Spatiotemporal Regulation of Receptor-Mediated Signaling: Fundamental Mechanistic Discoveries and Applications in Cancer
Location:140 DeBartolo Hall
Throughout the body, cells are cued to proliferate, migrate, differentiate, and die through the action of receptors, membrane-spanning proteins that translate extracellular cues (e.g., ligand binding) into cellular decisions through the regulation of intracellular biochemical pathways. This talk will highlight my lab’s efforts to dissect this process for the epidermal growth factor receptor (EGFR), a receptor tyrosine kinase that plays numerous roles in health and is frequently dysregulated in cancer. In the first part of the talk, I will discuss how computational approaches familiar to chemical engineers can be used to address longstanding fundamental questions in EGFR biology. In particular, I will describe the development of a systems-level model aimed at quantifying the kinetics with which EGFR is negatively regulated by protein tyrosine phosphatases at different intracellular locations. We have recently used this model to make new testable predictions for the effects of phosphatase-mediated regulation on EGFR endocytosis and EGFR inhibition by targeted therapeutics. The second part of my talk will focus on our efforts to understand the determinants of cancer cell response to EGFR inhibitors, which are finding increasing use in the treatment of a number of malignancies. In particular, I will discuss new findings for how a family of oncogenic EGFR mutations promotes cellular sensitivity to EGFR inhibitors by disrupting EGFR endocytosis and perturbing EGFR’s interaction with the protein tyrosine phosphatase SHP2. Overall, the results to be presented highlight new opportunities and challenges for translating our deepened mechanistic understanding into improved approaches for engineering EGFR-mediating signaling.
Dr. Matthew Lazzara
University of Pennsylvania
Dr. Matthew Lazzara did his undergraduate work at the University of Florida, where he earned highest honors in Chemical Engineering. At MIT, he earned his PhD with his dissertation on the “Effects of Plasma Proteins on the Sieving of Macromolecular Tracers on the Kidney.” After completing a postdoctoral appointment at MIT, Dr.Lazzara spent two years as a chemical engineering consultant for Millipore Corporation. He then returned to MIT as a National Cancer Institute NRSA Postdoctoral Fellow in the Department of Biological Engineering. Since 2008, Dr. Lazzara has held the position of Assistant Professor at the University of Pennsylvania, with primary appointment in the department of Chemical and Biomolecular Engineering. Dr. Lazzara’s research interests include cell signaling, receptor trafficking, phosphatases, targeted therapeutics for cancer, and renal physiology. Among a number of research achievements, Dr. Lazzara has developed the first models of effects of multi-solute steric interactions on solute partitioning and sieving in glomerular basement membrane. He also made the first measurements of effects of the plasma protein albumin on the partitioning of the renal tracer ficoll in synthetic hydrogels.