Cornell University PS-OC
Center on the Physics of Cancer Metabolism
Despite advances in breast cancer treatment, metastatic disease remains incurable and is of particular concern in patients with triple negative breast cancer (TNBC). Both aberrant metabolic signaling and physical properties of the microenvironment have been independently defined as hallmarks of cancers, and experimental evidence suggests that they may be functionally linked. However, the current lack of physiologically relevant culture models that capture relevant physical details prevents studying the specific mechanisms that link metabolic reprogramming, the physical microenvironment, and clinical outcomes of malignancy.
This PS-OC is interrogating the multiscale biological and physical (structural, mechanical, and solute transport) mechanisms regulating tumor metabolism and function, as well as the consequences on tumor development, metastatic progression, and therapy response. Collectively, it will generate physical sciences-driven mechanistic insights into TNBC with the ultimate promise of improving clinical outcomes.
Projects
Project 1: Effects of the Physical Microenvironment on Metabolism
Triple negative breast cancer (TNBC) and obesity lead to physical changes in the microenvironment, including aberrant multiscale structure and mechanics of the extracellular matrix, disturbed distributions of soluble factors, and population-level abnormalities in collective cell behavior. However, the functional interconnections between these physical variations and tumor metabolism remain unclear. This gap in understanding can be attributed to a lack of computational and experimental models that permit reliable prediction, recapitulation, and study of tumor and obesity-associated physical mechanisms in TNBC.
By integrating biomaterials, tissue engineering, microfabrication, and computational models, this PS-OC is investigating the hypothesis that physical changes in the microenvironment regulate malignancy by perturbing cellular metabolism. Furthermore, it is testing whether obesity primes for tumorigenesis through similar mechanisms.
To address these hypotheses, engineering-centric approaches are being integrated with transgenic mouse models, patient-derives xenografts, patient-derived organoid cultures, and drug testing. This approach will reveal novel mechanisms in tumor metabolic reprogramming for clinical translation.
Project 2: Metabolism-Mediated Changes of Microvesicle Biogenesis
This PS-OC project focuses on a key outcome of cancer cell metabolism: the generation of microvesicles (MVs), which are shed from the plasma membranes of cancer cells. MVs have been implicated in the metastatic process by changing the tumor microenvironment and stimulating tumor angiogenesis. Although we understand some of the biochemical signals triggering MV production, we know little about the physical determinants driving their formation, or how the physical microenvironment influences their biogenesis and function.
We are addressing these issues as follows:
- Determining the physical relationships governing MV biogenesis and size distribution
- Determining the reciprocal relationship between the physical properties of the extracellular matrix and MV formation
- Establishing physical read-outs such as vesicle size as indicators of MV function in tumor-stroma and reciprocal stroma-tumor vesicle transfer.
These studies should shed new light on how cancer cell metabolism stimulates MV biogenesis, and ultimately lead to novel therapeutic strategies.
Project 3: Physical and Metabolic Constraints of Cancer Cell Invasion
Cancer cell invasion from the primary tumor into surrounding tissues is a crucial step of the metastatic cascade, which is responsible for the vast majority of cancer deaths. We propose that invading cancer cells must expend significant energy to penetrate through tight interstitial spaces and adopt migration modes that minimize metabolic cost.
This research is addressing factors involved in cancer cell invasion:
- Examining how interaction between invading cells and the physical microenvironment determine energy consumption
- Determining how physical factors intrinsic to the cell, particularly nuclear deformability and the physical properties of the cell surface, modulate metabolic cost and migration efficiency
- Investigating how metabolic reprogramming in cancer cells affects migration efficiency by fueling biosynthetic pathways that alter cellular mechanics.
The experimental work is complemented by the modeling of cancer cell metabolism and physical interaction with the microenvironment. The overall objective is to predict outcomes of therapeutic metabolic interventions and to identify strategies to counter adaptive responses.
Cores
Core 1: Tissue Microfabrication
The elucidation of biophysical mechanisms that lead to metabolic aberrations in tumors and, in turn, impact cancer progression, requires specialized capabilities for the manipulation of cells, biological materials, and tissues, as well as for the development of computational models to evaluate hypotheses and interpret experimental data. Additionally, the assessment of the clinical relevance of these mechanisms and their translation toward therapeutic applications requires coordinated access to patient-derived samples with thorough clinical and genetic profiling and data basing.
The Tissue Microfabrication Core will provide PS-OC investigators a shared infrastructure that satisfies these requirements:
- Managing the acquisition, clinical and genomic characterization, data banking, and distribution of patient derived tissues
- Developing and fabricating advanced culture platforms and microfluidic devices for the characterization of cells and biomaterials
- Generating a hierarchy of computational models to support metabolic analysis and the design and interpretation of experiments
Core 2: Biophysics and Metabolic Imaging
This Core provides the optical imaging instrumentation, facilities and expertise for the high-resolution imaging, biophysical analysis, and image processing tasks required by the PSOC. It provides microscopy instrumentation for dynamic measurements of the cellular metabolic state using both fluorescent metabolic sensors and intrinsic sources (such as NADH and FAD containing proteins) for the visualization of tissue morphology, microvesicle shedding, and quantitative imaging of cellular nanoscale mechanical properties using several forms of super-resolution microscopy.
The Biophysical and Metabolic Imaging Core leverages both state-of-art commercial instrumentation, as well as custom-built instruments specifically optimized for the research needs of PSOC investigators and their projects.
Education and Outreach Unit
This PS-OC develops training tailored to the needs of physical scientists entering cancer research and to cancer biologists adopting physical science approaches. Training elements include classroom instruction, lab-based minicourses, and immersion experiences.
For physical science trainees, the focus is on gaining a solid grounding in modern cancer biology, developing critical laboratory skills that are less common in the physical sciences, and gaining exposure to clinical medicine and translational research.
For cancer biology trainees, the goal is to learn what physical science methods enable in biomedical research, develop aptitude in applying these approaches, and see an engineering lab from the inside.
Both groups of trainees participate in an innovative, student-led course on metabolism in cancer. Other programs aim to broaden the perspective of trainees and include a trainee-led Cancer Brainstorming Club, interactions with patient advocates, and planning for diverse careers. These activities aim to facilitate interactions between physical science/engineering and cancer biology/oncology that enhance cancer research.
Learn more at the Cornell Community Cancer Partnership website.
Investigators
Claudia Fischbach-Teschl, Ph.D.
Cornell University
Dr. Claudia Fischbach-Teschl is an Associate Professor in the Nancy E. and Peter C. Meinig School of Biomedical Engineering at Cornell University. She received her Ph.D. in Pharmaceutical Technology from the University of Regensburg, Germany, and holds an M.S. in Pharmacy from the Ludwigs-Maximilians-University, Munich, Germany. She conducted her postdoctoral work at Harvard University in the Division of Engineering and Applied Sciences and joined the faculty of Cornell in 2007.
Her research utilizes engineering tools and strategies to gain a better understanding of cancer development, progression, and therapy resistance with a particular focus on adipose stroma contributions to breast cancer, bone metastasis and tumor angiogenesis. She is a fellow of the American Institute for Medical and Biological Engineering and the Humboldt Foundation in Germany.
Lewis C. Cantley, Ph.D.
Weill Cornell Medical College
Dr. Lewis C. Cantley is Director of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medical College and New York Presbyterian Hospital. Dr. Cantley obtained a Ph.D. in biophysical chemistry from Cornell University in 1975 and did postdoctoral training at Harvard University.
Prior to taking the position at Weill Cornell, he taught and did research in biochemistry, physiology and cancer biology in Boston at Harvard University, Tufts University School of Medicine, and most recently at Beth Israel Deaconess Medical Center and Harvard Medical School. His laboratory discovered the PI 3-Kinase pathway that plays a critical role in insulin signaling and in cancers.
Himisha Beltran, M.D.
Weill Cornell Medical College
Dr. Himisha Beltran is a medical oncologist and physician scientist with a research focus in understanding mechanisms of treatment resistance in advanced prostate cancer and other malignancies. She directs the clinical activities within the Englander Institute for Precision Medicine at Weill Cornell Medicine.
Through the development of a clinical protocol for metastatic tumor biopsies, genomic sequencing, and patient-derived organoid development, Dr. Beltran works closely with a multidisciplinary team towards bringing next generation molecular studies, novel biomarkers and assays, and functionally validated drug targets into clinical application.
Richard Cerione, Ph.D.
Cornell University
Dr. Richard Cerione completed his Ph.D. in Biochemistry at Rutgers University, and was then an NIH postdoctoral fellow with Gordon Hammes at Cornell and a Howard Hughes Institute Fellow with Robert J. Lefkowitz at Duke University. He started his academic career at Cornell, where he is the Goldwin Smith Professor of Pharmacology and Chemical Biology in the Department of Molecular Medicine, and the Department of Chemistry and Chemical Biology.
His research is primarily focused on the signaling pathways that regulate cell growth, differentiation and development, with a particular interest in the roles of extracellular vesicles in these biological processes.
Andrew J. Dannenberg, M.D.
Weill Cornell Medical College
Dr. Andrew J. Dannenberg is the Henry R. Erle, MD-Roberts Family Professor of Medicine at Weill Cornell Medicine and Associate Director of Cancer Prevention at the Sandra and Edward Meyer Cancer Center. His laboratory has focused on elucidating the mechanisms underlying the inflammation-cancer connection.
Currently, a bench to bedside effort is being made to understand the link between obesity and cancer with an emphasis on adipose inflammation. The long-term goal of this research is to develop new strategies to reduce the risk of cancer or inhibit its progression. Dr. Dannenberg has authored more than 200 scientific articles. In 2011, he was awarded the American Association for Cancer Research-Prevent Cancer Foundation award for excellence in cancer prevention research.
Peter Friedl, M.D., Ph.D.
Radboud University Nijmegen Medical Centre
Dr. Peter Friedl received his M.D. from the University of Bochum in 1992 and his Ph.D. from the McGill University, Montreal in 1996. He became a director of the Microscopical Imaging Centre of the Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands in 2007, and has held a joint faculty position at the University of Texas MD Anderson Cancer Center since 2011.
His research interest is the mechanisms and plasticity of cell migration in immune regulation and cancer metastasis, with emphasis on cell-matrix adhesion, pericellular proteolysis and biophysics of cell migration and dynamic cell-cell cooperation during migration (“cell jamming”). His laboratory identified pathways determining diversity and plasticity of cell migration, collective cancer cell invasion, and the contribution of migration pathways to immune defense and cancer resistance.
Neil M. Iyengar, M.D.
Memorial Sloan Kettering Cancer Center (MSKCC)
Dr. Neil M. Iyengar is a medical oncologist and clinical-translational investigator at MSKCC, where he specializes in the care of patients with breast cancer. He also holds joint research appointments at the Rockefeller University Center for Clinical and Translational Science and Weill Cornell Medicine in New York.
Dr. Iyengar studies the role of obesity and inflammation in the development and progression of breast and several other cancers. Through a series of translational studies, obesity-related inflammation has been shown to contribute to worse outcomes in patients with cancer. He aims to develop specific, mechanism-based interventions that target adipose tissue inflammation in order to protect patients from its harmful cancer-promoting effects. He has been recognized for his work by several organizations including a Career Development Award from the Conquer Cancer Foundation of the American Society of Clinical Oncology.
Brian J. Kirby, Ph.D.
Cornell University
Dr. Brian J. Kirby is a Professor in the Cornell University Sibley School of Mechanical Engineering with a courtesy appointment in Hematology and Medical Oncology at Weill Cornell Medicine. Before joining Cornell, he worked in the Microfluidics Department at Sandia National Laboratories and obtained his B.S. and M.S. from the University of Michigan, and his Ph.D. from Stanford University.
He designs microfluidic devices for liquid biopsies and manipulation of cancer cells and vesicles with clinical application primarily to prostate and pancreatic cancers.
Jan Lammerding, Ph.D.
Cornell University
Dr. Jan Lammerding, Ph.D., is an Associate Professor in the Nancy E. and Peter C. Meinig School of Biomedical Engineering and the Weill Institute for Cell and Molecular Biology at Cornell University. After obtaining a Diplom Ingenieur degree in Mechanical Engineering in his native Germany, he completed his Ph.D. in Biological Engineering at the Massachusetts Institute of Technology, studying subcellular biomechanics and mechanotransduction signaling in the laboratories of Roger Kamm and Richard T. Lee (Brigham and Women’s Hospital/Harvard Medical School). Before joining Cornell University, Dr. Lammerding served as a faculty member at Harvard Medical School/Brigham and Women’s Hospital while also teaching in the Department of Biological Engineering at the Massachusetts Institute for Technology.
The research in the Lammerding laboratory is focused on developing novel experimental techniques to investigate the interplay between cellular mechanics and function, with a particular emphasis on the cell nucleus and its response to mechanical forces.
David Nanus, M.D.
Weill Cornell Medical College
Dr. David Nanus is the Chief of the Division of Hematology and Medical Oncology at Weill Cornell Medicine and New York-Presbyterian Hospital, Professor of Medicine and Urology, and Associate Director for Clinical Services at the Sandra and Edward Meyer Cancer Center. He was a co-investigator in the Phase I Cornell University Physical Science-Oncology Centers on the Microenvironment and Metastasis, collaborating with his colleagues at Weill Cornell and Cornell University in Ithaca to develop a microfluidic device that extracts prostate cancer circulating tumor cells.
Dr. Nanus is an internationally recognized leader in the treatment and care of patients with genitourinary (GU) cancers. He is actively involved in clinical, translational and basic research in GU malignancies, serving as principle or co-investigator on a variety of grants and clinical research trials that incorporate novel targeted therapies for patients.
Matthew Paszek, Ph.D.
Cornell University
Dr. Matthew Paszek is an Assistant Professor in the Robert Frederick Smith School of Chemical and Biomolecular Engineering at Cornell University. He received his B.S. in chemical engineering from Cornell University, and his Ph.D. in bioengineering from the University of Pennsylvania, where he investigated physical mechanisms underlying cancer progression. As a postdoctoral fellow at the University of California, San Francisco, he began his work on understanding the physical functions of glycans in regulating cell adhesion and signaling.
His current work focuses on developing a biophysical toolkit for research in cancer glycobiology, as well as forming a fundamental understanding of the function of the glycocalyx in cancer cell motility and cell-to-cell communication.
Mark A. Rubin, M.D.
Weill Cornell Medical College
Dr. Mark A. Rubin is the founding Director of The Englander Institute for Precision Medicine at Weill Cornell Medicine and NewYork-Presbyterian Hospital. A board-certified pathologist whose research has appeared in journals such as Nature, Science, Cell, and New England Journal of Medicine, Dr. Rubin’s clinical and laboratory investigations over the past 15 years have led to the discovery of several notable genetic alterations, including AMACR, Hepsin, EZH2, SPOP, MYCN , and AURKA.
A physician-scientist with expertise in cancer pathology, Dr. Rubin was one of the first to profile prostate tumor DNA using both comprehensive and targeted gene sequencing. His recent work emphasizes treatment-resistance in recurring cancers of the prostate and focuses on drug development.
Chris B. Schaffer, Ph.D.
Cornell University
Dr. Chris B. Schaffer is an Associate Professor in the Nancy E. and Peter C. Meinig School of Biomedical Engineering and the Associate Dean of Faculty at Cornell University. Dr. Schaffer received his Ph.D. in physics from Harvard University, where he worked with Eric Mazur. He was then a post-doc in David Kleinfeld’s neuroscience laboratory at the University of California, San Diego.
He now runs a lab at Cornell that develops advanced optical techniques to enable quantitative imaging and targeted manipulation of individual cells in the central nervous system of rodents, with the goal of constructing a microscopic-scale understanding of normal and disease-state physiological processes in the brain. One area of current focus is understanding the role of brain-blood flow disruptions in the development of Alzheimer’s disease. Dr. Schaffer is also active in developing novel educational strategies to teach science as a dynamic process for discovery that are used in outreach settings in middle and high-school science classes as well as in college-level courses.
Michael L. Shuler, Ph.D.
Cornell University
Dr. Michael L. Shuler, Ph.D., is the Eckert Professor of Engineering in the Nancy E. and Peter C. Meinig School of Biomedical Engineering and in the Robert Fredrick Smith School of Chemical and Biomolecular Engineering at Cornell University, and director of Cornell’s Nanobiotechnology Center. Dr. Shuler has degrees in chemical engineering (BS, Notre Dame, 1969 and Ph.D., Minnesota, 1973) and has been a faculty member at Cornell University since 1974.
Dr. Shuler’s research includes development of “Body-on-a-Chip” for testing pharmaceuticals for toxicity and efficacy; creation of production systems for useful compounds, such as paclitaxel from plant cell cultures; and construction of whole cell models relating genome to physiology. He is also CEO and President of Hesperos, a company founded to implement the “Body-on-a-Chip” system. Dr. Shuler and F. Kangi have authored a popular textbook, “Bioprocess Engineering; Basic Concepts”. Dr. Shuler has been elected to the National Academy of Engineering and the American Academy of Arts and Science and is a fellow of numerous professional societies.
Abraham Stroock, Ph.D.
Cornell University
Dr. Abraham Stroock is a Professor and Director of the Robert Fredrick Smith School of Chemical and Biomolecular Engineering at Cornell University. He received his Ph.D. in Chemical Physics from Harvard University for work with George Whitesides on micro-scale fluid dynamics and the development of microfluidic technologies.
His laboratory at Cornell has pioneered the application of microfluidic approaches to the challenge of controlling mass transfer within three-dimensional cell cultures and the formation of functional vascular structure in vitro. He is leading the PS-OC’s Tissue Microfabrication Core and working on both experimental and theoretical questions related to the impact of microenvironment on tumor metabolism.
Jeffrey Varner, Ph.D.
Cornell University
Dr. Jeffrey Varner is a Professor in the Robert Frederick Smith School of Chemical and Biomolecular Engineering at Cornell University. Jeffrey Varner holds a Ph.D. degree in Chemical Engineering from Purdue University, where he explored modeling and analysis of metabolic networks in the lab of Prof. Doraiswami Ramkrishna. He did a postdoc in the Department of Biology at the ETH-Zurich under the direction of Jay Bailey and a research position at Genencor-DuPont (Palo Alto, CA).
Dr. Varner joined the faculty of the Chemical and Biomolecular Engineering department at Cornell University as an Assistant Professor in 2006. In the fall of 2011, Prof. Varner was promoted to Associate Professor with tenure, and in 2016 to the rank of Professor. The Varner lab is interested in modeling and analysis of signal transduction and metabolic networks using kinetic and constraints-based modeling techniques, as well as automatic code generation, and model identification using multi-objective optimization.
Valerie Weaver, Ph.D.
University of California, San Francisco (UCSF)
Dr. Valerie Weaver is the Director of the Center for Bioengineering and Tissue Regeneration in the Department of Surgery, and is a Professor in the Departments of Surgery, Anatomy and Bioengineering and Therapeutic Sciences at UCSF. Dr. Weaver has more than 20 years of experience in leading interdisciplinary research in oncology, including the Bay Area Physical Sciences and Oncology program and the UCSF Tumor Microenvironment Brain Program, which merge approaches in the physical/engineering sciences with cancer cell biology and emphasize the role of the tumor microenvironment.
Dr. Weaver has been recognized for her research and leadership through receipt of several awards, including the Department of Defense Breast Cancer Research Program Scholar award in 2005 and Scholar expansion award in 2013 for exceptional creativity in breast cancer research, and the American Society for Cell Biology-Women in Cell Biology Midcareer award for sustained excellence in cell biology research in 2014. Most recently she was elected as the chair of the American Association for Cancer Research Tumor Microenvironment Network working group in 2015. Her research program focuses on the contribution of force - cell-intrinsic as well as extracellular matrix - to breast, pancreatic and glioblastoma tumor development and treatment.
Warren R. Zipfel, Ph.D.
Cornell University
Dr. Warren R. Zipfel is an Associate Professor in the Nancy E. and Peter C. Meinig School of Biomedical Engineering at Cornell University. He obtained his Ph.D. at Cornell, studying the photophysics of photosynthesis using time-resolved laser spectroscopy. He later worked as a Research Associate in Applied and Engineering Physics under Watt Webb in the area of laser-scanning microscopy, during which time he was involved in the development of multiphoton microscopy at Cornell.
His current research focuses on instrumentation and application developments in the areas of laser-scanning microscopy, fluorescence lifetime imaging (FLIM), super-resolution microscopy and single molecule level analysis of biological processes, which his lab applies to studies in cancer biology and transcriptional control.