PhD 2012, Ludwig-Maximilians University Munich
“My laboratory is interested in understanding the molecular mechanisms that underlie cancer cell proliferation and metastasis — two processes that arise from the targeted deregulation of cell division and motility. When cells divide and move, the actin cytoskeleton, a versatile and complex cellular machinery, is employed. We seek to improve our current molecular understanding of how cancer cells interfere with the proper cytoskeletal organization of formerly healthy cells' actin cytoskeletons. Specifically, we are studying how in addition to chemical signaling cues, mechanical forces may bear the fascinating capacity to tune the mechanical properties of the actin cytoskeleton, as well as essential accessory cytoskeletal components. This suggests an intriguing new layer of cellular regulation that can be critical in developing novel strategies to target cancer cell proliferation and metastasis.”
Dennis Zimmermann received his BS/MS from the Ludwig-Maximilians University in Munich (Germany). There, he continued his doctoral work under Professor Manfred Schliwa at the Institute for Cell Biology and received his PhD in 2012. Dennis completed his postdoctoral training at the University of Chicago in the laboratory of Professor David R. Kovar. During this period, he was supported by the German Research Foundation postdoctoral fellowship.
Cell motility and cell division are two cellular processes that are of particular significance as they represent the stronghold during health and disease. For instance, failure of the cell division machinery can lead to chromosome missegregation, and hence abnormal chromosome numbers representing one of the hallmarks of cancer development. Misguided cell motility of our immune cells impedes the immune system’s ability to scavenge for infections or tumor cells, allowing the progression of such diseases. For cells to divide and move, a versatile and complex cellular machinery termed the actin cytoskeleton (greek: skeleton of the cell) is employed. Cytoskeletal actin networks are constantly undergoing rapid shape changes, an essential characteristic facilitated through the close collaboration with so-called actin-binding proteins. Additionally, molecular motors (myosins) are employed to help transform cytoskeletal actin networks into cellular force-generators. Those rigid but flexible filamentous actin networks enable cells to generate, transduce, and resist mechanical force, an ability that allows migrating cells (immune cells or metastatic cancer cells) to remain intact while squeezing through tight spaces in blood vessels. To ensure proper cell function the underlying actin cytoskeleton and the factors that facilitate its dynamic organization must be tightly regulated. The notion that in addition to chemical signaling cues mechanical force may bear the capacity to tune and (mechano-) regulate key accessory components of the cytoskeleton, has only recently been recognized and suggests a fascinating new layer of regulation that requires further investigation. Zimmermann's research focuses on dissecting the molecular mechanisms through which key assembly factors (formins, Ena/VASP, Arp2/3 complex), as well as certain accessory factors of nascent cytoskeletal networks, are regulated by force. Zimmermann employs multi-color single-molecule microscopy and live cell imaging to manipulate and monitor actin network organization through force at the scale of one-millionth of a meter in real-time. Deciphering the mechanism of cytoskeletal mechano-regulation will be key in developing novel strategies to target cancer cell metastasis or immune cell migration.
1. Zimmermann, D., Abdel Motaal, B., Voith von Voithenberg, L., Schliwa, M., and Z. Ökten (2011) Diffusion of myosin V on microtubules: A Fine-tuned interaction for which E-hooks are dispensable. PLoS ONE 6(9): e25473.
2. Heym, R.G.1, Zimmermann, D.1, Edelmann, F.T., Israel, L., Ökten, Z., Kovar, D.R., and D. Niessing (2013) In vitro reconstitution of an mRNA-transport complex reveals mechanisms of assembly and motor activation. Journal of Cell Biology 203(6): 971-984. [1 contributed equally]
3. Haase S.1, Zimmermann, D.1, Olshina, M.A., Tan, Y.H., Stewart, R.J., Tonkin, C.J., Wong, W., Kovar, D.R., and J. Baum (2015) Depolymerisation and severing activities of actin depolymerisation factor (ADF) are functionally linked to distinct cellular processes in apicomplexan parasites. Molecular Biology of the Cell 26:3001-3012. [1 contributed equally]
4. Zimmermann, D.1, Santos, A.1, Kovar, D.R., and R.S. Rock (2015) Actin age orchestrates myosin-5 and myosin-6 run lengths. Current Biology 25: 2057-2062. [1 contributed equally]
5. Zimmermann, D., Morganthaler A.N., Kovar, D.R., and C. Suarez (2016) In vitro biochemical characterization of cytokinesis actin-binding proteins. Methods in Molecular Biology (Clifton, N.J.) 1369:151-179.
6. Zimmermann, D., Homa, K.E., Hocky, G.M., Pollard, L.W., De La Cruz, E.M., Voth, G.A., Trybus, K.M., and D.R. Kovar (2017) Mechanoregulated inhibition of formin facilitates contractile actomyosin ring assembly. Nature Communications.