title: Macrophages Enhance Migration in Inflammatory Breast Cancer Cells via RhoC GTPase Signaling.
abstract: Inflammatory breast cancer (IBC) is the most lethal form of breast cancer. All IBC patients have lymph node involvement and one-third of patients already have distant metastasis at diagnosis. This propensity for metastasis is a hallmark of IBC distinguishing it from less lethal non-inflammatory breast cancers (nIBC). Genetic profiling studies have been conducted to differentiate IBC from nIBC, but no IBC cancer-cell-specific gene signature has been identified. We hypothesized that a tumor-extrinsic factor, notably tumor-associated macrophages, promotes and contributes to IBC's extreme metastatic phenotype. To this end, we studied the effect of macrophage-conditioned media (MCM) on IBC. We show that two IBC cell lines are hyper-responsive to MCM as compared to normal-like breast and aggressive nIBC cell lines. We further interrogated IBC's hyper-responsiveness to MCM using a microfluidic migration device, which permits individual cell migration path tracing. We found the MCM "primes" the IBC cells' cellular machinery to become extremely migratory in response to a chemoattractant. We determined that interleukins -6, -8, and -10 within the MCM are sufficient to stimulate this enhanced IBC migration effect, and that the known metastatic oncogene, RhoC GTPase, is necessary for the enhanced migration response.
authors.affiliation: Program in Cellular and Molecular Biology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA.|Medical Scientist Training Program, University of Michigan Medical School, Ann Arbor, MI, 48109, USA.|Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48109, USA.
authors.forename: Steven G
authors.initials: SG
authors.lastname: Allen
authors.affiliation: Department of Electrical Engineering and Computer Science, University of Michigan, Ann Arbor, MI 48109, USA.|University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, 48109, USA.
authors.forename: Yu-Chih
authors.initials: YC
authors.lastname: Chen
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48109, USA.|Office for Health Equity and Inclusion, University of Michigan, Ann Arbor, MI, 48109, USA.
authors.forename: Julie M
authors.initials: JM
authors.lastname: Madden
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48109, USA.
authors.forename: Chelsea L
authors.initials: CL
authors.lastname: Fournier
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48109, USA.|Program in Cancer Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Megan A
authors.initials: MA
authors.lastname: Altemus
authors.affiliation: Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Ayse B
authors.initials: AB
authors.lastname: Hiziroglu
authors.affiliation: Department of Electrical Engineering and Computer Science, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Yu-Heng
authors.initials: YH
authors.lastname: Cheng
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48109, USA.
authors.forename: Zhi Fen
authors.initials: ZF
authors.lastname: Wu
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48109, USA.
authors.forename: Liwei
authors.initials: L
authors.lastname: Bao
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48109, USA.
authors.forename: Joel A
authors.initials: JA
authors.lastname: Yates
authors.affiliation: Department of Electrical Engineering and Computer Science, University of Michigan, Ann Arbor, MI 48109, USA.|Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Euisik
authors.initials: E
authors.lastname: Yoon
authors.affiliation: Program in Cellular and Molecular Biology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA.|Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48109, USA.|University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, 48109, USA.|Program in Cancer Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Sofia D
authors.initials: SD
authors.lastname: Merajver
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002630:Chemotactic Factors / Q000494:pharmacology; D064112:Clustered Regularly Interspaced Short Palindromic Repeats / Q000235:genetics; D017077:Culture Media, Conditioned / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D006801:Humans; D058922:Inflammatory Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D016753:Interleukin-10 / Q000032:analysis / Q000378:metabolism / Q000494:pharmacology; D015850:Interleukin-6 / Q000032:analysis / Q000378:metabolism / Q000494:pharmacology; D016209:Interleukin-8 / Q000032:analysis / Q000378:metabolism / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D044085:Microfluidics; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D000075024:rhoC GTP-Binding Protein / Q000378:metabolism*
chemical_list: D002630:Chemotactic Factors; D017077:Culture Media, Conditioned; D015850:Interleukin-6; D016209:Interleukin-8; D016753:Interleukin-10; D020928:Mitogen-Activated Protein Kinases; C066690:RHOC protein, human; D000075024:rhoC GTP-Binding Protein