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Can Soft Signals Turn Oncogenic: The Physical Biology of Cancer Engineering at the Molecular and Tissue Scales

Ravi Radhakrishnan, PhD

Chair, Department of Bioengineering

Professor, Bioengineering

Professor, Chemical and Biomolecular Engineering

University of Pennsylvania

Abstract:  The talk will focus on building predictive models in cell biology and bioengineering using equilibrium and non-equilibrium statistical mechanics, model exploration through multiscale modeling and high-performance computing, and collaboratively validating such models in in vitro physical science-based experiments, in vivo in cell culture, and in vivo in model organisms and human trials.

A theme, we discuss in relation to tumors of the soft tissues, the question “Can Soft Signals Turn Oncogenic?” There are emerging links between the stiffness of the tissue microenvironment and the tumorogenicity in several tumors of soft tissues, thereby bringing to light the importance of how cells transduce mechanical signals to alter signals and cell fate. We focus on molecular and subcellular mechanisms of curvature induction and sensing in cell membranes by a novel class of membrane remodeling proteins. We demonstrate how membrane morphologies such as protrusions can serve as signaling hubs to initiate and sustain survival as well as proliferative pathways in single cells that are initiated solely by physical stimulus and without any external biochemical cues.

We show that mechanism for cell-cell interactions and signaling communications can be potently mediated by extracellular vesicles (exosomes and macrovesicles) whose biogenesis is controlled by the mechanobiology of the cell and the extracellular microenvironment. Exosome-mediated intercellular signaling can potentiate immune response in cancer and we will describe our efforts to integrate our biophysics-based approach to next generation pharmacokinetic modeling approach towards developing predictive digital twins models for optimizing therapies in cancer and predicting chemo, radio, and immune sensitivity in patient cohorts and how they can inform clinical trials.

These works are funded by US NIH, NSF, and EU ERC.

Bio:  Ravi Radhakrishnan, Ph.D. holds the title of Professor of Bioengineering and Professor of Chemical and Biomolecular Engineering. He is a member of the graduate groups of Genomics and Computational Biology and Biochemistry and Molecular Biophysics. Radhakrishnan is currently the Chair of Bioengineering, a department in the School of Engineering and Applied Sciences with 220 undergraduates, 160 masters, 250 PhD students, 90 postdocs, and 51 faculty. In this capacity, Dr. Radhakrishnan heads the executive team which coordinates the teaching, advising, and research infrastructure for these scholars.

He is a founding member and served as the former Director of the Penn Institute for Computational Sciences (PICS), an interdisciplinary institute promoting research at the interface of multiscale modeling, machine learning, and high-performance supercomputing.

He is actively engaged in and funded through several National and International multidisciplinary consortia including the European Research Council’s Computational Horizons in Cancer (CHIC), US National Cancer Institute’s Physical Sciences in Oncology Network and Cancer Systems Biology Consortium, and US National Institute of Biomedical Imaging and Bioengineering’s Multiscale Modeling Consortium.

Ravi Radhakrishnan served as a project leader of the NCI funded Penn Physical Sciences in Oncology Center and is a Working Group Leader of the High-Performance Computing Working Group for an Inter-Governmental Consortium: Inter-Agency Modeling Group involving NIH, NSF, NASA, DOE, DOD, and DARPA. These have led to the establishment of the Penn Center for Anticancer Engineering (PACE) in 2022, in which Dr. Radhakrishnan in a founding member.

Radhakrishnan directs a computational research laboratory with research interests at the interface of biophysics, chemical physics, and biomedical engineering with applications to cellular engineering in cancer and immunology. The goal of his computational molecular systems biology laboratory is to provide quantitative multiscale and mechanistic characterization of complex systems and formulate accurate and predictive models for quantitative systems pharmacology and oncology applications. His lab specializes in several computational algorithms spanning the molecular and cellular scales, in conjunction with the theoretical formalisms of statistical mechanics, and applications of high-performance scientific computing in parallel architectures. The long-term vision of the Radhakrishnan lab is to build digital twin models for nanomedicine and oncology applications. He has successful and funded collaborations with pharmacologists, cell biologists, biophysical chemists, anesthesiologists, and oncologists primarily through grants from US National Science Foundation, US National Institutes of Health, and the European Research Council.

In the 17 years of experience as a PI, he has mentored 25 doctoral and 18 post-doctoral scholars. Radhakrishnan runs the 4+1 bridge-to-masters and bridge-to-phd programs in Bioengineering in partnership with two minority serving institutions (Coastal Carolina University and LaSalle University) and one HBCU (Lincoln University). He also coordinates the certificate program on high-performance computing in PICS and runs an undergraduate focused research outreach program for students in Western Africa in partnership with the NGO Afrisnet.

Radhakrishnan has authored over 170 articles in leading peer-reviewed Journals, 4 major softwares, serves as a referee for over 45 leading journals, publishers, and federal funding agencies. He has served as a panelist for over 45 research panels including at NSF, NIH, Air Force, DOE, and serves as the associate editor of frontiers in physiology, and serves on the editorial board of five journals including Scientific Reports of the Nature Publishing Group. He has received the Hewlett Packard Investigator award and is a Fellow of the American Institute of Medical and Biological Engineers, Fellow of the Biomedical Engineering Society, and Fellow (Overseas) of the Royal Society of Medicine.

Event Details

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