National Cancer Institute
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Princeton University

Princeton, NJ

Princeton University

Overview

Center Summary

Princeton University Physical Sciences-Oncology Center (PU PS-OC) will focus on how to control the evolution of cancer resistance to chemotherapy. Drug resistance is the major barrier to successful cancer treatment, and understanding its development will facilitate the creation of new agents with improved efficacy. These investigators will use the basics of physics to evaluate stress response mechanisms in a variety of fundamental as well as clinically relevant studies. This work will also focus on the evolution of this resistance to understand its origin and dynamics. The investigators hypothesize that evolution in a small, stressed microenvironment will generate the rapid emergence of resistance. This center will utilize novel microfabrication techniques and single cell genomic analysis to evaluate such a micro-environment amid metabolic and mechanical stressors. Moreover, these investigators will determine if stress can alter the types of mutations accumulated by cells. They will also address how a mutation can spread from an individual cell to the entire tumor.

Principal Investigator: Robert H. Austin, Ph.D.

Senior Scientific Investigator: Thea D. Tlsty, Ph.D.

Website: http://www.princeton.edu/psoc/

Collaborators: Johns Hopkins Medical Institute, Salk Institute, University of California-Santa Cruz, University of California-San Francisco

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Investigators

Image of Robert H. Austin, PhD

Robert H. Austin, Ph.D.

Robert H. Austin, PhD, is a Professor in the Department of Physics, Princeton University. He received a Ph.D. Physics in 1975 from The University of Illinois Urbana-Champaign studying under Prof. Hans Frauenfelder. Dr. Austin trained with Dr. Thomas Jovin and Prof. Manfred Eigen as a Postdoctoral Fellow at the Max Planck Institute for Biophysical Chemistry in Goettingen, Germany from 1976-1979. He joined in1979 the faculty at Princeton University.

Prof. Austin has studied a wide range of biological physics problems. He originally was involved in the discovery that proteins do not have a single unique structure but instead dynamically move over a free energy landscape in a conformation space. This work, which involved cryogenic optical studies, moved to using picosecond mid and far-infrared lasers to study possible non-linear quantum mechanical self-trapped states as possible channels for energy flow in proteins. He became interested in how transcription factors interact with DNA in work with Mike Hogan, and developed quantitative models for how mechanical helix distortion influences binding constants of transcription factors. In 1992 he developed nanofabrication techniques to sort and analyze biological objects, analyzing first genomic length of DNA and later proteins and cells. This work, which exploited the fabrication techniques of the semiconductor industry, has lead to his recent interest in evolution dynamics using micro/nanofabrication techniques to create microhabitats and fitness landscapes.

Image of Thea D. Tlsty, PhD

Thea D. Tlsty, Ph.D.

Thea Tlsty, PhD, is a Professor in the Department of Pathology, Director of the Program in Cell Cycling and Signaling in the UCSF Comprehensive Cancer Center and Director of the Center for Translational Research in the Molecular Genetics of Cancer at the University of California, San Francisco, School of Medicine, San Francisco, CA. She received a Ph.D. in Molecular Biology from Washington University. Dr. Tlsty trained with Dr. Robert Schimke at Stanford University as a Postdoctoral Fellow and Senior Research Associate in the Department of Biological Sciences before she was recruited to the University of North Carolina as Assistant Professor of Pathology and Member of the UNC Lineberger Comprehensive Cancer Center. In 1994 she joined the faculty at UCSF.

Dr. Tlsty studies genetic, epigenetic and functional changes involved in the earliest steps of epithelial cancers and how interactions between stromal components and epithelial cells collaborate to moderate carcinogenesis. Her research studies of human epithelial cells from healthy individuals are providing novel insights into how early molecular events affect genomic integrity and fuel carcinogenesis and malignant evolution. Prior work from her laboratory has shown that surrounding stroma can dramatically influence tumorigenesis both through signaling pathways and epigenetic reprogramming. She investigates how these changes are initiated and moderated, as well as their consequences for clinical disease. These insights are applied in risk assessment, early detection, and prognostic studies. Areas of particular interest include human breast carcinogenesis and the role of tumor suppressor genes in regulating premalignant phenotypes. Her studies use molecular, biochemical and cellular analyses to evaluate primary human cells, develop recombinant models of cell-cell interactions and apply novel information to intact human tissue.

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Projects

Project 1 – Bacterial Model Ecologies

Project Leader: Robert H. Austin (Princeton University)

The project couples evolutionary biology with nanotechnology to investigate the recurrence of resistance. Bacteria exhibit all of the fundamental phenomena giving rise to genomic instability. Additionally, the SOS response in bacteriology is a well-known mechanism for generation of genomic diversity under stress. Micro-fabrication techniques are used to create complex bacterial ecosystems with variable stress conditions.

Project 2 – Mammalian Cells and Ecosystems

Project Leader: Thea Tlsty (University of California-San Francisco)

Mammalian tissues are unique ecosystems with regulated interactions that parallel those within bacterial ecosystems. In order to understand the mechanisms of stress response to the activation of evolutionary forces underlying resistance to therapy, several agents are used as stressors to recapitulate rapid cell evolution. This project explores the genomic, epigenic and proteomic evolution of breast cancer cell ecology.

Project 3 – The Evolution of Cooperation in the Tumor Microenvironment

Project Leader: Kenneth J. Pienta (Johns Hopkins School of Medicine)

Using theoretical frameworks derived from game theory and evolutionary biology, and experimental approaches that take advantage of microhabitat patches and 3-dimensional culture systems, this project examines how the physical and chemical signals exchanged between the different cell types in tumors can promote or inhibit the growth of cancer cells.

Project 4 – Physical Ecology Design and Capabilities

Project Leader: James Sturm (Princeton University)

This project provides the overarching model and technology for the Princeton PS-OC. It uses the “microhabitat patch” (MPH) technology developed on a microfluidic chip platform at Princeton to allow the culturing of cells in highly confining interconnected and asymmetric microenvironments. The technology will include 2-dimensional and 3-dimensional arrays utilizing a system of pumps and valves to allow administration of metabolic and mechanical stressors over a variety of spatial patterns and temporal ranges.

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Cores

Core 1 - Microfluidic Facility Shared Resource and Imaging Center

Core Leader: Robert Austin (Princeton University)

The facility consists of two functional pieces – one for making and packaging the microfluidic chips, and another for using the chips to do experiments (in this case biological with a cancer focus. Both of these functional pieces will be set up for remote operation and web interfaces, so that team members at institutions besides Princeton can make use of them. The facility will also be heavily used by the outreach and education/training sections of the center, and we expect by the pilot and transnetwork projects as well.

Core 2 - Cell and Tissue Shared Resource

Core Leader: Thea Tltsy (University of California- San Francisco)

There is great power in comparing several human tissue types across the continuum of malignancy to identify commonalities in their response to stress and their potential to generate genetic diversity and activate evolutionary forces. In this application, all four Projects will use the human cells described in this core. The two tissue types we have chosen for our initial studies center on two of the most common tumor types in humans, breast and prostate tissues; each is hormonally driven and represents the most important clinical problems in both their early and late stages of malignant transformation.

Core 3 - Nano-Analysis Shared Resource for Genome Sequencing

Core Leader: Nader Pourmand (University of California- Santa Cruz)

The purpose of this Shared Resource is to provide specialized equipment and techniques for using sequencing methods to analyze gene expression, DNA methylation states, microRNA signatures, and gene translocation/duplication in the genome. This information will be used to better understand novel cancer pathways at the single cell level, including the rapid cell evolution response that allows some cancer cells to survive chemotherapy. This Shared Resource will expand upon current methodology of sequencing a few cells, bringing high throughput sequencing and other services and expertise to each Project, and the proposed procedure involves optimization of all steps, from isolation and lysis of, ultimately, a single cell, to whole genome amplification and analysis.

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