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 Entenberg; James Castracane; Vladislav Verkhusha; Patricia J. Keely; John Condeelis; Julio A. Aguirre-Ghiso

doi:10.1038/ncb3465

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 Entenberg, James Castracane, Vladislav Verkhusha, Patricia J. Keely, John Condeelis, Julio A. Aguirre-Ghiso

Research output: Contribution to journal › Article › peer-review

227 Scopus citations

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 NR2F1^hi/DEC2^hi/p27^hi/TGFβ2^hi and dormant. NR2F1 and HIF1α were required for p27 induction in post-hypoxic dormant DTCs, but these DTCs did not display GLUT1^hi 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 language	English (US)
Pages (from-to)	120-132
Number of pages	13
Journal	Nature Cell Biology
Volume	19
Issue number	2
DOIs	https://doi.org/10.1038/ncb3465
State	Published - Jan 31 2017

ASJC Scopus subject areas

Cell Biology

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Fluegen, G., Avivar-Valderas, A., Wang, Y., Padgen, M. R., Williams, J. K., Nobre, A. R., Calvo, V., Cheung, J. F., Bravo-Cordero, J. J., Entenberg, D., Castracane, J., Verkhusha, V., Keely, P. J., Condeelis, J., & 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

Fluegen, G, Avivar-Valderas, A, Wang, Y, Padgen, MR, Williams, JK, Nobre, AR, Calvo, V, Cheung, JF, Bravo-Cordero, JJ, Entenberg, D, Castracane, J, Verkhusha, V, Keely, PJ, Condeelis, J & 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

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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.",

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AU - Entenberg, David

AU - Castracane, James

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

Abstract

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