Time: 11 am to Noon EST
Human tumors are mosaics of heterogeneous cancer cell populations surrounded by a microenvironment that plays a key role in regulating growth, metastasis, and drug resistance. Understanding cell behavior in native tumor microenvironments and developing new strategies to deliver therapeutics directly to tumor cells can lead to major improvements in patient outcomes. Integrating novel experimental tools, such as microfluidics and multiplexed imaging with systems biology offers a bioengineering framework to model, measure and manipulate the interactions of cancer cells with their environment and to provide new insights into underlying biological mechanisms and cancer therapies.
In the first part of the talk, I will present an array of microfluidic and 3D culture platforms that can be used to study the effects of microenvironmental factors on tumor metastasis with a focus on mesothelial cells and macrophages. Using these systems, we show that mesothelial barrier function critically regulates ovarian cancer metastatic potential. Treatment with an adenylyl cyclase agonist decreased mesothelial permeability and slowed ovarian cancer invasion in a PKA-dependent manner. In addition to these studies of early metastatic spread, I will show how tumor-derived paracrine signals and extracellular matrix remodeling play a critical role in recruiting macrophages that in turn establish a pro-invasive and drug-resistant microenvironment.
In the second part of the talk, I will present an integrated experimental-computational approach to study the effects of fibroblasts on HER2-targeted therapy drug resistance in breast cancer. A two-cell circuit model was developed using dynamic measurements of tumor cell growth and death rates. To identify molecular mechanisms associated with fibroblast-mediated drug resistance we are profiling signaling pathway activity using multiplexed in situ immunofluorescence staining and reverse phase proteomics. The results from the proposed studies will lead to the identification of microenvironmental niches and associated tumor cell signaling pathways that could serve as biomarkers for patient stratification and provide important information for the design of rational combination therapies that will re-sensitize tumors to treatment.
Bio: Ioannis Zervantonakis is an Assistant Professor at the Department of Bioengineering, University of Pittsburgh and at the Hillman Cancer Center UPMC. From 2017-9, he was an Instructor of Cell Biology at Harvard Medical School and a postdoctoral fellow (2014-7) in the lab of Prof. J. Brugge. He received his Ph.D. (2012) from MIT in Mechanical Engineering under the direction of Prof. R. Kamm, his M.S. (2006) from the Technical University of Munich and his B.S. (2005) from the National Technical University in Athens. Ioannis is a recipient of a 2014 Department of Defense Breast Cancer Postdoctoral Fellowship and a 2017 NCI Pathway to Independence K99/R00 award. He serves as an Early-Career Associate Scientific Advisor to Science Translational Medicine, has received the 2020 Hillman Early-Career Fellow for Innovative Cancer Research Award and his laboratory is funded by an Elsa Pardee Foundation Award and two Magee Women Research Institute’s Pilot Awards.