What squishing cells can tell us about human disease – studying the interplay between cellular structure, mechanics, and function.
Cells in the human body reside in a physically stressful and demanding environment, being continuously exposed to large forces and deformations. Examples include not only contracting skeletal and cardiac muscle cells, bone and cartilage, but also immune cells, stem cells, and metastatic cancer cells that move through tight tissue spaces to reach distant sites in the body. It is now well established that cells respond to such physical challenges with characteristic changes in cellular organization, signaling, and function through a process referred to as ‘mechanotransduction’. The molecular mechanisms by which cells sense their physical environment and translate mechanical stimuli into biochemical signals remains incompletely understood. Nonetheless, it has become abundantly clear that defects in cellular mechanics or mechanotransduction signaling—arising from mutations or altered gene expression—can disturb cellular function and contribute to a large number of human diseases, ranging from muscular dystrophy to heart disease and cancer.
In the Lammerding laboratory, we investigate this intricate interplay between cellular structure, mechanics and function through an interdisciplinary research approach that combines engineering principles, microfabrication, and cell and molecular biology techniques, as well as the development and application of novel experimental assays. Our team is composed of students and postdoctoral researchers with a broad range of backgrounds, including (biomedical) engineering, biology, chemistry and other life sciences, who explore creative solutions to relevant biological and clinical problems. Our research is focused on the nuclear envelope and its interface with the surrounding cytoskeleton, as mutations in nuclear envelope proteins are responsible for more than 10 human diseases, such as muscular dystrophy, dilated cardiomyopathy, and premature aging (Hutchison-Gilford progeria syndrome). Furthermore, abnormal expression of nuclear envelope proteins expression has recently been identified in numerous cancers, often correlating with negative clinical outcomes. Work conducted in the Lammerding lab has already shown that mutations or loss of nuclear envelope proteins such as lamins render cells more sensitive to mechanical stress and also impair mechanotransduction signaling, providing a potential mechanism for the progressive muscle defects in many nuclear envelopathies. Furthermore, we have demonstrated that the deformability of the nucleus, the largest and most rigid cell organelle, constitutes a rate-limiting factor in the ability of cells to migrate through tight spaces, stimulating increased interest in understanding how highly motile cells such as neutrophils and metastatic cancer cells overcome this challenge.
Please check our Research Section for more details.
Kirby TJ. Lammerding J. Emerging views of the nucleus as a cellular mechanosensor. Nat Cell Biol. 2018. 20(4): 373-381
Bakhoum SF, Ngo B, Bakhoum AL, Cavallo JA, Murphy CJ, Ly P, Shah P, Sriram RK, Watkins TBK, Taunk NK, Duran M, Pauli C, Shaw C, Chadalavada K, Rajasekhar VK, Genovese G, Venkatesan S, Birkbak NJ, McGranahan N, Lundquist M, LaPlant Q, Healey JH, Elemento O, Chung CH, Lee NY, Imielenski M, Nanjangud G, Pe’er D, Cleveland D, Powell SN, Lammerding J, Swanton C, Cantley LC. Chromosomal instability promotes metastasis through a cytosolic DNA response. Nature. 2018. 553(7689): 467-472
Denais CM, Gilbert RM, Isermann P, McGregor AL, te Lindert M, Weigelin B, Davidson PM, Friedl P, Wolf K, Lammerding J. Nuclear envelope rupture and repair during cancer cell migration. Science. 2016. 352(6283): 353-358.
Davidson PM, Sliz J, Isermann P, Denais C, Lammerding J. Design of a microfluidic device to quantify intra-nuclear deformation during cell migration through confining environments. Integr Biol (Camb). 2015. 30(7): 1534-46.
Dialynas G, Shrestha OK, Ponce JM, Zwerger M, Thiemann DA, Young GH, Moore SA, Yu L, Lammerding J and Wallrath LL. Myopathic lamin mutations cause reductive stress and activate the Nrf2/Keap-1 pathway. PLoS Genetics. 2015. 11(5): e1005231. Published online May 21, 2015.
Ho CY, Jaalouk DE, Vartiainen MK, Lammerding J. Lamin A/C and emerin regulate MKL1/SRF activity by modulating actin dynamics. Nature 2013. 497(7450):507-11.
Isermann P, Lammerding J. Nuclear Mechanics and Mechanotransduction in Health and Disease. Curr Biol 2013. 23(24): R1113-R1121.
Zwerger M, Jaalouk DE, Lombardi ML, Isermann P, Mauermann M, Dialynas G, Herrmann H, Wallrath LL, Lammerding J. Myopathic lamin mutations impair nuclear stability in cells and tissue and disrupt nucleo-cytoskeletal coupling. Hum Mol Gen 2013. 22(12):2335-49