2021 Grantee: John Morris IV, PhD
University of North Carolina at Chapel Hill
Research Project: Dissecting Malignant Evolution Unleashed by p53 Inactivation in PDAC
Award: 2021 Pancreatic Cancer Action Network Career Development Award in memory of Skip Viragh
Award Period: July 1, 2021 – June 30, 2023
Dr. John P Morris IV is an assistant professor in the Pharmacology Department at the University of North Carolina, Chapel Hill School of Medicine, and a member of the Lineberger Cancer Center. He earned his PhD in the biomedical sciences graduate program at the University of California, San Francisco, with past PanCAN grantee Dr. Matthias Hebrok, where he studied how mutant KRAS interferes with normal pancreatic regeneration to establish the earliest stages of pancreas cancer development. His postdoctoral work with Dr. Scott Lowe at the Memorial Sloan Kettering Cancer Center focused on mechanisms by which tumor suppressors, like p53, constrain the switch from pre-cancer to cancer biology. He also identified novel tumor suppressor activities that can be re-engaged in malignant cells to produce anti-cancer effects.
The Morris lab studies how cancer-causing mutations perturb evolutionarily selected programs that dictate cell fate decisions during normal development and organ homeostasis. Using genetically engineered models that combine precise control of cancer mutations with the ability to trace their consequences in vivo, his group investigates the routes by which heterogeneous (diverse), malignant cell fates develop during pancreatic cancer progression with the goal of identifying actionable strategies to eliminate them.
Pancreatic cancer remains so difficult to treat in part because of remarkable differences between the genetic landscapes and molecular properties of cells in different tumors and in different populations coexisting in the same tumor. This heterogeneity occurs even in cells with the same driver mutations, changes in genes that enable pancreatic cancer to form. Therefore, these cancer drivers do not result in uniform paths to cancer development, but rather enable the evolution of diverse paths that may impact patients’ treatment options and outcomes.
The goal of Dr. Morris’ proposal is to use novel mouse models that permit stepwise characterization and perturbation of evolutionary routes that recapitulate the diversity of the human disease to define targetable aspects of pancreatic cancer heterogeneity.
These models focus on cancer progression after the ordered acquisition of the two most frequent genetic events observed in pancreatic ductal adenocarcinoma (the most common and aggressive type of pancreatic cancer): mutations in the gene KRAS and inactivation of the tumor suppressor p53. Loss of p53 function acts to unleash the progression from pre-malignant to malignant disease and permits cells to select for changes in the genome and in gene expression, two major sources of pancreatic cancer heterogeneity, that ultimately confer malignant fitness.
Dr. Morris and his team will determine how specific genomic and gene expression changes enabled by the selective inactivation of p53 establish diverse malignant identities and are functionally linked to lethal aspects of pancreatic ductal adenocarcinoma. Together, this work will define hallmarks underlying distinct evolutionary paths to pancreatic cancer unleashed by core genetic drivers of the disease. This insight will inform efforts to better stratify and treat pancreatic cancers by addressing their specific heterogeneity and natural histories.