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Pharmacology and Molecular Sciences, Medicine (Pulmonary Division), Oncology, Chemical and Biomolecular Engineering
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Cytokinesis and Cell Shape Control
Multi-cellular living organisms grow from single cells into multicellular, complex systems composed of highly diverse cell-types organized into tissues, which in turn form organs and organ systems. To organize and maintain this complex architecture, the organism must undergo constant renewal through cell proliferation and elimination of unwanted cells. This process of tissue development and homeostasis requires chemical and mechanical information to be sensed by the cells within the tissues, and in turn, interpreted to guide their decision making: to divide, migrate, constrict, or die. Failure in these processes lead to diverse diseases, such as hypertension, degeneration, and cancer. We initially studied cytokinesis (cell division) as a model cell behavior that incorporates internally generated signals with external mechanical cues to drive healthy cell shape change. We have discerned the mechanics that drive this process, and identified how the cell senses external forces (mechanosensing) and transmits them to changes in the chemical signaling pathways that guide cytokinesis. While we continue to study how these processes direct cytokinesis, we are also learning how these same principles apply to diseases such as cancer and lung disease. For example, we have identified a mechanoresponsive program associated with pancreatic cancer progression. Furthermore, we have developed a strategy for modulating this mechanoresponsive system with small molecules and found that this approach has utility in reducing metastasis of pancreatic and colorectal cancers. In a totally different context, namely lung airway epithelia, we have discovered that many of the same mechanical principles apply to healthy airway function, but these physical properties are disrupted by toxins such as cigarette smoke, leading to chronic obstructive pulmonary disease (COPD). Using our platforms, we have already identified genetic protectors of the airway epithelia from cigarette smoke and are now looking for small molecules that can do the same. In short, our approach allows us to go from discovery of fundamental principles of cell shape control in model systems to implications for human disease, allowing us to leverage model systems spanning a billion years of evolution.
Luo T, Mohan K, Iglesias PA, Robinson DN. Molecular mechanisms of cellular mechanosensing. Nat. Mater. 2013; 12: 1064-1071.
Surcel A, Ng W-P, West-Foyle H, Zhu Q, Ren Y, Avery L, Krenc AK, Meyers D, Rock RS, Anders RA, Freel Meyers C, Robinson DN. Pharmacological activation of myosin II paralogs to correct cell mechanics defects. Proc. Natl. Acad. Sci. USA 2015; 112(5): 1428-1433.
Schiffhauer ES, Luo T, Mohan K, Srivastava V, Qian X, Griffis E, Iglesias PA, Robinson DN. Mechanoaccumulative elements of the mammalian actin cytoskeleton. Curr. Biol. 2016; 26: 1473-1479.
Nishida K, Brune KA, Putcha N, Mandke P, O’Neal WK, Shade D, Srivastava V, Wang M, An SS, Drummond MB, Hansel NN, Robinson DN, Sidhaye V. Cigarette smoke disrupts monolayer integrity by altering epithelial cell-cell adhesion and cortical tension. Am. J. Physiol. – Lung Cell Mol. Physiol. 2017; 313(3): L581-L591.
West-Foyle H, Kothari P, Osborne J, Robinson DN. 14-3-3 proteins tune non-muscle myosin-II assembly. J. Biol. Chem. 2018; 293(18), 6751-6761.
Kothari P, Srivastava V, Aggarwal V, Tchernyshyov I, Van Eyk J, Ha T, and Robinson DN. Contractility kits promote assembly of the mechanoresponsive cytoskeletal network. J. Cell Sci. 2019; 132(2): 1-12. (First author BCMB student Priyanka Kothari was featured in a “First Person – Priyanka Kothari” interview, J. Cell Sci 2019 132: jcs229195)
Schiffhauer ES, Ren Y, Iglesias V, Kothari P, Iglesias PA, Robinson DN. Myosin IIB assembly-state determines myosin IIB mechanosensitive dynamics. J. Cell Biol. 2019; 218(3): 895-908.
Kothari P, Johnson C, Sandone C, Iglesias PA, Robinson DN. How the mechanobiome drives cell behavior, viewed through the lens of control theory. J. Cell Sci. 2019; 132:1-10. jcs234476.
Surcel A, Schiffhauer ES, Thomas DG, Zhu Q, DiNapoli K, Herbig M, Otto O, West-Foyle H, Jacobi A, Kräter M, Plak K, Guck J, Jaffee EM, Iglesias PA, Anders RA, Robinson DN. Targeting mechanoresponsive proteins in pancreatic cancer: 4-hydroxyacetophenone blocks dissemination and invasion by activating MYH14. Cancer Res. 2019; 79: 4665-4678.