What is mechanobiology?
Our research is in the area of Mechanobiology. Mechanobiology is the scientific study of the mechanisms by which cell generated mechanical forces and/or the cellular mechanical environment impact cell and tissue structure and function. We are particularly interested in the mechanobiology of human diseases including cancer.
Cell and tissue structure
Cancer diagnosis is commonly based on alterations to cell- and tissue-structure. We are trying to unravel how structural alterations emerge through coupled molecular and mechanical changes to cells and tissues. The ultimate goal is to develop new therapies to combat cancer. Our recent work has focused on alterations to nuclear proteins and nuclear morphology in human cancers, and to tissue structure in glandular cancers.
Tamashunas, A.C., Tocco,V.J., Matthews, J., Zhang, Q., Atanasova, K.R., Paschall, L., Pathak, S., Ratnayake, R., Stephens, A.D., Luesch, H., Licht, J.D., Lele, T.P., 2020, High-throughput gene screen reveals modulators of nuclear shape, Molecular Biology of the Cell. Jun 15;31(13):1392-1402.
Zhang, Q., Narayanan, V., Mui, K.L., O’Bryan, C.S., Anderson, R.H., Birendra, K.C., Davis, J.I., Denis, K.B., Antoku, S., Roux, K.J., Dickinson, R.B., Angelini, T.E., Gundersen, G.G, Conway, D.E., Lele, T.P., 2019, Mechanical stabilization of the glandular acinus by linker of nucleoskeleton and cytoskeleton complex, Current Biology, 29(17):2826-2839.
Fluctuations and collapse of a glandular acinus.
Cell migration through confining 3D environments
Cells migrate through interstitial fibrous spaces of solid tissue during key physiological processes like wound healing and cancer cell invasion. To migrate, the cells must deform the nucleus to fit through interstitial spaces that are typically smaller than the nuclear size. We are currently studying how the cell mechanically deforms the nucleus, and how this deformation causes nuclear rupture, DNA damage and changes in gene expression.
Lele, T.P., Dickinson, R.B., and Gundersen, G.G., 2018, Mechanical principles of nuclear shaping and positioning, Journal of Cell Biology, 217(10):3330-3342.
Halfmann, C., Sears, R., Katiyar, A., Busselman, B., Aman, L., Zhang, Q., O’Bryan, C., Angelini, T.E., Lele, T.P., Roux, K., 2019, Repair of nuclear ruptures requires barrier-to-autointegration factor, Journal of Cell Biology, 218(7):2136-2149.
Tocco, V.J., Li, Y., Christopher, K.G., Matthews, J.H., Aggarwal, V., Paschall, L, Luesch, H., Licht, J.D., Dickinson, R.B., and Lele, T.P. 2017, The nucleus is irreversibly shaped by motion of cell boundaries in cancer and non-cancer cells, Journal of Cellular Physiology. 233(2):1446-1454.
NIH 3T3 fibroblasts stably expressing GFP-BAF (green) and mCherry-NLS (red) migrating through confinement channels. Scale bar is 10 microns.
Cell adaptation to the mechanical micro-environment
A hallmark of cancer is alterations to the mechanical properties of the tumor and its microenvironmentin vivo. Mechanical alterations include changes to the mechanical stiffness of the microenvironment, and elevated mechanical stresses on tumor cells. We are interested in how cells adapt to changes in the mechanical properties of the microenvironment. For example, we have recently discovered that the stiffness of the microenvironment can exert natural selection on genetically variable starting cell populations.
Purkayastha, P., Pendyala, K., Saxena, A.S., Hakimjavadi, H., Chamala, S., Dixit, P., Baer, C.F., Lele, T.P., Reverse plasticity underlies rapid evolution by clonal selection within populations of fibroblasts propagated on a novel soft substrate, 2021, Molecular Biology and Evolution.Jul 29;38(8):3279-3293.
Purkayastha, P., Jaiswal, M., Lele, T.P., Molecular cancer cell responses to solid compressive stress and interstitial fluid pressure, 2021, Cytoskeleton.
Lele, T.P., Brock, A., Peyton, S., 2019, Emerging concepts and tools in cell mechanomemory, Annals of Biomedical Engineering48(7):2103-2112