title: Microfluidic source-sink model reveals effects of biophysically distinct CXCL12 isoforms in breast cancer chemotaxis.
abstract: Chemokines critically regulate chemotaxis in normal and pathologic states, but there is limited understanding of how multicellular interactions generate gradients needed for cell migration. Previous studies of chemotaxis of CXCR4+ cells toward chemokine CXCL12 suggest the requirement of cells expressing scavenger receptor CXCR7 in a source-sink system. We leveraged an established microfluidic device to discover that chemotaxis of CXCR4 cells toward distinct isoforms of CXCL12 required CXCR7 scavenging only under conditions with higher than optimal levels of CXCL12. Chemotaxis toward CXCL12-β and -γ isoforms, which have greater binding to extracellular molecules and have been largely overlooked, was less dependent on CXCR7 than the more commonly studied CXCL12-α. Chemotaxis of CXCR4+ cells toward even low levels of CXCL12-γ and CXCL12-β still occurred during treatment with a FDA-approved inhibitor of CXCR4. We also detected CXCL12-γ only in breast cancers from patients with advanced disease. Physiological gradient formation within the device facilitated interrogation of key differences in chemotaxis among CXCL12 isoforms and suggests CXCL12-γ as a biomarker for metastatic cancer.
authors.affiliation: Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: S P
authors.initials: SP
authors.lastname: Cavnar
authors.forename: P
authors.initials: P
authors.lastname: Ray
authors.forename: P
authors.initials: P
authors.lastname: Moudgil
authors.forename: S L
authors.initials: SL
authors.lastname: Chang
authors.forename: K E
authors.initials: KE
authors.lastname: Luker
authors.forename: J J
authors.initials: JJ
authors.lastname: Linderman
authors.forename: S
authors.initials: S
authors.lastname: Takayama
authors.forename: G D
authors.initials: GD
authors.lastname: Luker
mesh_terms: D000818:Animals; D001596:Benzylamines; D001943:Breast Neoplasms / Q000276:immunology*; D045744:Cell Line, Tumor; D054377:Chemokine CXCL12 / Q000235:genetics / Q000276:immunology*; D002633:Chemotaxis / Q000276:immunology*; D000080027:Cyclams; D005260:Female; D006571:Heterocyclic Compounds / Q000494:pharmacology; D006801:Humans; D008810:Mice, Inbred C57BL; D044085:Microfluidics; D008856:Microscopy, Fluorescence; D008858:Microscopy, Phase-Contrast; D020033:Protein Isoforms / Q000235:genetics / Q000276:immunology; D012334:RNA, Neoplasm / Q000737:chemistry / Q000235:genetics; D054387:Receptors, CXCR / Q000037:antagonists & inhibitors / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D001596:Benzylamines; D054377:Chemokine CXCL12; D000080027:Cyclams; D006571:Heterocyclic Compounds; D020033:Protein Isoforms; D012334:RNA, Neoplasm; D054387:Receptors, CXCR; C088327:plerixafor