Nuclear Dysfunction in Cancer: The Role of Mechanical Stresses Transmitted by the LINC Complex
List of Collaborating Institutions
Columbia University, New York
University of Massachusetts Medical School, Worcester
The nuclear lamina is physically connected through nuclear envelope proteins to the cytoskeleton by the LINC complex (linker of nucleoskeleton to cytoskeleton), which spans the nuclear envelope and allows the transmission of mechanical forces to the nucleus. LINC complex proteins are frequently mutated or dysregulated in cancer, and some of these mutations have been proposed to be cancer drivers. Yet, how alterations to the LINC complex might promote cancer development is not known. Our overarching hypothesis is that cytoskeletal force transmission to the nucleus is altered in cancer due to driver mutations in LINC proteins contributing to loss of epithelial polarity, aberrant tissue structure, abnormal gene expression, transformation and invasive cancer cell migration. The cancer nucleus remains highly understudied, with much to learn known about the physical principles that govern nuclear positioning, dysmorphia and chromatin organization, and how altered nuclear stresses contribute to cancer cell dysfunction. This necessarily requires an integrated understanding of both molecular and physical mechanisms. Extensive expertise gained in other systems will be coupled with new approaches for measuring forces on the nucleus. These include a direct force probe to interrogate nuclear mechanical responses in living cells and nuclear tension sensors for the study of nuclear forces in both cancer and normal cells. Physically-based computational models will be used to interpret the resulting data.
Examples of mechanical stresses that can position the nucleus. These include tensile stress (corresponding to a net force FT), compressive stress (FC), or shear stress (FS). Depending on the cell context, different stresses can be dominant. For example, tensile actomyosin forces may position the nucleus during 2D cell crawling, and actomyosin retrograde flow can position the nucleus away from the leading edge during the initial phase of wound healing. Compressive stresses generated, for example, by trailing edge detachment can translate the nucleus toward the leading edge. Microtubule motors can translate the nucleus by shearing it (FS) or rotate it by exerting a torque on it (TM). Kinesin motor action is not shown in the figure for clarity. Dissipative nuclear stresses generated due to moving boundaries may also contribute to nuclear positioning (not shown). A balance between a subset of or all of these forces determines nuclear position. TAN lines, transmembrane actin-associated nuclear lines. Reproduced from Lele et al, J Cell Biol (2018) 217 (10): 3330-3342.
- Define alterations to LINC complex- transmitted mechanical stresses in cancer.
- Determine how the LINC complex contributes to altering the epigenetic organization of the genome during progression to breast cancer.
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Tanmay P. Lele, Ph.D., Principal Investigator
Dr. Lele is a Professor in the Department of Chemical Engineering at the University of Florida. He received the Ph.D. in 2002 in Chemical Engineering from Purdue University. His research is in the area of Mechanobiology, with focused efforts in understanding the molecular mechanisms by which cell generated mechanical forces and associated signaling pathways enable cell and tissue functions. He has contributed to the development and application of new methods for sub-cellular mechanical perturbations including laser ablation of cytoskeletal structures and direct nuclear force probes. Current research projects in the laboratory include quantitative measurements of nuclear forces, the effect of mechanical stresses on nuclear functions and gene expression, cellular adaptation to mechanical properties of the extracellular matrix, and the mechanics of tissue development. A key interest is in the field of cancer mechanobiology, with a focus on the role of the nucleus in the development of aberrant tissue structure and function. A distinctive feature of his work is that experimental findings are either motivated by or interpreted with mathematical modeling/computational predictions.
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Gregg G. Gundersen, Ph.D.
Gregg Gundersen received his Ph.D. in Biochemistry from the University of Washington and did postdoctoral research in Cell Biology at UCLA and Caltech before joining the faculty at Columbia University in 1989 where he is currently Professor of Pathology & Cell Biology. Dr. Gundersen’s studies focus on the role of the cytoskeleton in cell organization, polarization and migration. He has studied tubulin post-translation modifications, the role of Rho GTPases in regulating microtubules and coordinating cytoskeletal responses and the endocytic disassembly and recycling of focal adhesion components. Recently, his laboratory made the unexpected finding that the nucleus, rather than the centrosome, moves during centrosome reorientation in migrating cells and has uncovered a novel adhesive structure in the nuclear envelope that assembles to couple nuclei to moving actin filaments. His continuing studies are examining the role of nuclear positioning in cell polarity, migration and disease and the role of integrin recycling in cell migration and invasion.
Richard B. Dickinson, Ph.D.
Dr. Dickinson is a Professor of Chemical Engineering at the University of Florida. He received a BS from University of Washington and a PhD from the University of Minnesota, both in Chemical Engineering His postdoctoral appointments were in Chemical Engineering at the University of Wisconsin and as a NATO Fellow at the University of Bonn (Theoretical Biology). Professor Dickinson has supervised or co-supervised 20 PhD graduates and published over seventy research articles in cellular/molecular bioengineering. With his students and collaborators, he has made seminal contributions in the areas of cytoskeleton filament dynamics, bacterial adhesion, and cell motility. These include the discovery of the insertional polymerization mechanism of actin filament assembly, the first direct measurement of long-range force-distance profile between a single bacterium and a surface using optical tweezers, determination of the molecular mechanisms of microtubule-mediated centrosome centering, and unraveling the forces and mechanics of nucleus shaping in response to cell spreading and migration.
Jonathan D. Licht, M.D.
Jonathan D. Licht, MD, is the Director of the University of Florida Health Cancer Center, holding the Marshall E. Rinker, Sr. Foundation and David B. and Leighan R. Rinker Chair. Dr. Licht’s laboratory studies aberrant gene regulation, specifically the role of abnormal function of histone methyl transferases and histone demethylases in diseases such as multiple myeloma and is developing small molecule strategies to normalize gene regulation and treat disease. NCI funded for nearly 30 years, Dr. Licht is also Principal Investigator of a Leukemia and Lymphoma Society Specialized Center and a Multiple Myeloma Research Foundation program grant both in epigenetics. He is an investigator in the Dana-Farber SPORE in myeloma and co-leader in a NCI-funded Chicago Region Physical Sciences Oncology Center. For 10 years Dr. Licht served as Senior Editor of Clinical Cancer Research and is currently an Associate Editor of Oncogene and serves on the editorial boards of Cancer Cell, Cancer Research and Clinical Cancer Research. Dr. Licht is a past councilor of the American Society of Hematology, and co-led the 2017 ASH/EHA Translational Research Training program. He currently serves as chair of the Taskforce for Hematological Malignancies of the American Association for Cancer Research, serves on the Medical/Scientific Board of the Leukemia and Lymphoma Society and is chair of the NIH Mechanisms of Cancer Therpeutics-1 Study Section. Dr. Licht has published nearly 190 original articles, reviews and book chapters. Dr. Licht has mentored over 40 graduate students and postdoctoral fellows and 20 faculty members.
Jeffrey A. Nickerson, Ph.D.
Dr. Nickerson earned a PhD in Biochemistry at Michigan State University. His postgraduate work in molecular, cell and cancer biology was at MIT where he was a Cancer Research Institute Postdoctoral Scholar, a Postdoctoral Associate, and a Research Scientist. He was co-founder of the MIT spinoff Matritech, a cancer diagnostics company that developed multiple FDA approved tests for bladder cancer. He established his own laboratory in the Department of Cell Biology of the University of Massachusetts Medical School and then in the Division of Genes & Development of the Department of Pediatrics. He is also a member of the cancer center and the director of the Cell Biology Confocal Microscopy Core. He has taken an integrated approach to the study of nuclear and chromatin architecture, combining techniques from biochemistry, molecular biology, and cell biology as well as developing new methods for electron microscopy and for live cell screening of nuclear complex formation. His recent work on cancer has focused on the alterations in nuclear structure, chromatin architecture, and SWI/SNF chromatin remodeling that contribute to breast cancer progression. This project has identified novel targets for the epigenetic therapy of breast cancer.
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