Interplay between mechanotransduction and force generation underlies cancer cell division in three dimensionally confining viscoelastic microenvironments
Abstract/Contents
- Abstract
- In physiological tissues, such as growing tumor spheroids, cells are surrounded by adjacent cells and viscoelastic extracellular matrices (ECMs). This confining microenvironment can mechanically constrain the growth of cells and the morphological changes required for mitosis. However, little is known about how the viscoelastic properties of ECM influence cell cycle progression, and how cells overcome the mechanical constraints to undergo mitosis. Here we probed the viscoelasticity of ECM and its impact on cancer cell division. First, we investigated the viscoelastic and viscoplastic properties of collagen gels, a primary component in ECM. Gels of collagen were found to exhibit remarkable viscoelastic properties; at greater deformations, they become stiffer but then flow more rapidly to relax this increase in stiffness, a behavior named strain-enhanced stress relaxion. We found that this behavior arises from force-dependent unbinding of weak bonds between collagen fibers. Collagen gels also exhibit mechanical plasticity, a property that leads to permanent deformation in response to a mechanical stress. The plastic properties of collagen gels allow cells to mechanical remodel the collagen. Next, we examined cell division in confining viscoelastic hydrogels. In confining hydrogels, cells are able to sense when growth is sufficient for division to proceed via a growth responsive TRPV4-PI3K/Akt-p27Kip1 signaling axis. When cells do progress to mitosis in the confining hydrogels, they are able to generate substantial protrusive forces that deform the microenvironment along the mitotic axis, clearing space for mitotic elongation to proceed. These forces result from interpolar spindle elongation and lateral contraction of the actomyosin ring, which drives expansion along the mitotic axis through volume conservation. Finally, we developed a new materials approach to tuning viscoelasticity of alginate-PEG hydrogels. Together, these findings shed light on the mechanical interactions between cells and their confining viscoelastic microenvironments during cell division.
Description
| Type of resource | text |
|---|---|
| Form | electronic resource; remote; computer; online resource |
| Extent | 1 online resource. |
| Place | California |
| Place | [Stanford, California] |
| Publisher | [Stanford University] |
| Copyright date | 2019; ©2019 |
| Publication date | 2019; 2019 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Nam, Sungmin |
|---|---|
| Degree supervisor | Chaudhuri, Ovijit |
| Thesis advisor | Chaudhuri, Ovijit |
| Thesis advisor | Huang, Kerwyn Casey, 1979- |
| Thesis advisor | Levenston, Marc Elliot |
| Degree committee member | Huang, Kerwyn Casey, 1979- |
| Degree committee member | Levenston, Marc Elliot |
| Associated with | Stanford University, Department of Mechanical Engineering. |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Sungmin Nam. |
|---|---|
| Note | Submitted to the Department of Mechanical Engineering. |
| Thesis | Thesis Ph.D. Stanford University 2019. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2019 by Sungmin Nam
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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