Cell, Isoform, and Environment Factors Shape Gradients and Modulate Chemotaxis

Authored by Jennifer J Linderman, S Laura Chang, Stephen P Cavnar, Shuichi Takayama, Gary D Luker

Date Published: 2015

DOI: 10.1371/journal.pone.0123450

Sponsors: United States National Institutes of Health (NIH) United States National Science Foundation (NSF)

Platforms: No platforms listed

Model Documentation: Other Narrative Flow charts

Model Code URLs: Model code not found

Abstract

Chemokine gradient formation requires multiple processes that include ligand secretion and diffusion, receptor binding and internalization, and immobilization of ligand to surfaces. To understand how these events dynamically shape gradients and influence ensuing cell chemotaxis, we built a multi-scale hybrid agent-based model linking gradient formation, cell responses, and receptor-level information. The CXCL12/CXCR4/CXCR7 signaling axis is highly implicated in metastasis of many cancers. We model CXCL12 gradient formation as it is impacted by CXCR4 and CXCR7, with particular focus on the three most highly expressed isoforms of CXCL12. We trained and validated our model using data from an in vitro microfluidic source-sink device. Our simulations demonstrate how isoform differences on the molecular level affect gradient formation and cell responses. We determine that ligand properties specific to CXCL12 isoforms (binding to the migration surface and to CXCR4) significantly impact migration and explain differences in in vitro chemotaxis data. We extend our model to analyze CXCL12 gradient formation in a tumor environment and find that short distance, steep gradients characteristic of the CXCL12-gamma isoform are effective at driving chemotaxis. We highlight the importance of CXCL12-gamma in cancer cell migration: its high effective affinity for both extracellular surface sites and CXCR4 strongly promote CXCR4+ cell migration. CXCL12-gamma is also more difficult to inhibit, and we predict that co-inhibition of CXCR4 and CXCR7 is necessary to effectively hinder CXCL12-gamma-induced migration. These findings support the growing importance of understanding differences in protein isoforms, and in particular their implications for cancer treatment.

Tags

Model Tumor-growth Sensitivity-analysis T-cells Chemokine receptor Breast-cancer Beta-arrestin Cxcr4 Cxcl12 Dimerization