From Scaling Concepts in Mechanosensing to Breaking the envelope around cancer genomes
Prof. Dennis E. Discher, University of Pennsylvania
Scaling concepts have been successfully applied for many years to synthetic polymers, but application to biology seems under-studied even though cells and tissues are built from polymers. Tissues such as brain and fat are very soft while tissues such as muscle and bone are stiff or even rigid – even when probed at the nanoscale, but the effects on cells are just now being discovered. Having shown that matrix stiffness helps specify tissue lineages in vitro , we used mass spectrometry to quantify protein levels in embryonic, mature, and cancerous tissues and studied tissues as well as cells on substrates of tuned stiffness [2, 3]. Extracellular collagen polymers directly determine tissue stiffness with near-classical scaling, and for embryonic heart, contractile beating of the organ and of isolated cells on gels is maximal when the stiffness is that of the normal tissue, consistent with a ‘use it or lose it’ mechanism. Acto-myosin assembly likewise increases with stiffness and stresses the nucleus, which upregulates a nuclear structure protein called lamin-A (related to keratin in fingernails) that again scales with stiffness via ‘use it or lose it’. Lamin-A assembly has evolved to control nuclear stiffness and strength, and it varies widely between tissues and diseases including cancer. Differentiation of various stem cell types is generally modulated by lamin-A levels downstream of matrix stiffness , with various pathways co-regulated by lamin-A. Complementary insights are obtained for DNA damage and repair with stem cells and cancer cells , with evidence of invasion through rigid pores providing insight into mutation scaling in cancer .
1. A. Engler, S. Sen, H.L. Sweeney, and D.E. Discher. Matrix elasticity directs stem cell lineage specification. Cell 126: 677-689 (2006).
2. J. Swift, I.L. Ivanovska, A. Buxboim, T. Harada, P.C. D.P. Dingal, J. Pinter, J.D. Pajerowski, K. Spinler, J-W. Shin, M. Tewari, F. Rehfeldt, D.W. Speicher, and D.E. Discher. Nuclear Lamin-A Scales with Tissue Stiffness and Enhances Matrix-directed Differentiation. Science 341: 1240104-1 to 15 (2013).
3. S. Majkut, T. Idema, J. Swift, C. Krieger, A. Liu, and D.E. Discher. Heart-specific stiffening in early embryos parallels matrix and myosin levels to optimize beating. Current Biology 23: 2434-2439 (2013).
4. J. Irianto, Y. Xia, C.R. Pfeifer, A. Athirasala, J. Ji, C. Alvey, M. Tewari, R.R. Bennett, S.M. Harding, A.J. Liu, R.A. Greenberg, and D.E. Discher. DNA damage follows repair factor depletion and portends genome variation in cancer cells after pore migration. Current Biology 27, 210–223 (2017).
5. J. Irianto, C. Pfeifer, Y. Xia, D.E. Discher. Mechanosensing matrix. Cell 165: 1820 (2016).