title: Time-dependent transcriptional profiling links gene expression to mitogen-activated protein kinase kinase 4 (MKK4)-mediated suppression of omental metastatic colonization.
abstract: Although metastasis is the most lethal attribute of cancer, critical gaps in our knowledge of how cancer cells effectively colonize distant sites remain. For example, little is known about the cellular and molecular events that occur during the timecourse of metastatic colonization. To address this we are using the mitogen-activated protein kinase kinase 4 (MKK4) metastasis suppressor as a tool to identify these events. Specifically, we report a microarray expression-based strategy to identify genes whose transcription is altered in SKOV3ip.1 human ovarian cancer cells that express ectopic MKK4 throughout the course of in vivo metastatic colonization. The majority of genes identified fell into the categories of cytokinesis, cytoskeleton remodeling, and cell adhesion, and their expression was repressed in MKK4-expressing cells relative to vector controls. The greatest transcriptional divergence was concomitant with impaired proliferation at 14 days post injection (dpi). Specifically, 763 genes were differentially expressed (FDR < 0.05) between lesions that expressed ectopic MKK4 and paired controls. In contrast, only seven genes were differentially expressed at the experimental endpoint, when MKK4-expressing and control cells had formed macroscopic metastases. Application of our cohort of differentially expressed genes to three independent clinical datasets demonstrated a strong correlation between our findings and metastatic phenotypes in patient samples. Our results highlight the dynamic nature of metastatic colonization and reinforce the importance of examining both molecular and cellular phenotypes over time when studying metastasis formation.
authors.affiliation: Department of Human Genetics, The University of Chicago, Chicago, IL, USA.
authors.forename: Russell O
authors.initials: RO
authors.lastname: Bainer
authors.affiliation: The Committee on Cancer Biology, The University of Chicago, Chicago, IL, USA.
authors.forename: Jennifer Taylor
authors.initials: JT
authors.lastname: Veneris
authors.affiliation: Department of Obstetrics and Gynecology, The University of Chicago, Chicago, IL, USA.
authors.forename: S Diane
authors.initials: SD
authors.lastname: Yamada
authors.affiliation: Department of Pathology, The University of Chicago, Chicago, IL, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Montag
authors.affiliation: Department of Pathology, The University of Chicago, Chicago, IL, USA.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Lingen
authors.affiliation: Department of Human Genetics, The University of Chicago, Chicago, IL, USA.
authors.forename: Yoav
authors.initials: Y
authors.lastname: Gilad
authors.affiliation: The Committee on Cancer Biology, The University of Chicago, Chicago, IL, USA.
authors.forename: Carrie W
authors.initials: CW
authors.lastname: Rinker-Schaeffer
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007124:Immunoenzyme Techniques; D048670:MAP Kinase Kinase 4 / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D009852:Omentum / Q000378:metabolism / Q000473:pathology*; D010051:Ovarian Neoplasms / Q000201:enzymology* / Q000235:genetics* / Q000556:secondary; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay
chemical_list: D014408:Biomarkers, Tumor; D012333:RNA, Messenger; D048670:MAP Kinase Kinase 4; C482559:MAP2K4 protein, human