Cell and Developmental Biology Programme Dennis Discher

11/04/202315:00R_473.10_AULACell and Developmental Biology ProgrammeDennis DischerRobert D. Bent chaired Professor, and Director of NCI-Physical Sciences Oncology Center-Project.University of Pennsyvania, Philadelphia, PA"Physically driven genetic change"Host: Pérez González, GemmaAbstract:ABSTRACT
Genetic differences are increasingly evident within tissues, tumors, and even embryos, but any contributions to such processes from the physical surroundings of cells remain obscure. Epigenetic processes in differentiation as well as nuclear mechanics are clearly modulated by tissue stiffness, and extensive sequencing also makes clear that liquid tumors and tissues have fewer genetic changes than solid tumors and tissues (regardless of p53 status). The first part of this talk will describe efforts to address whether matrix rigidity and a putative tumor suppressor Myosin-IIa affect heritable DNA sequence in cells. To track colonies with rare but viable genetic changes, we developed a method for live-cell monitoring of chromosome copy number loss under diverse perturbations, including Myosin-II inhibition in confined mitosis. Squeezing of mitotic cells is seen in vivo and kills in vitro, but stem cells and cancer cells that survive show heritable loss of the new Chromosome-reporters (ChReporters), and Myosin-II suppression increases such loss in confinement but not in standard 2D cultures. Further examples of physically driven genome instability will help illustrate the principle.

References: Engler, et al. Matrix elasticity directs stem cell lineage specification. Cell (2006). Swift, et al. Nuclear Lamin-A Scales with Tissue Stiffness and Enhances Matrix-directed Differentiation. Science (2013). Cho, et al. Mechanosensing by the lamina protects against nuclear rupture, DNA damage, and cell-cycle arrest Developmental Cell (2019). Vashisth, et al. Scaling concepts in ‘omics: Nuclear lamin-B scales with tumor growth and often predicts poor prognosis, unlike fibrosis. PNAS (2021).

BIO
Discher began at Penn in 1996 after a PhD at UC Berkeley & UC San Francisco and following an NSF Fellowship in computational biophysics in British Columbia. His lab focused first on membrane biophysics and mimetics, and then discovered matrix elasticity effects on stem cell differentiation and nucleus mechanosensing. Recent efforts are focused on mechanobiology of DNA damage and genome variation, as well as ‘self’ pathways in macrophage attack of solid tumors. He is on the Editorial Board of Science, and an elected member of the US National Academy of Medicine, the US National Academy of Engineering, and the American Association for the Advancement of Science.