Phenotypic heterogeneity of disseminated tumour cells is preset by primary tumour hypoxic microenvironments

Georg Fluegen, Alvaro Avivar-Valderas, Yarong Wang, Michael R. Padgen, James K. Williams, Ana Rita Nobre, Veronica Calvo, Julie F. Cheung, Jose Javier Bravo-Cordero, David R. Entenberg, James Castracane, Vladislav Verkhusha, Patricia J. Keely, John S. Condeelis, Julio A. Aguirre-Ghiso

Research output: Contribution to journalArticle

69 Citations (Scopus)

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/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.

Original languageEnglish (US)
Pages (from-to)120-132
Number of pages13
JournalNature Cell Biology
Volume19
Issue number2
DOIs
StatePublished - Jan 31 2017

Fingerprint

Tumor Microenvironment
Neoplasms
Breast Neoplasms
Cell- and Tissue-Based Therapy
Transgenic Mice
Up-Regulation
Recurrence
Drug Therapy

ASJC Scopus subject areas

  • Cell Biology

Cite this

Fluegen, G., Avivar-Valderas, A., Wang, Y., Padgen, M. R., Williams, J. K., Nobre, A. R., ... Aguirre-Ghiso, J. A. (2017). Phenotypic heterogeneity of disseminated tumour cells is preset by primary tumour hypoxic microenvironments. Nature Cell Biology, 19(2), 120-132. https://doi.org/10.1038/ncb3465

Phenotypic heterogeneity of disseminated tumour cells is preset by primary tumour hypoxic microenvironments. / Fluegen, Georg; Avivar-Valderas, Alvaro; Wang, Yarong; Padgen, Michael R.; Williams, James K.; Nobre, Ana Rita; Calvo, Veronica; Cheung, Julie F.; Bravo-Cordero, Jose Javier; Entenberg, David R.; Castracane, James; Verkhusha, Vladislav; Keely, Patricia J.; Condeelis, John S.; Aguirre-Ghiso, Julio A.

In: Nature Cell Biology, Vol. 19, No. 2, 31.01.2017, p. 120-132.

Research output: Contribution to journalArticle

Fluegen, G, Avivar-Valderas, A, Wang, Y, Padgen, MR, Williams, JK, Nobre, AR, Calvo, V, Cheung, JF, Bravo-Cordero, JJ, Entenberg, DR, Castracane, J, Verkhusha, V, Keely, PJ, Condeelis, JS & Aguirre-Ghiso, JA 2017, 'Phenotypic heterogeneity of disseminated tumour cells is preset by primary tumour hypoxic microenvironments', Nature Cell Biology, vol. 19, no. 2, pp. 120-132. https://doi.org/10.1038/ncb3465
Fluegen, Georg ; Avivar-Valderas, Alvaro ; Wang, Yarong ; Padgen, Michael R. ; Williams, James K. ; Nobre, Ana Rita ; Calvo, Veronica ; Cheung, Julie F. ; Bravo-Cordero, Jose Javier ; Entenberg, David R. ; Castracane, James ; Verkhusha, Vladislav ; Keely, Patricia J. ; Condeelis, John S. ; Aguirre-Ghiso, Julio A. / Phenotypic heterogeneity of disseminated tumour cells is preset by primary tumour hypoxic microenvironments. In: Nature Cell Biology. 2017 ; Vol. 19, No. 2. pp. 120-132.
@article{8a827ce9c5174a628f037faef5e0b999,
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/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.",
author = "Georg Fluegen and Alvaro Avivar-Valderas and Yarong Wang and Padgen, {Michael R.} and Williams, {James K.} and Nobre, {Ana Rita} and Veronica Calvo and Cheung, {Julie F.} and Bravo-Cordero, {Jose Javier} and Entenberg, {David R.} and James Castracane and Vladislav Verkhusha and Keely, {Patricia J.} and Condeelis, {John S.} and Aguirre-Ghiso, {Julio A.}",
year = "2017",
month = "1",
day = "31",
doi = "10.1038/ncb3465",
language = "English (US)",
volume = "19",
pages = "120--132",
journal = "Nature Cell Biology",
issn = "1465-7392",
publisher = "Nature Publishing Group",
number = "2",

}

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 R.

AU - Castracane, James

AU - Verkhusha, Vladislav

AU - Keely, Patricia J.

AU - Condeelis, John S.

AU - Aguirre-Ghiso, Julio A.

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.

UR - http://www.scopus.com/inward/record.url?scp=85010868094&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85010868094&partnerID=8YFLogxK

U2 - 10.1038/ncb3465

DO - 10.1038/ncb3465

M3 - Article

VL - 19

SP - 120

EP - 132

JO - Nature Cell Biology

JF - Nature Cell Biology

SN - 1465-7392

IS - 2

ER -