Johns Hopkins Physical Sciences Oncology Center (PS-OC)
List of Collaborating Institutions
Washington University School of Medicine
University of Pennsylvania Abramson Cancer Center
University of Arizona
The Johns Hopkins Physical Sciences Oncology Center will develop an integrated approach for a systematic, quantitative understanding of the physical and chemical cues mediating local invasion from the hypoxic primary tumor to distant organs, through single and collective invasion into the stromal matrix and confined migration along confining tracks, which represent some of the early critical steps in the metastatic cascade. To address the complexity of the combined effects of hypoxia, extracellular matrix microstructure and confinement on tumor cell invasion, we have developed three inter-related projects. Computational biophysicists will establish a computational core to systematically develop a quantitative understanding of physical cues in the metastatic cascade. PSOC projects will share innovative biophysical methods and experts. This PSOC takes a trans-disciplinary, integrated approach, combining the fields of physics, biomedical engineering, cancer biology, ecology, and clinical medicine, to transform our understanding of metastatic cancer, opening new paradigms for prognosis and treatment.
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Dr. Denis Wirtz
Dr. Denis Wirtz earned a Physics Engineering degree at the Ecole Polytechnique of the Université Libre de Bruxelles (Belgium) in 1988. With a Hoover fellowship, he moved to Stanford University, where he earned a PhD in 1993 in Chemical Engineering for work in polymer physics. With a “Human Capital Mobility” fellowship of the European Union, he did postdoctoral research at the Ecole Supérieure de Physique et Chimie Industrielles (ESPCI) in Paris, France. He joined the faculty of the Department of Chemical and Biomolecular Engineering at Johns Hopkins University in 1994 and was promoted to the rank of full professor in 2003. He is currently T.H. Smoot Professor of Engineering Science. Wirtz has made important contributions to molecular and biophysical mechanisms of cell motility and adhesion and nuclear dynamics in health and disease. He pioneered the method of particle-tracking microrheology to probe the rheological properties of complex fluids and living cells and tissues.
Dr. Kenneth Pienta
Dr. Kenneth Pienta is a Professor of Urology, Oncology, and Pharmacology and Molecular Sciences and a two-time American Cancer Society Clinical Research Professor Award recipient. Between 1995 and 2013, Dr. Pienta served as the Director of the Prostate Specialized Program of Research Excellence (SPORE) at The University of Michigan, with a proven, peer-reviewed track record in organizing and administering a translational research program that successfully incorporates bench research, agent development, and clinical application. He has made major contributions in understanding prostate cancer biology and improving diagnosis and treatment. He is the Director of Research for the Brady Urological Institute at Johns Hopkins University School of Medicine and the Program Leader for the Prostate Cancer Program of the Sidney Kimmel Comprehensive Cancer Center. He also serves as the co-Director of the Johns Hopkins University inHealth Signature Initiative, a trans-University, cross-disciplinary effort to coordinate and apply the intelligent use of population health data for individual patients.
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Project 1: The Role of Physical Cues in Collective Cell Invasion
The ability of tumors to invade adjacent tissues, leading to local or distant metastasis, is a hallmark of cancer. Cancer cells frequently invade as groups of adherent cells in a process termed collective invasion. Previous studies have primarily focused on single cell or semi-collective (multicellular streaming) cell invasion. Single cell models for metastasis have direct implications for tumors whose cells migrate constitutively as individual cells, such as leukemias and lymphomas, or after cell detachment from a primary tumor via epithelial-to- mesenchymal transition (EMT). However, EMT has long been controversial among pathologists as breast tumors at metastatic sites typically display epithelial features. While EMT-like gene signatures can be observed in specific mouse models and breast cancer subtypes, the majority of breast tumors do not exhibit clear molecular features of EMT. Intravital microscopy studies reveal that tumor cells preferentially migrate collectively along pre-existing channels that are defined by various anatomical structures in vivo. However, it is currently unknown how the physical properties of the microenvironment, such as confinement and compliance, regulate the molecular mechanisms of collective cell invasion. Intriguing preliminary data reveal that cancer cells migrate through wide (≥50 µm) tracks as a collective unit. However, as confinement increases, the cancer cells spontaneously disseminate, first as clusters of 2-5 cells and eventually, in very narrow tracks (≤10 µm), as single cells. We hypothesize that the physical microenvironment induces a signaling cascade of events that transforms the classical collective to single cell invasion. To test this hypothesis, we will employ a multidisciplinary approach combining novel bioengineering tools and mathematical modeling with sophisticated molecular cell biology and imaging techniques and in vivo models. In Aim 1, we will develop an integrated experimental and computational model of collective cell movement in confined geometries modeling primary tumor invasion, and dissect the mechanisms by which cell-cell contact is released during mechanically-induced transitions to single cell movement, focusing on the role of E-cadherin cleavage and possible EMT induction. In Aim 2, we will delineate the relative contributions of actomyosin contractility, small GTPases and osmotic engine model to locomotion in rigid versus compliant confined microenvironments. In Aim 3, we will validate our in vitro understanding of the dissemination and locomotion of cancer cells in more complex microenvironments characteristic of in vivo breast tumors using an organotypic 3D culture system and genetically engineered mouse models. Elucidation of the underlying mechanisms of collective cancer cell invasion will offer insights into our understanding of how cancer cells spread through the body, and it could shift the currently prevailing single cell paradigm in cancer to incorporate concepts of mechanical signaling, cell-cell adhesion, and cell-cell cooperation.
The majority of cancer mortality arises because tumors cells leave their primary site, giving rise to metastatic tumors in other organs. While there are many and complex biologic aspects of tumor progression leading to cancer metastasis, local invasion through the basement membrane of epithelia and migration of primary tumor cells through the extracellular matrix (ECM) to access lymphatic and vascular channels is clearly a critical early step. Tumor cells can invade and migrate individually or as groups. Accumulating pathologic and in vivo experimental evidence now indicates that the most common form of tumor cell migration is likely as a collective group. While we have learned a great deal about the cell biologic, biochemical, and biophysical mechanisms underlying the migration of individual cells in 2D, 3D and in vivo, our understanding about the regulation of collective cell migration in cancer metastasis is at an early stage. Organization of cells into collective groups and their migration of cells is governed by a number of forces: passive (elastic and adhesive forces), frictional (resistance to cells sliding past one another and cells sliding across a substrate), active (protrusive and contractile forces), and traction forces upon the underlying or surrounding ECM. Which forces are critical for the collective migration of tumor cells, and how, is not understood. The overarching hypothesis of this proposal is that cell-ECM and cell-cell interactions will combine through adhesion crosstalk to modulate tumor collective cell migration by altering cooperativity of motion and force generation. To test this hypothesis we have developed computational tools, and 2D and in vivo 3D experimental models that measure various physical forces within and around a group of tumor cells as they organize to migrate in a collective through the tumor stroma and within the tumor epithelium. Our approach to the problem is iterative: using computational simulations to inform experimental testing of how various forces contribute to the organization and motion of collective groups of tumor cells. We propose four specific aims using these tools to address this problem: Aim 1. To determine an integrated experimental and computational model of how tumor cell-intrinsic changes in adhesion influence collective migration. Aim 2. To determine how changes in the tumor environment affect collective migration of tumor cell. Aim 3. To determine how cell-cell and cell-ECM forces influence the nature of tumor cell collective migration in clinically relevant primary human breast tumor samples. Aim 4. To develop a computational model of collective cell migration dynamics in tissues.
Sarcoma is a malignant cancer derived from transformed cells of mesenchymal origin. Progression and metastasis of sarcomas is regulated by microenvironmental cues. Low intratumoral O2 (hypoxia) most dramatically increases pulmonary metastasis, and poor clinical outcomes, though we do not yet completely understand the critical effects of hypoxia on sarcoma cells and the microenvironment. Thus, defining how primary tumor cells respond to O2 in their microenvironment is essential for understanding metastasis and identification of novel therapeutic targets.
Our recent work has shown that hypoxia promotes sarcoma metastasis through induction of HIF1-PLOD2 and the subsequent deposition of aberrant collagen that leads to distant metastasis. However, we do not yet know 1) how cell migration/invasion is altered in the presence of the O2 gradients that occur in tumors, 2) which collagen modifying-enzymes define the ECM, and 3) precisely how cells’ motility is modified in response to altered collagen structure in the microenvironment. The proposed studies address each of these unknowns. To model the O2-gradients that develop in tumors as they outgrow their vascular supply, we developed novel O2-controlling hydrogels that can serve as 3D hypoxic microenvironments.
We hypothesize that sarcoma cell invasion and migration is guided by increased O2 tension and facilitated by hypoxia-induced ECM remodeling. We will determine if O2 gradients regulate the direction, speed and distance of migrating sarcoma cells, how these factors depend on hypoxic ECM remodeling, focusing on collagen microstructure. Our approach will integrate mathematical modeling and experimental in vitro and in vivo models, linking O2-ECM-cellular invasion and migration in sarcomas. The specific aims are: (1) To determine sarcoma cell and tumor graft responses to spatial oxygen gradients; (2) To characterize collagen remodeling during sarcoma invasion under hypoxic gradients; (3) To determine how collagen fiber organization regulates hypoxic invasion and migration. The results of the experiments proposed here will identify the molecular and physical mechanisms underlying the initial steps of metastasis, invasion and migration, and develop predictive models for these mechanism, all leading to novel therapeutic targets.
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The computational core will provide theory and modeling hands-on expertise to all of the projects in the Center. The computational core will also actively develop user-friendly software packages for assisting data collection, as well as Matlab routines and software for running simulations by non-experts. Tutorials on modeling concepts, modeling results, and developed software will be conducted at center-wide retreats as well as center symposia twice a year. All of the developed software packages will be made available to researchers in the Center as well as the larger community. The aims of the computational aims are: (1) Develop a 3D computational framework for simulating single-cell migration simultaneously with reaction-diffusion-advection equations for complex biochemical signaling pathways. (2) Construct a computational platform for simulating discrete numbers of interacting motile cells. Incorporate key physical parameters as well as coarse-grained modeling of biochemical signaling pathways. (3) Bridge from discrete models of single cells to 3D continuum algorithms for simulating the migration of multicellular groups.
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Education and Outreach Activities
The PSOC at JHU uses a variety of activities and strategies to support our education and outreach initiatives. The center hosts two major events. The first is the annual symposium, co-hosted with the Institute for NanoBioTechnology (INBT). This symposium is a platform for faculty, students, and guest speakers to showcase the most recent and relevant research and share ideas, information, techniques, and methods. The other event is the summer seminar series. This provides further opportunities for researchers to interact, share knowledge, and collaborate. Training is an important aspect to prepare the next generation of researchers. We not only train current students and postdocs, but we also train students outside PS-OC research labs when possible. The center hosted a high school intern from the Baltimore area and an undergraduate intern from Arizona State University. It has also provided tours of the research labs to the Baltimore Leadership School for Young Women. The PS-OC at JHU utilizes leverages the internet and print publications to highlight important work, opportunities, and education content. Articles are posted on the website and social media. They also appear in the annual Nano-Bio Report produced by INBT. Additionally, the center publishes a newsletter for PS-OC members. We also collaborate with other media outlets when possible. Andrew Ewald and his research have been featured in Johns Hopkins Magazine and has a video explaining his breast cancer research. Denis Wirtz’s and his former PhD student, Hasini Jayatilaka’s, research on metastasis signaling pathways was also featured. This media coverage successfully garnered worldwide coverage in over 70 media outlets. Past outreach activities included the center’s investigating PI, Denis Wirtz, advocating for cancer research on Capitol Hill. He met with Maryland Senator Chris Van Hollen’s staff, Delaware U.S Representative Lisa Blunt Rochester’s staff, and Congresswoman Debbie Wasserman Schultz, a 10-year breast cancer survivor, from Florida’s 23rd Congressional District.
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