Adaptive Chromatin Remodeling Drives Glioblastoma Stem Cell Plasticity and Drug Tolerance

Brian B. Liau; Cem Sievers; Laura K. Donohue; Shawn M. Gillespie; William A. Flavahan; Tyler E. Miller; Andrew S. Venteicher; Christine H. Hebert; Christopher D. Carey; Scott J. Rodig; Sarah J. Shareef; Fadi J. Najm; Peter van Galen; Hiroaki Wakimoto; Daniel P. Cahill; Jeremy N. Rich; Jon C. Aster; Mario L. Suvà; Anoop P. Patel; Bradley E. Bernstein

doi:10.1016/j.stem.2016.11.003

Adaptive Chromatin Remodeling Drives Glioblastoma Stem Cell Plasticity and Drug Tolerance

Brian B. Liau, Cem Sievers, Laura K. Donohue, Shawn M. Gillespie, William A. Flavahan, Tyler E. Miller, Andrew S. Venteicher, Christine H. Hebert, Christopher D. Carey, Scott J. Rodig, Sarah J. Shareef, Fadi J. Najm, Peter van Galen, Hiroaki Wakimoto, Daniel P. Cahill, Jeremy N. Rich, Jon C. Aster, Mario L. Suvà, Anoop P. Patel, Bradley E. Bernstein

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

276 Scopus citations

Abstract

Glioblastoma, the most common and aggressive malignant brain tumor, is propagated by stem-like cancer cells refractory to existing therapies. Understanding the molecular mechanisms that control glioblastoma stem cell (GSC) proliferation and drug resistance may reveal opportunities for therapeutic interventions. Here we show that GSCs can reversibly transition to a slow-cycling, persistent state in response to targeted kinase inhibitors. In this state, GSCs upregulate primitive developmental programs and are dependent upon Notch signaling. This transition is accompanied by widespread redistribution of repressive histone methylation. Accordingly, persister GSCs upregulate, and are dependent on, the histone demethylases KDM6A/B. Slow-cycling cells with high Notch activity and histone demethylase expression are present in primary glioblastomas before treatment, potentially contributing to relapse. Our findings illustrate how cancer cells may hijack aspects of native developmental programs for deranged proliferation, adaptation, and tolerance. They also suggest strategies for eliminating refractory tumor cells by targeting epigenetic and developmental pathways.

Original language	English (US)
Pages (from-to)	233-246.e7
Journal	Cell Stem Cell
Volume	20
Issue number	2
DOIs	https://doi.org/10.1016/j.stem.2016.11.003
State	Published - Feb 2 2017
Externally published	Yes

Bibliographical note

Funding Information:
We thank S. Muller-Knapp and the Structural Genomics Consortium (Oxford, UK), Russell Ryan, Nicol? Riggi, and Henry Pelish for helpful discussions. We thank David Sabatini and Kris Wood for Notch1 intracellular domain-pcw107 and William Hahn and David Root for p-DONR223-PDGFRA M260I. B.B.L. is supported by a Jane Coffin Childs Memorial Fund postdoctoral fellowship. C.S. is supported by a European Molecular Biology Organization (EMBO) fellowship (ALTF 654-2014) and a Swiss National Science Foundation fellowship. P.v.G. is supported by an EMBO Fellowship (ALTF 1207-2014). A.P.P. is supported by the NIH/NINDS (R25NS065743). W.A.F. is supported by an American Brain Tumor Association grant. B.E.B. is an American Cancer Society research professor. This research was supported by funds from the Howard Hughes Medical Institute, the National Human Genome Research Institute, the National Cancer Institute (P50CA165962), and the National Brain Tumor Society.

Publisher Copyright:
© 2017 Elsevier Inc.

Keywords

KDM6A/B
Notch
cancer
chromatin
drug resistance
epigenetics
glioblastoma
histone demethylases
stem cell

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.stem.2016.11.003

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Liau, B. B., Sievers, C., Donohue, L. K., Gillespie, S. M., Flavahan, W. A., Miller, T. E., Venteicher, A. S., Hebert, C. H., Carey, C. D., Rodig, S. J., Shareef, S. J., Najm, F. J., van Galen, P., Wakimoto, H., Cahill, D. P., Rich, J. N., Aster, J. C., Suvà, M. L., Patel, A. P., & Bernstein, B. E. (2017). Adaptive Chromatin Remodeling Drives Glioblastoma Stem Cell Plasticity and Drug Tolerance. Cell Stem Cell, 20(2), 233-246.e7. https://doi.org/10.1016/j.stem.2016.11.003

Liau, BB, Sievers, C, Donohue, LK, Gillespie, SM, Flavahan, WA, Miller, TE, Venteicher, AS, Hebert, CH, Carey, CD, Rodig, SJ, Shareef, SJ, Najm, FJ, van Galen, P, Wakimoto, H, Cahill, DP, Rich, JN, Aster, JC, Suvà, ML, Patel, AP & Bernstein, BE 2017, 'Adaptive Chromatin Remodeling Drives Glioblastoma Stem Cell Plasticity and Drug Tolerance', Cell Stem Cell, vol. 20, no. 2, pp. 233-246.e7. https://doi.org/10.1016/j.stem.2016.11.003

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abstract = "Glioblastoma, the most common and aggressive malignant brain tumor, is propagated by stem-like cancer cells refractory to existing therapies. Understanding the molecular mechanisms that control glioblastoma stem cell (GSC) proliferation and drug resistance may reveal opportunities for therapeutic interventions. Here we show that GSCs can reversibly transition to a slow-cycling, persistent state in response to targeted kinase inhibitors. In this state, GSCs upregulate primitive developmental programs and are dependent upon Notch signaling. This transition is accompanied by widespread redistribution of repressive histone methylation. Accordingly, persister GSCs upregulate, and are dependent on, the histone demethylases KDM6A/B. Slow-cycling cells with high Notch activity and histone demethylase expression are present in primary glioblastomas before treatment, potentially contributing to relapse. Our findings illustrate how cancer cells may hijack aspects of native developmental programs for deranged proliferation, adaptation, and tolerance. They also suggest strategies for eliminating refractory tumor cells by targeting epigenetic and developmental pathways.",

keywords = "KDM6A/B, Notch, cancer, chromatin, drug resistance, epigenetics, glioblastoma, histone demethylases, stem cell",

author = "Liau, {Brian B.} and Cem Sievers and Donohue, {Laura K.} and Gillespie, {Shawn M.} and Flavahan, {William A.} and Miller, {Tyler E.} and Venteicher, {Andrew S.} and Hebert, {Christine H.} and Carey, {Christopher D.} and Rodig, {Scott J.} and Shareef, {Sarah J.} and Najm, {Fadi J.} and {van Galen}, Peter and Hiroaki Wakimoto and Cahill, {Daniel P.} and Rich, {Jeremy N.} and Aster, {Jon C.} and Suv{\`a}, {Mario L.} and Patel, {Anoop P.} and Bernstein, {Bradley E.}",

note = "Funding Information: We thank S. Muller-Knapp and the Structural Genomics Consortium (Oxford, UK), Russell Ryan, Nicol? Riggi, and Henry Pelish for helpful discussions. We thank David Sabatini and Kris Wood for Notch1 intracellular domain-pcw107 and William Hahn and David Root for p-DONR223-PDGFRA M260I. B.B.L. is supported by a Jane Coffin Childs Memorial Fund postdoctoral fellowship. C.S. is supported by a European Molecular Biology Organization (EMBO) fellowship (ALTF 654-2014) and a Swiss National Science Foundation fellowship. P.v.G. is supported by an EMBO Fellowship (ALTF 1207-2014). A.P.P. is supported by the NIH/NINDS (R25NS065743). W.A.F. is supported by an American Brain Tumor Association grant. B.E.B. is an American Cancer Society research professor. This research was supported by funds from the Howard Hughes Medical Institute, the National Human Genome Research Institute, the National Cancer Institute (P50CA165962), and the National Brain Tumor Society. Publisher Copyright: {\textcopyright} 2017 Elsevier Inc.",

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AU - Sievers, Cem

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AU - Gillespie, Shawn M.

AU - Flavahan, William A.

AU - Miller, Tyler E.

AU - Venteicher, Andrew S.

AU - Hebert, Christine H.

AU - Carey, Christopher D.

AU - Rodig, Scott J.

AU - Shareef, Sarah J.

AU - Najm, Fadi J.

AU - van Galen, Peter

AU - Wakimoto, Hiroaki

AU - Cahill, Daniel P.

AU - Rich, Jeremy N.

AU - Aster, Jon C.

AU - Suvà, Mario L.

AU - Patel, Anoop P.

AU - Bernstein, Bradley E.

N1 - Funding Information: We thank S. Muller-Knapp and the Structural Genomics Consortium (Oxford, UK), Russell Ryan, Nicol? Riggi, and Henry Pelish for helpful discussions. We thank David Sabatini and Kris Wood for Notch1 intracellular domain-pcw107 and William Hahn and David Root for p-DONR223-PDGFRA M260I. B.B.L. is supported by a Jane Coffin Childs Memorial Fund postdoctoral fellowship. C.S. is supported by a European Molecular Biology Organization (EMBO) fellowship (ALTF 654-2014) and a Swiss National Science Foundation fellowship. P.v.G. is supported by an EMBO Fellowship (ALTF 1207-2014). A.P.P. is supported by the NIH/NINDS (R25NS065743). W.A.F. is supported by an American Brain Tumor Association grant. B.E.B. is an American Cancer Society research professor. This research was supported by funds from the Howard Hughes Medical Institute, the National Human Genome Research Institute, the National Cancer Institute (P50CA165962), and the National Brain Tumor Society. Publisher Copyright: © 2017 Elsevier Inc.

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N2 - Glioblastoma, the most common and aggressive malignant brain tumor, is propagated by stem-like cancer cells refractory to existing therapies. Understanding the molecular mechanisms that control glioblastoma stem cell (GSC) proliferation and drug resistance may reveal opportunities for therapeutic interventions. Here we show that GSCs can reversibly transition to a slow-cycling, persistent state in response to targeted kinase inhibitors. In this state, GSCs upregulate primitive developmental programs and are dependent upon Notch signaling. This transition is accompanied by widespread redistribution of repressive histone methylation. Accordingly, persister GSCs upregulate, and are dependent on, the histone demethylases KDM6A/B. Slow-cycling cells with high Notch activity and histone demethylase expression are present in primary glioblastomas before treatment, potentially contributing to relapse. Our findings illustrate how cancer cells may hijack aspects of native developmental programs for deranged proliferation, adaptation, and tolerance. They also suggest strategies for eliminating refractory tumor cells by targeting epigenetic and developmental pathways.

AB - Glioblastoma, the most common and aggressive malignant brain tumor, is propagated by stem-like cancer cells refractory to existing therapies. Understanding the molecular mechanisms that control glioblastoma stem cell (GSC) proliferation and drug resistance may reveal opportunities for therapeutic interventions. Here we show that GSCs can reversibly transition to a slow-cycling, persistent state in response to targeted kinase inhibitors. In this state, GSCs upregulate primitive developmental programs and are dependent upon Notch signaling. This transition is accompanied by widespread redistribution of repressive histone methylation. Accordingly, persister GSCs upregulate, and are dependent on, the histone demethylases KDM6A/B. Slow-cycling cells with high Notch activity and histone demethylase expression are present in primary glioblastomas before treatment, potentially contributing to relapse. Our findings illustrate how cancer cells may hijack aspects of native developmental programs for deranged proliferation, adaptation, and tolerance. They also suggest strategies for eliminating refractory tumor cells by targeting epigenetic and developmental pathways.

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Adaptive Chromatin Remodeling Drives Glioblastoma Stem Cell Plasticity and Drug Tolerance

Abstract

Bibliographical note

Keywords

UN SDGs

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