title: Plasticity between Epithelial and Mesenchymal States Unlinks EMT from Metastasis-Enhancing Stem Cell Capacity.
abstract: Forced overexpression and/or downregulation of proteins regulating epithelial-to-mesenchymal transition (EMT) has been reported to alter metastasis by changing migration and stem cell capacity of tumor cells. However, these manipulations artificially keep cells in fixed states, while in vivo cells may adapt transient and reversible states. Here, we have tested the existence and role of epithelial-mesenchymal plasticity in metastasis of mammary tumors without artificially modifying EMT regulators. In these tumors, we found by intravital microscopy that the motile tumor cells have undergone EMT, while their epithelial counterparts were not migratory. Moreover, we found that epithelial-mesenchymal plasticity renders any EMT-induced stemness differences, as reported previously, irrelevant for metastatic outgrowth, because mesenchymal cells that arrive at secondary sites convert to the epithelial state within one or two divisions, thereby obtaining the same stem cell potential as their arrived epithelial counterparts. We conclude that epithelial-mesenchymal plasticity supports migration but additionally eliminates stemness-enhanced metastatic outgrowth differences.
authors.affiliation: Cancer Genomics Center-Hubrecht Institute-KNAW & University Medical Centre Utrecht, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands.
authors.forename: Evelyne
authors.initials: E
authors.lastname: Beerling
authors.affiliation: Cancer Genomics Center-Hubrecht Institute-KNAW & University Medical Centre Utrecht, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands.
authors.forename: Daniëlle
authors.initials: D
authors.lastname: Seinstra
authors.affiliation: Cancer Genomics Center-Hubrecht Institute-KNAW & University Medical Centre Utrecht, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands; Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
authors.forename: Elzo
authors.initials: E
authors.lastname: de Wit
authors.affiliation: Cancer Genomics Center-Hubrecht Institute-KNAW & University Medical Centre Utrecht, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands.
authors.forename: Lennart
authors.initials: L
authors.lastname: Kester
authors.affiliation: Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
authors.forename: Daphne
authors.initials: D
authors.lastname: van der Velden
authors.affiliation: Cancer Genomics Center-Hubrecht Institute-KNAW & University Medical Centre Utrecht, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands.
authors.forename: Carrie
authors.initials: C
authors.lastname: Maynard
authors.affiliation: Cancer Genomics Center-Hubrecht Institute-KNAW & University Medical Centre Utrecht, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands.
authors.forename: Ronny
authors.initials: R
authors.lastname: Schäfer
authors.affiliation: Department of Pathology, University Medical Centre Utrecht, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands.
authors.forename: Paul
authors.initials: P
authors.lastname: van Diest
authors.affiliation: Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
authors.forename: Emile
authors.initials: E
authors.lastname: Voest
authors.affiliation: Cancer Genomics Center-Hubrecht Institute-KNAW & University Medical Centre Utrecht, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands.
authors.forename: Alexander
authors.initials: A
authors.lastname: van Oudenaarden
authors.affiliation: Cancer Genomics Center-Hubrecht Institute-KNAW & University Medical Centre Utrecht, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands. Electronic address: n.vrisekoop@umcutrecht.nl.
authors.forename: Nienke
authors.initials: N
authors.lastname: Vrisekoop
authors.affiliation: Cancer Genomics Center-Hubrecht Institute-KNAW & University Medical Centre Utrecht, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands. Electronic address: j.vanrheenen@hubrecht.eu.
authors.forename: Jacco
authors.initials: J
authors.lastname: van Rheenen
mesh_terms: D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D015820:Cadherins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D044584:Carcinoma, Ductal / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000473:pathology / Q000556:secondary; D051379:Mice; D018345:Mice, Knockout; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D015375:Receptors, Interleukin-2 / Q000172:deficiency / Q000235:genetics
chemical_list: D000952:Antigens, Polyomavirus Transforming; D015820:Cadherins; D034741:RNA, Small Interfering; D015375:Receptors, Interleukin-2
keywords: cancer; epithelial-to-mesenchymal transition (EMT); intravital microscopy