Extracellular matrix mechanical plasticity regulates cancer cell migration through confining microenvironments
Abstract/Contents
- Abstract
- Breast cancer cells must invade and migrate through nanoporous basement membranes (BM) and dense stromal tissue to metastasize during ductal carcinoma progression. Studies of cancer cell migration have shown that there are two modes: one that is protease-dependent, involving cells degrading matrix with invadopodia, and one that is protease-independent, requiring micron-sized pores or pre-existing channels for cells to squeeze through. Invasion of the BM is thought to require protease degradation, due to its confining, nanometer-sized pores. However, many studies investigating how pore size limits invasion have utilized rigid or elastic pores. By contrast, many extracellular matrices (ECM) exhibit viscoelasticity and mechanical plasticity, irreversibly deforming in response to force, so that pore size may be malleable. Here, we examined the impact of matrix mechanical plasticity on cancer invasion in confining microenvironments. We developed nanoporous and BM ligand-presenting, interpenetrating network (IPN) hydrogels for 3D culture in which plasticity could be modulated independent of stiffness and ligand concentration. Strikingly, cells in high plasticity IPNs exhibited spread morphologies and carried out protease-independent migration, while cells in low plasticity IPNs stayed rounded and did not migrate. Mechanistically, cells in high plasticity IPNs cyclically extended invadopodia, which were identified by their Tks5 dependence as well as their Tks5-actin and cortactin-actin colocalization. Cells used invadopodia, which were several microns wide and on the order of 20 microns long, to exert contractile and protrusive forces on the matrix and mechanically open up lasting channels within the matrix. These reveal a function of invadopodia in generating force, independent of their function in matrix degradation. Cells migrated only after channels were about 2-3 microns wide, which is the width required for the nucleus to deform through an opening during migration. Rac1 and Arp 2/3 mediated cellular protrusivity, while Rho-mediated actomyosin contractility was additionally required for cells to squeeze through the openings they formed. Finally, cells generated protrusive forces at the leading edge during migration. These findings uncover a new mode of protease-independent migration in which cells can migrate through confining matrix if it exhibits sufficient mechanical plasticity. Human breast cancer tissue, and the biological ECMs reconstituted basement membrane matrix and collagen-1, were all found to exhibit substantial mechanical plasticity, indicating the physiological relevance of this migration mode. Broadly, these results establish plasticity, a mechanical property distinct from stiffness, as an important regulator of cancer cell invasion and metastasis.
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 | 2018; ©2018 |
| Publication date | 2018; 2018 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Wisdom, Katrina M |
|---|---|
| Degree supervisor | Chaudhuri, Ovijit |
| Thesis advisor | Chaudhuri, Ovijit |
| Thesis advisor | Heilshorn, Sarah |
| Thesis advisor | Levenston, Marc Elliot |
| Degree committee member | Heilshorn, Sarah |
| Degree committee member | Levenston, Marc Elliot |
| Associated with | Stanford University, Department of Mechanical Engineering. |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Katrina M. Wisdom. |
|---|---|
| Note | Submitted to the Department of Mechanical Engineering. |
| Thesis | Thesis Ph.D. Stanford University 2018. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2018 by Katrina Michelle Wisdom
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
Also listed in
Loading usage metrics...