2022 Grantee: Brittany Allen-Petersen, PhD
Research Project: The Role of PP2A in Regulating Pancreatic Cancer Macropinocytosis
Award: 2022 Pancreatic Cancer Action Network Career Development Award funded by The Rockhammer Charitable Fund
Award Period: July 1, 2022 – June 30, 2024
Dr. Brittany Allen-Petersen is an Assistant Professor in the Department of Biological Sciences at Purdue University and a member of the Purdue Center for Cancer Research. After receiving her PhD from the University of Colorado-Anschutz Medical Campus, Dr. Allen-Petersen completed her postdoctoral studies at the Oregon Health & Science University. During this time, her work focused on the posttranslational regulation of c-MYC and the therapeutic potential of phosphatase activators in pancreatic cancer.
The Allen-Petersen lab studies the impact of phosphatase deregulation on tumor initiation and progression, with a specific focus on KRAS-driven pancreatic cancer. These studies take advantage of genetic mouse models, 3D culture and novel small molecules to interrogate the tumor suppressive potential of protein phosphatases as key “off-switches” to oncogenic signaling. She has received several awards for her work, including funding through the National Cancer Institute.
KRAS is the most frequently mutated protein in pancreatic cancer cases (about 90%) and has been shown to contribute to a variety of tumor characteristics. Mutant KRAS has been shown to significantly alter metabolic pathways in cancer cells to reduce cellular stress and sustain abnormally high proliferation (growth) rates. Metabolic pathways involve breaking down food and other substances in order to create energy for cellular processes.
Pancreatic cancer cells display a potent dependency on an amino acid (a building block of proteins), glutamine, for survival. Interestingly, pancreatic cancer tumors have been shown to have reduced glutamine levels compared to nearby normal tissues, presumably due to the hypovascular (low blood supply) nature of these tumors. Expression of mutant KRAS overcomes this depleted state by driving a process called macropinocytosis in order to replenish glutamine and maintain survival signaling. Macropinocytosis is a metabolic scavenging pathway in which cells “drink” in their environment to obtain the nutrients necessary for cellular functions. Inhibition of macropinocytosis results in pancreatic cancer cell death, highlighting the importance of mechanistically defining the pathways contributing to this critical cellular process.
Protein phosphatase 2A (PP2A) regulates several key tumor-promoting pathways that get activated as a result of mutant KRAS. The active PP2A complex is made of three main subunits, and while PP2A as a whole is considered tumor suppressive, the contribution of individual PP2A subunits to tumor progression and survival is poorly understood. Dr. Allen-Petersen and her team’s preliminary studies demonstrate that turning on the activity of PP2A significantly upregulates genes associated with glutamine deprivation and drives aberrant macropinocytosis, implicating PP2A as a novel regulator of pancreatic cancer metabolism. Here, the researchers propose to investigate 1) the role of PP2A in regulating pancreatic cancer glutamine signaling and 2) the effect of therapeutic PP2A activation on macropinocytosis and pancreatic cancer survival in cell (in vitro) and animal (in vivo) models. Ultimately, the results of these studies will help inform the development of new therapeutic agents focused on leveraging phosphatases to exploit metabolic vulnerabilities in pancreatic cancer.