Quiescent Sox2+ Cells Drive Hierarchical Growth and Relapse in Sonic Hedgehog Subgroup Medulloblastoma

被引：233

作者：

Vanner, Robert J. ^{[1
,2
,3
,4
]}

Remke, Marc ^{[1
,2
,3
,5
]}

Gallo, Marco ^{[1
,2
,3
]}

Selvadurai, Hayden J. ^{[1
,2
,3
]}

Coutinho, Fiona ^{[1
,2
,3
,4
]}

Lee, Lilian ^{[1
,2
,3
]}

Kushida, Michelle ^{[1
,2
,3
]}

Head, Renee ^{[1
,2
,3
]}

Morrissy, Sorana ^{[1
,2
,3
]}

Zhu, Xueming ^{[1
,2
,3
]}

Aviv, Tzvi ^{[1
,2
,3
]}

Voisin, Veronique ^{[6
]}

Clarke, Ian D. ^{[1
,2
,3
,7
]}

Li, Yisu ^{[8
]}

Mungall, Andrew J. ^{[8
]}

Moore, Richard A. ^{[8
]}

Ma, Yussanne ^{[8
]}

Jones, Steven J. M. ^{[8
]}

Marra, Marco A. ^{[8
]}

Malkin, David ^{[9
]}

Northcott, Paul A. ^{[10
]}

Kool, Marcel ^{[10
]}

Pfister, Stefan M. ^{[10
,11
]}

Bader, Gary ^{[6
]}

Hochedlinger, Konrad ^{[12
,13
,14
]}

Korshunov, Andrey ^{[15
,16
]}

Taylor, Michael D. ^{[1
,2
,3
,5
]}

Dirks, Peter B. ^{[1
,2
,3
,4
,5
]}

机构：

[1] Hosp Sick Children, Arthur & Sonia Labatt Brain Tumour Res Ctr, Toronto, ON M5G 1L7, Canada

[2] Hosp Sick Children, Div Neurosurg, Toronto, ON M5G 1L7, Canada

[3] Hosp Sick Children, Program Dev & Stem Cell Biol, Toronto, ON M5G 1X8, Canada

[4] Univ Toronto, Dept Mol Genet, Toronto, ON M5S 1A8, Canada

[5] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON M5S 1A8, Canada

[6] Univ Toronto, Donnelly Ctr, Toronto, ON M5S 1A8, Canada

[7] OCAD Univ, Toronto, ON M5T1W1, Canada

[8] BC Canc Agcy, Canadas Michael Smith Genome Sci Ctr, Vancouver, BC VSZ 4S6, Canada

[9] Univ Toronto, Div Hematol Oncol, Dept Pediat, HSC, Toronto, ON M6S 1A8, Canada

[10] German Canc Res Ctr DKFZ Heidelberg, Div Pediat Neurooncol, D-69120 Heidelberg, Germany

[11] Univ Heidelberg Hosp, Dept Pediat Oncol Hematol & Immunol, D-69120 Heidelberg, Germany

[12] Massachusetts Gen Hosp Canc Ctr, Boston, MA 02114 USA

[13] Ctr Regenerat Med, Boston, MA 02114 USA

[14] Harvard Stem Cell Inst, Cambridge, MA 02138 USA

[15] Heidelberg Univ, Dept Neuropathol, D-69120 Heidelberg, Germany

[16] DKFZ, German Canc Res Ctr, Clin Cooperat Unit Neuropathol, D-69120 Heidelberg, Germany

来源：

CANCER CELL | 2014年 / 26卷 / 01期

基金：

加拿大健康研究院;

关键词：

CANCER STEM-CELLS; PATHWAY INHIBITOR; INITIATING CELLS; PROGENITOR CELLS; MELANOMA-CELLS; MOUSE MODEL; ADULT STEM; TUMOR; MARKER; IDENTIFICATION;

D O I：

10.1016/j.ccr.2014.05.005

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Functional heterogeneity within tumors presents a significant therapeutic challenge. Here we show that quiescent, therapy-resistant Sox(2+) cells propagate sonic hedgehog subgroup nnedulloblastoma by a mechanism that mirrors a neurogenic program. Rare Sox(2+) cells produce rapidly cycling doublecortin(+) progenitors that, together with their postmitotic progeny expressing NeuN, comprise tumor bulk. Sox(2+) cells are enriched following anti-mitotic chemotherapy and Smoothened inhibition, creating a reservoir for tumor regrowth. Lineage traces from Sox(2+) cells increase following treatment, suggesting that this population is responsible for relapse. Targeting Sox(2+) cells with the antineoplastic mithramycin abrogated tumor growth. Addressing functional heterogeneity and eliminating Sox(2+) cells presents a promising therapeutic paradigm for treatment of sonic hedgehog subgroup medulloblastoma.

引用

页码：33 / 47

页数：15

共 54 条

[1] Sox2 Requirement in Sonic Hedgehog-Associated Medulloblastoma [J].