title: Epithelial-mesenchymal transition can suppress major attributes of                     human epithelial tumor-initiating cells.
abstract: Malignant progression in cancer requires populations of tumor-initiating cells                     (TICs) endowed with unlimited self renewal, survival under stress, and                     establishment of distant metastases. Additionally, the acquisition of invasive                     properties driven by epithelial-mesenchymal transition (EMT) is critical for the                     evolution of neoplastic cells into fully metastatic populations. Here, we                     characterize 2 human cellular models derived from prostate and bladder cancer                     cell lines to better understand the relationship between TIC and EMT programs in                     local invasiveness and distant metastasis. The model tumor subpopulations that                     expressed a strong epithelial gene program were enriched in highly metastatic                     TICs, while a second subpopulation with stable mesenchymal traits was                     impoverished in TICs. Constitutive overexpression of the transcription factor                     Snai1 in the epithelial/TIC-enriched populations engaged a mesenchymal gene                     program and suppressed their self renewal and metastatic phenotypes. Conversely,                     knockdown of EMT factors in the mesenchymal-like prostate cancer cell                     subpopulation caused a gain in epithelial features and properties of TICs. Both                     tumor cell subpopulations cooperated so that the nonmetastatic mesenchymal-like                     prostate cancer subpopulation enhanced the in vitro invasiveness of the                     metastatic epithelial subpopulation and, in vivo, promoted the escape of the                     latter from primary implantation sites and accelerated their metastatic                     colonization. Our models provide new insights into how dynamic interactions                     among epithelial, self-renewal, and mesenchymal gene programs determine the                     plasticity of epithelial TICs.
authors.affiliation: Department of Cell Biology, Barcelona Institute of Molecular Biology, Consejo Superior de Investigaciones Científicas (CSIC), Barcelona, Spain.
authors.forename: Toni
authors.initials: T
authors.lastname: Celià-Terrassa
authors.forename: Oscar
authors.initials: O
authors.lastname: Meca-Cortés
authors.forename: Francesca
authors.initials: F
authors.lastname: Mateo
authors.forename: Alexia
authors.initials: A
authors.lastname: Martínez de Paz
authors.forename: Nuria
authors.initials: N
authors.lastname: Rubio
authors.forename: Anna
authors.initials: A
authors.lastname: Arnal-Estapé
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Ell
authors.forename: Raquel
authors.initials: R
authors.lastname: Bermudo
authors.forename: Alba
authors.initials: A
authors.lastname: Díaz
authors.forename: Marta
authors.initials: M
authors.lastname: Guerra-Rebollo
authors.forename: Juan José
authors.initials: JJ
authors.lastname: Lozano
authors.forename: Conchi
authors.initials: C
authors.lastname: Estarás
authors.forename: Catalina
authors.initials: C
authors.lastname: Ulloa
authors.forename: Daniel
authors.initials: D
authors.lastname: Álvarez-Simón
authors.forename: Jordi
authors.initials: J
authors.lastname: Milà
authors.forename: Ramón
authors.initials: R
authors.lastname: Vilella
authors.forename: Rosanna
authors.initials: R
authors.lastname: Paciucci
authors.forename: Marian
authors.initials: M
authors.lastname: Martínez-Balbás
authors.forename: Antonio García
authors.initials: AG
authors.lastname: de Herreros
authors.forename: Roger R
authors.initials: RR
authors.lastname: Gomis
authors.forename: Yibin
authors.initials: Y
authors.lastname: Kang
authors.forename: Jerónimo
authors.initials: J
authors.lastname: Blanco
authors.forename: Pedro L
authors.initials: PL
authors.lastname: Fernández
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Thomson
mesh_terms: D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics / Q000378:metabolism; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D048430:Cell Shape; D018920:Coculture Techniques; D004847:Epithelial Cells / Q000473:pathology* / Q000502:physiology; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009361:Neoplasm Invasiveness / Q000473:pathology*; D009362:Neoplasm Metastasis / Q000473:pathology*; D009367:Neoplasm Staging; D009368:Neoplasm Transplantation; D011471:Prostatic Neoplasms; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D000071250:Snail Family Transcription Factors; D018874:Spheroids, Cellular / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D051879:Twist-Related Protein 1 / Q000235:genetics / Q000378:metabolism; D001749:Urinary Bladder Neoplasms; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: D000943:Antigens, Differentiation; D015820:Cadherins; D018398:Homeodomain Proteins; D012097:Repressor Proteins; C000604407:SNAI1 protein, human; C000604429:Snai1 protein, mouse; D000071250:Snail Family Transcription Factors; C486274:TWIST2 protein, human; D014157:Transcription Factors; D051879:Twist-Related Protein 1; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1