title: Cell, isoform, and environment factors shape gradients and modulate chemotaxis.
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-γ isoform are effective at driving chemotaxis. We highlight the importance of CXCL12-γ in cancer cell migration: its high effective affinity for both extracellular surface sites and CXCR4 strongly promote CXCR4+ cell migration. CXCL12-γ is also more difficult to inhibit, and we predict that co-inhibition of CXCR4 and CXCR7 is necessary to effectively hinder CXCL12-γ-induced migration. These findings support the growing importance of understanding differences in protein isoforms, and in particular their implications for cancer treatment.
authors.affiliation: Department of Chemical Engineering, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: S Laura
authors.initials: SL
authors.lastname: Chang
authors.affiliation: Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Cavnar
authors.affiliation: Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan, United States of America; Department of Macromolecular Science and Engineering, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Shuichi
authors.initials: S
authors.lastname: Takayama
authors.affiliation: Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan, United States of America; Center for Molecular Imaging, Department of Radiology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America; Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors.forename: Gary D
authors.initials: GD
authors.lastname: Luker
authors.affiliation: Department of Chemical Engineering, University of Michigan, Ann Arbor, Michigan, United States of America; Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Linderman
mesh_terms: D000465:Algorithms; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000276:immunology; D054377:Chemokine CXCL12 / Q000378:metabolism; D002633:Chemotaxis / Q000276:immunology* / Q000502:physiology; D006801:Humans; D008024:Ligands; D008954:Models, Biological; D011485:Protein Binding; D020033:Protein Isoforms; D054387:Receptors, CXCR / Q000378:metabolism; D011971:Receptors, Immunologic; D015203:Reproducibility of Results
chemical_list: C501896:ACKR3 protein, human; D054377:Chemokine CXCL12; D008024:Ligands; D020033:Protein Isoforms; D054387:Receptors, CXCR; D011971:Receptors, Immunologic