TET2 controls chemoresistant slow-cycling cancer cell survival and tumor recurrence

被引：78

作者：

Puig, Isabel ^{[1
]}

Tenbaum, Stephan P. ^{[1
]}

Chicote, Irene ^{[1
]}

Arques, Oriol ^{[1
]}

Martinez-Quintanilla, Jordi ^{[1
]}

Cuesta-Borras, Estefania ^{[1
]}

Ramirez, Lorena ^{[2
]}

Gonzalo, Pilar ^{[3
]}

Soto, Atenea ^{[4
,5
]}

Aguilar, Susana ^{[6
]}

Eguizabal, Cristina ^{[7
]}

Caratu, Ginevra ^{[8
]}

Prat, Aleix ^{[9
]}

Argiles, Guillem ^{[2
]}

Landolfi, Stefania ^{[5
,10
]}

Casanovas, Oriol ^{[6
]}

Serra, Violeta ^{[11
,12
]}

Villanueva, Alberto ^{[13
]}

Arroyo, Alicia G. ^{[3
]}

Terracciano, Luigi ^{[14
]}

Nuciforo, Paolo ^{[15
]}

Seoane, Joan ^{[4
,5
,12
]}

Recio, Juan A. ^{[16
]}

Vivancos, Ana ^{[8
]}

Dienstmann, Rodrigo ^{[5
,17
]}

Tabernero, Josep ^{[2
,12
]}

Palmer, Hector G. ^{[1
,12
]}

机构：

[1] Vall dHebron Inst Oncol, Stem Cells & Canc Grp, Barcelona, Spain

[2] Vall dHebron Univ Hosp, Vall dHebron Inst Oncol, Dept Med Oncol, Gastrointestinal & Endocrine Tumors Grp, Barcelona, Spain

[3] Ctr Nacl Invest Cardiovasc Carlos III, Matrix Metalloproteinases Angiogenesis & Inflamma, Madrid, Spain

[4] Vall dHebron Univ Hosp, Inst Catalana Recerca & Estudis Avancats, Vall dHebron Inst Oncol, Gene Express & Canc Grp, Barcelona, Spain

[5] Univ Autonoma Barcelona, Cerdanyola Del Valles, Spain

[6] Inst Invest Biomed Bellvitge, Tumor Angiogenesis Grp, Barcelona, Spain

[7] Basque Ctr Transfus & Human Tissues, Cell Therapy & Stem Cell Grp, Galdakao, Spain

[8] Vall dHebron Inst Oncol, Canc Genom Grp, Barcelona, Spain

[9] Univ Barcelona, Translat Genom & Targeted Therapeut Solid Tumors, August Pi & Sunyer Biomed Res Inst IDIBAPS,Med On, Translat Genom Grp,Vall dHebron Inst Oncol,Hosp C, Barcelona, Spain

[10] Vall dHebron Univ Hosp, Dept Pathol, Barcelona, Spain

[11] Vall dHebron Inst Oncol, Expt Therapeut Grp, Barcelona, Spain

[12] Ctr Invest Biomed Red Canc CIBERONC, Madrid, Spain

[13] Inst Invest Biomed Bellvitge, Chemoresistance Grp, Barcelona, Spain

[14] Univ Hosp, Inst Pathol, Mol Pathol Div, Basel, Switzerland

[15] Vall dHebron Inst Oncol, Mol Oncol Grp, Barcelona, Spain

[16] Vall dHebron Res Inst, Melanoma Program, Anim Models & Canc Lab, Barcelona, Spain

[17] Vall dHebron Inst Oncol, Oncol Data Sci ODysSey Grp, Barcelona, Spain

来源：

JOURNAL OF CLINICAL INVESTIGATION | 2018年 / 128卷 / 09期

关键词：

LABEL-RETAINING CELLS; STEM-CELLS; 5-HYDROXYMETHYLCYTOSINE; 5-METHYLCYTOSINE; MECHANISMS; INHIBITORS; ALPHA; HETEROGENEITY; POPULATION; PROTEINS;

D O I：

10.1172/JCI96393

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

Dormant or slow-cycling tumor cells can form a residual chemoresistant reservoir responsible for relapse in patients, years after curative surgery and adjuvant therapy. We have adapted the pulse-chase expression of H2BeGFP for labeling and isolating slow-cycling cancer cells (SCCCs). SCCCs showed cancer initiation potential and enhanced chemoresistance. Cells at this slow-cycling status presented a distinctive nongenetic and cell-autonomous gene expression profile shared across different tumor types. We identified TET2 epigenetic enzyme as a key factor controlling SCCC numbers, survival, and tumor recurrence. 5-Hydroxymethylcytosine (5hmC), generated by TET2 enzymatic activity, labeled the SCCC genome in carcinomas and was a predictive biomarker of relapse and survival in cancer patients. We have shown the enhanced chemoresistance of SCCCs and revealed 5hmC as a biomarker for their clinical identification and TET2 as a potential drug target for SCCC elimination that could extend patients' survival.

引用

页码：3887 / 3905

页数：19

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