Date of Award

2020

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Physics & Astronomy

First Advisor

Dennis E. Discher

Abstract

Analysis of published cancer genome sequencing data reveals that cancers arising in stiff tissues, such as lung and skin, exhibit more than 30-fold higher mutation rates than those arising in soft tissues, like marrow and brain. This scaling relationship suggests a possible mechanical source of cancerous mutations. We hypothesize that when cancer cells squeeze through small holes in stiff fibrous tissues during tumorigenic invasion, they sustain nuclear stress, leading to DNA damage and ultimately genomic variation. Consistent with this hypothesis, we show that migration of diverse cancer cell lines through constricting pores causes excess DNA damage as well as a transient delay in cell cycle progression. We present evidence that the observed increase in DNA damage could be due to partial depletion of DNA repair proteins throughout the nucleus, which physically inhibits repair of routine DNA breaks. In particular, we describe two ways in which constricted migration mis-localizes, and thus partially depletes, mobile nuclear factors including DNA repair proteins: (1) curvature-driven nuclear rupture, causing leakage of mobile factors from the nucleus into the cytoplasm; and (2) phase separation of mobile nuclear factors from chromatin inside the constriction. Altogether, this thesis presents biophysical studies that aim to shed light on an intriguing scaling relationship from cancer genomics.

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