title: Phenotypic heterogeneity of disseminated tumour cells is preset by primary tumour hypoxic microenvironments.
abstract: Hypoxia is a poor-prognosis microenvironmental hallmark of solid tumours, but it is unclear how it influences the fate of disseminated tumour cells (DTCs) in target organs. Here we report that hypoxic HNSCC and breast primary tumour microenvironments displayed upregulation of key dormancy (NR2F1, DEC2, p27) and hypoxia (GLUT1, HIF1α) genes. Analysis of solitary DTCs in PDX and transgenic mice revealed that post-hypoxic DTCs were frequently NR2F1hi/DEC2hi/p27hi/TGFβ2hiand dormant. NR2F1 and HIF1α were required for p27 induction in post-hypoxic dormant DTCs, but these DTCs did not display GLUT1hiexpression. Post-hypoxic DTCs evaded chemotherapy and, unlike ER-breast cancer cells, post-hypoxic ER+breast cancer cells were more prone to enter NR2F1-dependent dormancy. We propose that primary tumour hypoxic microenvironments give rise to a subpopulation of dormant DTCs that evade therapy. These post-hypoxic dormant DTCs may be the source of disease relapse and poor prognosis associated with hypoxia.
authors.affiliation: Department of Medicine and Department of Otolaryngology, Tisch Cancer Institute, Black Family Stem Cell Institute, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, New York 10029, USA.|Department of General, Visceral and Pediatric Surgery, Medical Faculty, University Hospital of the Heinrich-Heine-University Düsseldorf, Düsseldorf 40225, Germany.
authors.forename: Georg
authors.identifier: 0000-0002-9322-1659
authors.initials: G
authors.lastname: Fluegen
authors.affiliation: Department of Medicine and Department of Otolaryngology, Tisch Cancer Institute, Black Family Stem Cell Institute, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, New York 10029, USA.
authors.forename: Alvaro
authors.initials: A
authors.lastname: Avivar-Valderas
authors.affiliation: Department of Anatomy and Structural Biology, Gruss Lipper Biophotonics Center, Integrated Imaging Program, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, USA.
authors.forename: Yarong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Colleges of Nanoscale Science and Engineering, SUNY Polytechnic Institute, Albany, New York 12203, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Padgen
authors.affiliation: Colleges of Nanoscale Science and Engineering, SUNY Polytechnic Institute, Albany, New York 12203, USA.
authors.forename: James K
authors.initials: JK
authors.lastname: Williams
authors.affiliation: Department of Medicine and Department of Otolaryngology, Tisch Cancer Institute, Black Family Stem Cell Institute, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, New York 10029, USA.
authors.forename: Ana Rita
authors.initials: AR
authors.lastname: Nobre
authors.affiliation: Department of Medicine and Department of Otolaryngology, Tisch Cancer Institute, Black Family Stem Cell Institute, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, New York 10029, USA.
authors.forename: Veronica
authors.initials: V
authors.lastname: Calvo
authors.affiliation: Department of Medicine and Department of Otolaryngology, Tisch Cancer Institute, Black Family Stem Cell Institute, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, New York 10029, USA.
authors.forename: Julie F
authors.initials: JF
authors.lastname: Cheung
authors.affiliation: Department of Medicine and Department of Otolaryngology, Tisch Cancer Institute, Black Family Stem Cell Institute, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, New York 10029, USA.
authors.forename: Jose Javier
authors.initials: JJ
authors.lastname: Bravo-Cordero
authors.affiliation: Department of Anatomy and Structural Biology, Gruss Lipper Biophotonics Center, Integrated Imaging Program, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, USA.
authors.forename: David
authors.initials: D
authors.lastname: Entenberg
authors.affiliation: Colleges of Nanoscale Science and Engineering, SUNY Polytechnic Institute, Albany, New York 12203, USA.
authors.forename: James
authors.initials: J
authors.lastname: Castracane
authors.affiliation: Department of Anatomy and Structural Biology, Gruss Lipper Biophotonics Center, Integrated Imaging Program, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, USA.
authors.forename: Vladislav
authors.initials: V
authors.lastname: Verkhusha
authors.affiliation: Department of Cell and Regenerative Biology, Laboratory of Molecular Biology, University of Wisconsin-Madison, 1525 Linden Drive, Madison, Wisconsin 53706, USA.
authors.forename: Patricia J
authors.initials: PJ
authors.lastname: Keely
authors.affiliation: Department of Anatomy and Structural Biology, Gruss Lipper Biophotonics Center, Integrated Imaging Program, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, USA.
authors.forename: John
authors.initials: J
authors.lastname: Condeelis
authors.affiliation: Department of Medicine and Department of Otolaryngology, Tisch Cancer Institute, Black Family Stem Cell Institute, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, New York 10029, USA.
authors.forename: Julio A
authors.initials: JA
authors.lastname: Aguirre-Ghiso
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000378:metabolism*; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D051838:COUP Transcription Factor I / Q000378:metabolism; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002469:Cell Separation / Q000379:methods; D006801:Humans; D051379:Mice; D009362:Neoplasm Metastasis; D010641:Phenotype; D059016:Tumor Microenvironment
chemical_list: D051838:COUP Transcription Factor I; C497589:NR2F1 protein, human