TY - JOUR
T1 - Phenotypic heterogeneity of disseminated tumour cells is preset by primary tumour hypoxic microenvironments
AU - Fluegen, Georg
AU - Avivar-Valderas, Alvaro
AU - Wang, Yarong
AU - Padgen, Michael R.
AU - Williams, James K.
AU - Nobre, Ana Rita
AU - Calvo, Veronica
AU - Cheung, Julie F.
AU - Bravo-Cordero, Jose Javier
AU - Entenberg, David
AU - Castracane, James
AU - Verkhusha, Vladislav
AU - Keely, Patricia J.
AU - Condeelis, John
AU - Aguirre-Ghiso, Julio A.
N1 - Funding Information:
We thank the Aguirre-Ghiso, Condeelis and Castracane laboratories for useful discussions. We thank N. Linde and M. S. Sosa for help and advice during initial phases of this study on the detection of TGFβ2 and NR2F1. This study was supported by: the Samuel Waxman Cancer Research Foundation Tumor Dormancy Program to J.A.A.-G.; the NIH/NCI TMEN U54CA163131 to J.Condeelis, P.J.K., J.Castracane and J.A.A.-G.; NIH/NCI grants CA109182 and CA191430 to J.A.A.-G.; DoD-BCRP Breakthrough Award (BC132674) to J.A.A.-G. and J.Condeelis; NCI Cancer Center P30 grant CA196521 to J.A.A.-G.; the TCI Young Scientist Cancer Research Award JJR Fund and NCI K22CA196750 grants to J.J.B.-C.; and the German Research Foundation (DFG) Fellowship (FL 865/1-1) and University Hospital Duesseldorf, Department of General and Visceral Surgery to G.F. Special optical devices were constructed and validated in the Gruss Lippoer Biophotonic Center and Integrated Imaging Program at Einstein. All imaging was performed in the Microscopy CORE at the Icahn School of Medicine at Mount Sinai. We thank N. Tzavaras (Microscopy CORE) for his technical help.
Publisher Copyright:
© 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
PY - 2017/1/31
Y1 - 2017/1/31
N2 - 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/TGFβ2hi and dormant. NR2F1 and HIF1α were required for p27 induction in post-hypoxic dormant DTCs, but these DTCs did not display GLUT1hi expression. 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.
AB - 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/TGFβ2hi and dormant. NR2F1 and HIF1α were required for p27 induction in post-hypoxic dormant DTCs, but these DTCs did not display GLUT1hi expression. 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.
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U2 - 10.1038/ncb3465
DO - 10.1038/ncb3465
M3 - Article
C2 - 28114271
AN - SCOPUS:85010868094
SN - 1465-7392
VL - 19
SP - 120
EP - 132
JO - Nature Cell Biology
JF - Nature Cell Biology
IS - 2
ER -
