title: An epigenetically distinct breast cancer cell subpopulation promotes collective invasion.
abstract: Tumor cells can engage in a process called collective invasion, in which cohesive groups of cells invade through interstitial tissue. Here, we identified an epigenetically distinct subpopulation of breast tumor cells that have an enhanced capacity to collectively invade. Analysis of spheroid invasion in an organotypic culture system revealed that these "trailblazer" cells are capable of initiating collective invasion and promote non-trailblazer cell invasion, indicating a commensal relationship among subpopulations within heterogenous tumors. Canonical mesenchymal markers were not sufficient to distinguish trailblazer cells from non-trailblazer cells, suggesting that defining the molecular underpinnings of the trailblazer phenotype could reveal collective invasion-specific mechanisms. Functional analysis determined that DOCK10, ITGA11, DAB2, PDFGRA, VASN, PPAP2B, and LPAR1 are highly expressed in trailblazer cells and required to initiate collective invasion, with DOCK10 essential for metastasis. In patients with triple-negative breast cancer, expression of these 7 genes correlated with poor outcome. Together, our results indicate that spontaneous conversion of the epigenetic state in a subpopulation of cells can promote a transition from in situ to invasive growth through induction of a cooperative form of collective invasion and suggest that therapeutic inhibition of trailblazer cell invasion may help prevent metastasis.
authors.forename: Jill M
authors.initials: JM
authors.lastname: Westcott
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Prechtl
authors.forename: Erin A
authors.initials: EA
authors.lastname: Maine
authors.forename: Tuyen T
authors.initials: TT
authors.lastname: Dang
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Esparza
authors.forename: Han
authors.initials: H
authors.lastname: Sun
authors.forename: Yunyun
authors.initials: Y
authors.lastname: Zhou
authors.forename: Yang
authors.initials: Y
authors.lastname: Xie
authors.forename: Gray W
authors.initials: GW
authors.lastname: Pearson
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000401:mortality / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D022081:Cell Surface Extensions / Q000502:physiology / Q000648:ultrastructure; D044127:Epigenesis, Genetic / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition; D005109:Extracellular Matrix; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D052138:Genes, Neoplasm; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009361:Neoplasm Invasiveness / Q000235:genetics* / Q000473:pathology; D009362:Neoplasm Metastasis / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology*; D034622:RNA Interference; D013047:Specific Pathogen-Free Organisms; D018874:Spheroids, Cellular; D064726:Triple Negative Breast Neoplasms / Q000235:genetics / Q000401:mortality / Q000473:pathology
chemical_list: D009363:Neoplasm Proteins
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