Matthew J. Lazzara
Ph.D., Massachusetts Institute of Technology (2003)
B.S., University of Florida (1997)
Honors and Awards
- American Cancer Society Research Scholar Grant, 2015
- Outstanding Faculty Award, AIChE Delaware Valley, 2013
- S. Reid Warren, Jr. Award for Excellence in Teaching, 2011
- NIH National Research Service Award Postdoctoral Fellowship, 2005-2007
Cell signaling, receptor trafficking, cellular engineering, computational modeling, targeted therapeutics for cancer, transport phenomena in biological systems
Cell signaling is the biochemical process cells use to make decisions about virtually everything they do – migrate, differentiate, survive, die, and more. Signaling involves networks of intracellular proteins whose concentrations, modification states, or localization change in response to events such as receptor-ligand binding. Cells interpret these signaling network changes, using rules scientists are only beginning to decipher, to execute decision processes. While proper signaling is critical to normal development and health, aberrant signaling leads to numerous diseases, including cancer. Thus, the ability to engineer signaling processes or intervene effectively in aberrant signaling has huge medical implications. Our lab integrates experimental and computational methods to study fundamental aspects of cell signaling regulation and applied aspects of cell signaling including the efficacy of therapeutics that target particular signaling pathways in cancer. Some specific areas of interest are now briefly described.
Epithelial-mesenchymal transition (EMT) in cancer. EMT is a normal cellular developmental process that can be hijacked in cancers of epithelial origin. Mesenchymally de-differentiated cancer cells are more chemoresistant, and potentially more invasive, than their epithelial counterparts. Our lab is using systems biology methods to study the multivariate signaling processes that control EMT as a means of designing more effective therapies for cancers where EMT plays a role.
Newly discovered roles for signaling regulatory proteins in cancer. One of the complexities of cell signaling is that the functions of signaling proteins can be context-dependent. For example, our lab has discovered that the proteins SHP2 and SPRY2 play unique roles in glioblastoma multiforme (GBM), the most common malignancy of the brain in adults. We are using signaling network-level measurements and models to study these context-dependent roles of SHP2 and SPRY2 to identify pharmacological approaches to recapitulate the desirable consequences of the depletion of these proteins in GBM tumors.
Fundamental studies of cell signaling regulation. Cell signaling involves the regulation of networks of proteins over multiple time and length scales. The complexity of these intracellular reaction-diffusion processes can be managed and dissected through mechanistic modeling approaches that are familiar to engineers to generate predictive understanding of system behavior. Our lab applies these kinds of mechanistic modeling approaches to develop new fundamental understanding of signaling mechanisms such as the regulation of phosphorylation-dependent complexes of signaling proteins downstream of receptor tyrosine kinase activation. Ultimately, this deep mechanistic understanding will be needed to understand how to intervene effectively in aberrant signaling in disease.
Day EK, Sosale NG, and Lazzara MJ. Cell signaling regulation by protein phosphorylation: a multivariate, heterogeneous, and context-dependent process. Current Opinion in Biotechnology 40: 185-92, 2016.
Buonato JM, Lan IS, and Lazzara MJ. EGF augments TGFβ-induced epithelial-mesenchymal transition by promoting SHP2 binding to GAB1. Journal of Cell Science 128: 3898-909, 2015.
Furcht CM, Buonato JM, and Lazzara MJ. EGFR-activated Src family kinases maintain GAB1-SHP2 complexes distal from EGFR. Science Signaling 8: ra46, 2015.
Walsh AM, Kapoor GS, Buonato JM, Mathew LK, Bi Y, Davuluri RV, Simon MC, O’Rourke DM, and Lazzara MJ. Sprouty2 drives drug resistance and proliferation in glioblastoma. Molecular Cancer Research 13: 1227-37, 2015.
Buonato JM and Lazzara MJ. ERK1/2 blockade prevents epithelial-mesenchymal transition and promotes cellular sensitivity to EGFR inhibition in lung cancer cells. Cancer Research 74: 309-319, 2014.