used imaging to discover new programs that control cancer progression, and carried out preclinical work that has formed the basis of clinical trials testing new agents for drug-resistant leukemias – leading to the recent approval of Glasdegib to treat aggressive leukemia – and pancreatic cancer. The current work I describe shows that the paradigm we established for hematologic malignancies is a remarkably general principle used repeatedly in the regulation of many deadly cancers including pancreatic cancer. Our prior studies have collectively set the stage for new avenues of research we will pursue over the course of the next few years. In particular we plan to: 1) Define how differentiated benign lesions transition to aggressive undifferentiated malignancies and develop targeting strategies; 2) Understand cancer heterogeneity and define intrinsic and micro-environmental mechanisms that support therapy resistant cells; 3) Trace the origins and evolution of distinct subtypes of pancreatic cancer; and 4) Identify new strategies for early detection and early interception in pancreatic cancer. Collectively, these studies will provide a deeper understanding of key challenges in cancer biology, including early detection, drug resistance and disease recurrence, and will identify new targets and approaches to therapy that may lead to significantly improved patient outcomes.