Center for Modeling Tumor Cell Migration Mechanics
List of Collaborating Institutions
Cleveland Clinic, Mayo Clinic
Cell migration is a common feature of high-grade cancer, with invasion and metastasis being primary causes of cancer related death. As a result, our Center will focus on understanding the fundamental mechanics and chemistry of how cells generate forces to move through complex and mechanically challenging tumor microenvironments. The organizing framework of our Center is to then directly target the mechanical machinery and structural elements that drive cell migration. As it is these elements that serve as the most downstream convergence point of the upstream genetic alterations, disruption of these critical elements provides viable, clinically-relevant targets. By focusing directly on the “nuts and bolts” of cell migration, we will be targeting the most vital and non-redundant part of the system. Specifically, we propose integrated modeling and experiments to investigate the molecular mechanics of cell migration and how the tumor microenvironment regulates disease progression as a function of the underlying carcinoma genetics. We will experimentally test our computational cell migration simulator for the mechanical dynamics of cell migration that will ultimately be used to: 1) identify novel drug targets/target combinations in silico
, 2) define molecular mechanical subtypes of tumors for patient stratification, 3) guide the engineering of in vitro
microsystems and in vivo
animal models to better mimic the human disease, and 4) simulate tumor progression under different potential treatment strategies. Finally, we will develop a simulator-driven reverse genetics approach to elucidate the functional mechanical consequences of driver mutations and seek to manipulate the physical characteristics of a tumor to simultaneously bias against immune suppressor cells and promote the antitumor immune response.
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David Odde, Ph.D.
David Odde is a professor of biomedical engineering at the University of Minnesota who studies the mechanics of cell division, polarization, and migration. Trained academically as a chemical engineer, Odde joined the newly created Department of Biomedical Engineering at the University of Minnesota in 1999. In his research, Odde’s group builds computer models of cellular and molecular self-assembly and force-generation-dissipation dynamics, and tests the models experimentally using digital microscopic imaging of cells ex vivo and in engineered microenvironments. Current applications include the modeling of chemotherapeutic effects on cell division, molecular mechanisms of neurodegeneration, and migration of cancer cells through complex microenvironments such as the brain. Ultimately, his group seeks to use the models to perform virtual screens of potential therapeutic strategies. Dr. Odde is an elected Fellow of the American Institute for Medical and Biological Engineering (AIMBE) and of the Biomedical Engineering Society (BMES).
David Largaespada, Ph.D.
Dr. Largaespada is an authority on mouse genetics, gene modification and cancer genes. He received his B.S. in Genetics and Cell Biology from the University of Minnesota in 1987 and his Ph.D. in Molecular Biology with Dr. Rex Risser at the University of Wisconsin-Madison in 1992. He spent five years as a postdoctoral fellow in Frederick, Maryland at the National Cancer Institute. He joined the faculty of the University of Minnesota in late 1996, and is currently a Full Professor in the Department of Genetics, Cell Biology and Development and the Department of Pediatrics at the University of Minnesota. He also serves as associate director for Basic Science at the University of Minnesota Masonic Cancer Center. Dr. Largaespada is working to exploit insertional mutagenesis for cancer gene discovery and functional genomics in the mouse. He has pioneered the use of a vertebrate-active transposon system, called Sleeping Beauty (SB), for insertional mutagenesis in mouse somatic and germline cells, and for gene therapy. Using SB he has developed a powerful method to find new cancer genes using transgenic mouse models.
Steven Rosenfeld, M.D., Ph.D.
Dr. Rosenfeld has over 25 years of experience as a widely published, NIH-funded investigator in the biochemistry of molecular myosin motors, more recently applied translationally to the problem of glioma dispersion and proliferation. He also been an investigator in neuro-oncology for over twenty years, including as Director of the Brain Tumor Research and Treatment Program at the University of Alabama at Birmingham, as Principal Investigator in a brain tumor program project grant and as Director of the UAB Brain Cancer SPORE, as Chief of Neuro-Oncology at Columbia University, and most recently, as the Melvin H. Burkhardt Professor of Neuro-Oncology and Director of the Brain Tumor Research Center of Excellence at the Cleveland Clinic, as Co-Director of the Neuro-Oncology Program at the Case Comprehensive Cancer Center , as a member of the External Advisory Boards of the Mayo Clinic Cancer Center and the Mayo Clinic and University of Alabama at Birmingham Brain Cancer SPORE programs, and as a member of the Steering Committee of the Adult Brain Tumor Consortium (ABTC).
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Project 1: Physical modeling and dynamics of tumor cell migration mechanics (David Odde, Ph.D., PI)
A key feature of highly aggressive cancers is their invasiveness, where transformed cells disseminate by crawling through the local micro-environment, ultimately causing death as the tumor invades and metastasizes. If these processes of cell motility could be suppressed, it would potentially extend lifespan and increase the potential effectiveness for local and global therapeutic treatments. However, we do not adequately understand the mechanical and chemical basis of cancer cell migration in complex and mechanically challenging microenvironments. The goal of this project is to develop and use a mathematical/computational model that will allow us to simulate cancer migration on a computer, and, in the longer-term, perform virtual in silico drug screening. Specifically, during this project we will mechanically parameterize glioblastoma (GBM) and pancreatic ductal adenocarcinoma (PDA) tumor cell migration so that patient outcomes can be predicted and new therapeutic strategies identified. Employing physical modeling for whole cell model migration, we have developed a “Cell Migration Simulator, v1.0,” (CMS1.0) to capture fundamental intracellular and extracellular mechanical processes regulating cell migration. Here, CMS1.0 will be used to 1) mechanically parameterize tumor heterogeneity, 2) bias immune-cancer cell interaction away from suppression and toward killing, and 3) elucidate proto-oncogene mechanism. Finally, we will also further develop the CMS1.0 to include more explicit F-actin dynamics, cell mechanics, and environmental fiber mechanics. In the process, we will build a physical sciences-based, patient-oriented approach toward understanding and controlling a key driver of cancer progression, cell migration. Thus, the project will establish the quantitative framework necessary to develop a model-driven approach to brain and pancreatic cancer invasion, so that therapies can be designed and engineered for better, more predictable outcomes.
Project 2: Cell Migration in Mechanically Complex Microenvironments (Paolo Provenzano, Ph.D., PI)
Cancers are complex systems commonly associated with a robust fibroinflammatory stromal response, or desmoplastic reaction. This is highly relevant as it is now recognized that, in many solid tumors, the stromal compartment and its local microenvironments significantly influence disease progression. Through disease progression this desmoplastic reaction continues and often intensifies, offering critical support to malignant cells as they progress to invasive and often fully metastastic disease while also providing drug-free sanctuaries that limit access of small molecule therapies. Likewise, even the earliest stages of disease are associated with a robust immune reaction that evolves with disease progression. Here tumor microenvironments appear to form sanctuaries for immune evasion and in fact are comprised, in part, of infiltrated immune cells that have been subverted to act as active collaborators that enable tumor progression. Interestingly, while robust biochemical stimuli are present in tumors, they are not the only factor. These microenvironments also provide robust physical cues that conspire to promote disease progression. For instance, in solid tumors there are fundamental roles of extracellular matrix stiffness, composition and architecture that profoundly influence outcome. However, to date, the molecular and physical mechanisms by which matrix stiffness and architecture, and their relative contributions, influence tumor cell behavior are not well known. Here, we propose specific and integrated experiments and modeling to explicitly investigate the physical and molecular mechanisms by which the tumor microenvironment regulates disease progression as a function of the underlying carcinoma genetics. Quantitative analysis and parameterization of data will facilitate model development and model predictions will be tested experimentally. Specifically, we will employ a series of 2D and 3D assays with varying stiffness and architecture of increasing complexity, and multiscale network modeling, to parse out the relative contributions of contact guidance cues and durotactic effects in complex microenvironments. Integration of chemical gradients will be used to parse out dominance, antagonism or synergy between chemical and physical cues. Further, we hypothesize that physical cues in the cellular microenvironment drive communication between different tumor cell populations and regulate immune cell infiltration and function. Thus, we seek to identify regimes where manipulating operant physical characteristics of a tumor reduces carcinoma cell advancement while simultaneously hampering immune evasion and promoting the antitumor response.
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Core 1: Cellular Microenvironment Engineering (David Wood, Ph.D. and Patrick Alford, Ph.D., PIs)
The Cell Microenvironment core will provide enabling technologies and develop new methods for controlling the cellular microenvironment and measuring its effect on cancer cell migration. The primary goals of the core will be to probe microenvironmental regulators of cell migration to inform mathematical models, probe cell migration within a physiologically relevant context, and develop highly parallelized platforms for high throughput studies. Technologies will include, but not be limited to, tools for controlling the mechanical environment, controlling cell and environment architecture, controlling cell organization within the microenvironment, controlling chemical gradients, controlling extracellular chemistry, measuring cell migration, and measuring cell force generation. In addition, tools will be developed for high-throughput cell migration measurement and high-throughput tissue isolation. The Cell Microenvironment core will support both Project 1 and Project 2 within this center as well as any applicable pilot projects.
Core 2: Cell and Whole Animal Genome Engineering (David Largaespada, Ph.D., and Anindya Bagchi, Ph.D., PIs)
The Cell and Whole Animal Genetic Engineering core will provide both projects with genetically engineered cell lines and mice for analyzing cell and/or tumor behavior under a variety of conditions. The core brings together expertise from two highly trained mouse and somatic cell geneticists, Dr. David Largaespada and Dr. Anindya Bagchi, both with expertise in modeling cancer in mice and with a wide array of cells. Thus, this core will generate two specific resources for both projects #1 and #2. The first is cohorts of mice that reliably develop pancreatic, glioma or medulloblastoma tumors due to the inheritance of germline transgenes, mutant alleles in their endogenous locus, or due to transposon-mediated gene delivery to the brain. Likewise, Core 2 will support studies perturbing the genetic events examined in each project. Additional models will be developed as needed. The models will be provided to project #1 and #2 scientists in age-matched cohorts and of both genders. Specifically, these will be models of glioma and medulloblastoma initiated in mice by transposon delivery of shRNA and cDNAs. A second resource is to provide genetically altered human cancer cell lines for project #1 and #2. These cell lines will harbor loss of function mutations, or specific single nucleotide variants (SNV), in genes of interest. They will be produced using TAL endonuclease or CRISPR/Cas9 gene targeting, without or with oligonucleotide substrates, to create “knockout” cell lines due to imprecise non-homologous end joining (NHEJ) in the former case, or SNVs via homology directed repair (HDR) in the latter case.
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Education and Outreach Activities
As model complexity increases to moderate levels (~5-10 parameters), we have found that the models are surprisingly difficult to understand intuitively. We find that for moderately complex models, our intuitive reasoning is often incorrect, a humbling discovery. Part of the difficulty of model deconstruction is that the computer is essentially mute after a simulation run, and does not lend direct insight into the process.
If the computer had human-like intelligence, then we could engage in discussion with it regarding the essential features of the model. Since such computers are not on the immediate horizon, we have started to explore programming humans to act as the agents in the simulation. Such programming can be physically demanding, and may involve violent collisions as dictated by the level of thermal forces and diffusion. Therefore, our initial exploration involves collaboration with a professional dance company, Black Label Movement – directed by Carl Flink. Flink’s dancers, whom he refers to as “movers”, are now highly trained in diffusion reaction, self-assembly, and forces after five years of collaboration with Dr. Odde in a collaboration we call the “Moving Cell” project. These movers rapidly assimilate model rules, and carry out human-scale simulations over a few minutes, a process we call “bodystorming”, where bodies and minds work together to rapidly construct and deconstruct models.
Our bodystorming engages Center researchers, clinicians, patients, caregivers and we are working with the UMN PSOC patient advocate Carole Baas to develop a new bodystorming experience focused on the experience of cancer survivors. The interactions facilitated by bodystorming use human movement as a facilitator to break down disciplinary language barriers between cancer researchers, patients, clinicians, and caregivers enabling substantive new discourse that accelerates the science.
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