Agent-based modeling predicts RAC1 is critical for ovarian cancer metastasis

Experimental and computational studies pinpoint rate-limiting step(s) in metastasis governed by Rac1. Using ovarian cancer cell and animal models, Rac1 expression was manipulated, and quantitative measurements of cell-cell and cell-substrate adhesion, cell invasion, mesothelial clearance, and perito...

Full description

Saved in:
Bibliographic Details
Published in:Molecular biology of the cell 2022-12, Vol.33 (14), p.ar138-ar138
Main Authors: Rivera, Melanie, Toledo-Jacobo, Leslie, Romero, Elsa, Oprea, Tudor I, Moses, Melanie E, Hudson, Laurie G, Wandinger-Ness, Angela, Grimes, Martha M
Format: Article
Language:English
Subjects:
Animals
Cell Adhesion
Cell Line, Tumor
Cell Movement
Female
Humans
Lung - metabolism
Neoplasm Metastasis - pathology
Ovarian Neoplasms - metabolism
Ovarian Neoplasms - pathology
rac1 GTP-Binding Protein - metabolism
Systems Analysis
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Experimental and computational studies pinpoint rate-limiting step(s) in metastasis governed by Rac1. Using ovarian cancer cell and animal models, Rac1 expression was manipulated, and quantitative measurements of cell-cell and cell-substrate adhesion, cell invasion, mesothelial clearance, and peritoneal tumor growth discriminated the tumor behaviors most highly influenced by Rac1. The experimental data were used to parameterize an agent-based computational model simulating peritoneal niche colonization, intravasation, and hematogenous metastasis to distant organs. Increased ovarian cancer cell survival afforded by the more rapid adhesion and intravasation upon Rac1 overexpression is predicted to increase the numbers of and the rates at which tumor cells are disseminated to distant sites. Surprisingly, crowding of cancer cells along the blood vessel was found to decrease the numbers of cells reaching a distant niche irrespective of Rac1 overexpression or knockdown, suggesting that sites for tumor cell intravasation are rate limiting and become accessible if cells intravasate rapidly or are displaced due to diminished viability. Modeling predictions were confirmed through animal studies of Rac1-dependent metastasis to the lung. Collectively, the experimental and modeling approaches identify cell adhesion, rapid intravasation, and survival in the blood as parameters in the ovarian metastatic cascade that are most critically dependent on Rac1.
ISSN:1059-1524
1939-4586
DOI:10.1091/mbc.E21-11-0540