Stanford Physical Sciences-Oncology Center (Stanford PS-OC) will determine how mechanobiology influences tumorigenesis in breast cancer. This center’s primary focus will be on the triple negative subtype of basal breast cancer, which lacks the estrogen, progesterone, and Her2/neu receptors. Patients with this more aggressive, triple negative subtype have fewer treatment options and an overall poor prognosis. These investigators hypothesize that the malignant phenotype is maintained by exchanges with its microenvironment and that reversion can occur if these pressures are normalized. This center will also examine how mechanical signals trigger genetic changes that induce tumorigenesis. Groundbreaking force probes and imaging techniques will gauge the forces within breast cancer model systems. The integration of these state-of-the-art tools in the physical, theoretical and biological sciences will cultivate models of various interactions of the model systems with their microenvironment. Furthermore, cellular plasticity and reversion research will be executed and could lead to potential therapeutics targeted to the cellular microenvironment.
Principal Investigator: Jan Liphardt, Ph.D.
Senior Scientific Investigator: Valerie M. Weaver, Ph.D.
Collaborators: Lawrence Berkeley National Laboratory, University of California-San Francisco
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Jan Liphardt, Ph.D.
Jan Liphardt, PhD, is an Associate Prof. of Bioengineering at Stanford University. His scientific training is in single-molecule biophysics and thermodynamics of small systems. The main focus of his research is to determine how biological systems function. Systems under investigation range from the self-organisation of receptors in membranes, the transport of cargos through biological pores, and the control of the DNA loopscape in the nucleus. Typically, research in his lab involves super-resolution light microscopy, optical tweezers, or optical control strategies. More information can be found on his website: http://liphardtlab.stanford.edu/.
Valerie M. Weaver, Ph.D.
Valerie M. Weaver, PhD, is the Director of the Center for Bioengineering and Tissue Regeneration in the Department of Surgery and Associate Professor in the Department of Surgery and Anatomy and Bioengineering and Therapeutic Sciences at UCSF. Her group studies the molecular mechanisms whereby extracellular matrix receptors and mechanical force and matrix topology modulate normal and transformed cell behavior and alter embryonic cell fate. The research involves bioengineered matrices, microscopy techniques (traction force microscopy, atomic force microscopy, second harmonic generation microscopy), cell biology and animal work.
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Joe Gray, Ph.D.
Joe Gray, Ph.D., is the Chair of Bioengineering at OHSU. He is a pioneer in characterizing the genomic, transcriptional and proteomic abnormalities that occur in selected cancers.
Frank McCormick, Ph.D.
Frank McCormick, Ph.D., is the Director of the Helen Diller Family Comprehensive Cancer Center. He analyzes signaling complexes involving Ras proteins at the plasma membrane at the molecular level. This includes stoichiometry of Ras proteins and their effectors, in resting and active states, and proteins that regulate determine these dynamic transitions.
Jay Groves, Ph.D.
The Groves lab focuses on chemistry in complex environments where, for example, collective properties of the system feedback onto the molecular scale chemical events. Such multi-scale coupling is widespread in biological systems, from dynamical movements within a protein to morphological transitions of whole cells. The lab pursues a variety of research projects emphasizing physical mechanisms of molecular self-organization and the role of spatial patterning as a regulator of differential outcomes from otherwise chemically equivalent systems.
Mina Bissell, Ph.D.
Mina Bissell, Ph.D., pioneered the idea that the microenvironment of a cancer cell influences whether it becomes a cancer cell. Her lab aims to establish the fundamental morphological and force dynamics of tissue reversion in breast cancer cell lines.
James A. Sethian, Ph.D.
James A. Sethian, Ph.D., is Professor of Mathematics at UC Berkeley and Head of the Mathematics Department at the Lawrence Berkeley National Laboratory. His work is on the construction and application of algorithms to compute the dynamics and physics of moving interfaces, especially under the effects of hydrodynamical, mechanical, and chemical forces.
Dan Fletcher, Ph.D.
We study the effect of external forces on the movement and organization of cells and tissues. Using a custom gel compression system, we investigate the role of stress, strain, and loading history on tumor reversion.
Sanjay Kumar, M.D., Ph.D.
We study how cells sense, process, and respond to mechanical and other biophysical signals in their environment. Using a combination of single-cell imaging and mechanics methods, materials fabrication, and computational modeling, we investigate both fundamental mechanisms that underlie cellular mechanotransduction and roles this mode of signaling may play in tumor and stem cell biology.
Claire Tomlin, Ph.D.
Claire Tomlin, Ph.D., is a Professor in the Berkeley EECS department. She studies control theory; hybrid and embedded systems; and biological cell networks.
Gerard Marriott, Ph.D.
The Marriott lab designs and uses new optical probes and microscope imaging techniques to investigate protein function and dynamics over a hierarchy of organizational levels, ranging from single molecules to cells within animals.
Hana El-Samad, Ph.D.
Our research is poised at the interface of biology, mathematics, dynamical systems, and control theory. We work on the premise that the application of the appropriate mathematical tools to the investigation of cellular networks, when coupled with iterative rounds of experiments, will dramatically accelerate the pace of biological discoveries.
Hope S. Rugo, M.D.
Hope S. Rugo, M.D., is Professor of Medicine at UCSF and Director of the UCSF Breast Oncology Clinical Trials Program. Dr. Rugo is the lead of our education and outreach program.
Sylvain Costes, Ph.D.
Sylvain Costes, Ph.D., is a scientist at LBNL working on modeling disruption of organized cell populations. His group is establishing agent-based models that attempt to mimic cell behavior when grown as monolayer or in three-dimensions.
Xiaolin Nan M.S.
Xiaolin received his B.S. and M.S. in Chemistry from Peking University, Beijing, and a Ph.D. in Biophysics from Harvard University, Cambridge. Xiaolin first joined the PS-OC as a postdoctoral fellow with Dr. Steven Chu at the University of California, Berkeley, and worked closely with Dr. Joe Gray at the Lawrence Berkeley National Laboratory and Dr. Frank McCormick at the University of California at San Francisco. In this time he established a unique biological system for controlled expression of tagged proteins for single-molecule counting and localization using super resolution imaging based on PALM and STORM principles that provided novel insights into the regulation and action of the Ras and Raf oncogenes. Currently he is an Assistant Professor at the Oregon Health & Science University.
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Project 1 – Fundamental Mechano-Chemical Mechanisms of Signaling in Cancer
Project Leader: Jay Groves (University of California- Berkeley)
Project 1 seeks a fundamental understanding of how the mechanical environment of a cell influences its intracellular signaling. Specifically, we will investigate the interplay of chemistry and mechanics in the EphA2 receptor signaling pathway as well as Ras signaling. By controlling the mechanical forces that drive receptor spatial organization, we may be able to elicit structural and functional phenotypes characteristic of defined phases of tumor progression.
Project 2 – Mechanobiology of Acinar Stability
Project Leader: Valerie Weaver (University of California- San Francisco)
Project 2 explores how force regulates subcellular organization of adhesion molecules to promote acini morphogenesis. While a reductionist approach is typically used to clarify the molecular mechanisms that drive development and maintain homeostasis, we take the view that cell and tissue behavior are phenotypically plastic, mediated by adhesion and modified by mechanical force. We will test the idea that (1) force regulates the organization of proteins at the subcellular level to alter cellular organization at the tissue level and (2) that emergent properties of multi-cellular tissues and feedback mechanisms alter the responsiveness of cells to mechanical cues within a growing tumor.
Project 3 – Dynamics in the Tissue State Space: From Normal to Tumor and Back
Project Leader: Jan Liphardt (Stanford University)
Cancer is both a disease of uncontrolled growth and loss of organ architecture. Remarkably, as shown by animal studies and 3D cell culture models, enforcing a ‘normal’ context or architecture on malignant cells can cause them to behave like non-malignant cells, despite retaining a host of genetic mutations. This ‘reversion’ of malignant cells to a non-malignant phenotype is an example of the plasticity (malleability) of cells, which can change their organization and function in response to external signals in their microenvironment. This projects seeks to uncover fundamentals of tissue plasticity and outline new strategies to understand both how tumors lose structure and how to restore tumors to a non-malignant state.
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