Mechanosensing –from Scaling and Nuclear Rupture in Aging to a Macrophage Checkpoint for Biomaterials & Cancer

Scaling concepts have been successfully applied for decades in physics, including polymer physics, but applications to
biology seem under-developed 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
relations to polymers and effects on cells are just now being uncovered. Having shown that matrix stiffness helps
specify tissue lineages in vitro [1], we quantified protein levels in embryonic, mature, and cancerous tissues and also
studied 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 synthetic
gels is maximal when the stiffness is that of normal tissue, consistent with a ‘use it or lose it’ mechanism of tension-
inhibited degradation. Cytoskeletal 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.
Lamin-A assembly has evolved to tune nuclear stiffness and strength, and it varies widely between tissues and diseases
including cancer. Differentiation is generally modulated by lamin-A levels downstream of matrix stiffness [2], with
various pathways co-regulated by lamin-A. Recent studies relate to DNA damage and repair with stem cells and cancer
cells [4] and to a macrophage checkpoint [5].

1. A. Engler, S. … D.E. Discher. Matrix elasticity directs stem cell lineage specification. Cell 126: 677-689 (2006).
2. J. Swift, I.L. Ivanovska, … 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, … D.E. Discher. Heart-specific stiffening in early embryos parallels matrix and myosin levels to optimize beating. Current
Biology 23: 2434-2439 (2013).
4. Y Xia, … DE Discher. Nuclear rupture at sites of high curvature compromises retention of DNA repair factors Journal of Cell Biology 217:
3796-3808 (2018).
5. C.M. Alvey, … D.E. Discher. SIRPA-inhibited, marrow-derived macrophages engorge, accumulate, and differentiate in antibody-targeted
regression of solid tumors. Current Biology 27: 2065-2077 (2017).

BIO
Dennis Discher is the Robert D. Bent Professor at the University of Pennsylvania and Director of a National Cancer Institute-funded
Physical Sciences Oncology Center at Penn, where he has been since 1996. His lab discovered matrix elasticity effects on stem cell
differentiation and generally takes a soft matter physics and polymers approach to cell & molecular mechano-biology questions.
Recent efforts focus most intensely on mechanobiological determinants of DNA damage and genome variation, as well as
macrophage engineering to infiltrate and attack tumors. He is a member of the US National Academy of Medicine, the US National
Academy of Engineering, and the American Association for the Advancement of Science. His PhD from UC Berkeley & UC San
Francisco in membrane biophysics and splicing biochemistry was followed by a Postdoctoral Fellowship in computational biophysics
at University of British Columbia & Simon Fraser University, and his appointments at Penn are in Engineering & Applied Science as
well as the Graduate Groups in Physics and Pharmacology. Additional honors and service include the Friedrich Wilhelm Bessel
Award from the Humboldt Foundation of Germany, various NIH and National Academy committees, and member of the Editorial
Board of Science.