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TET2 controls chemoresistant slow-cycling cancer cell survival and tumor recurrence
Isabel Puig, … , Josep Tabernero, Héctor G. Palmer
Isabel Puig, … , Josep Tabernero, Héctor G. Palmer
Published June 26, 2018
Citation Information: J Clin Invest. 2018;128(9):3887-3905. https://doi.org/10.1172/JCI96393.
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Research Article Oncology

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

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Abstract

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.

Authors

Isabel Puig, Stephan P. Tenbaum, Irene Chicote, Oriol Arqués, Jordi Martínez-Quintanilla, Estefania Cuesta-Borrás, Lorena Ramírez, Pilar Gonzalo, Atenea Soto, Susana Aguilar, Cristina Eguizabal, Ginevra Caratù, Aleix Prat, Guillem Argilés, Stefania Landolfi, Oriol Casanovas, Violeta Serra, Alberto Villanueva, Alicia G. Arroyo, Luigi Terracciano, Paolo Nuciforo, Joan Seoane, Juan A. Recio, Ana Vivancos, Rodrigo Dienstmann, Josep Tabernero, Héctor G. Palmer

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Figure 1

An H2BeGFP pulse-chase system marks slow-cycling cells.

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An H2BeGFP pulse-chase system marks slow-cycling cells.
(A) Schematic re...
(A) Schematic representation of tetracycline-inducible lentiviral pSIN-TRE-H2BeGFP-rtTA2 construct. H2BeGFP is expressed via a tetracycline response element–containing promoter (TRE), which is activated by the reverse tetracycline transactivator (rtTA) induced in the presence of the tetracycline derivative doxycycline (DOX). RSV, constitutive promoter Rous sarcoma virus; RRE, Rev response element; cPPT, central polypurine tract; hPGK, human phosphoglycerate kinase promoter; WPRE, woodchuck hepatitis virus post-transcriptional regulatory element. (B) Chromatin accumulation of H2BeGFP in infected colon cancer cells upon DOX treatment. (C and D) Representative immunofluorescence picture of H2BeGFP-infected minitumors (MTs) growing embedded in Matrigel for colorectal (CRC) models or in suspension for melanoma (MEL) and glioblastoma (GBM) cancer models generated from single-cell suspensions. Cultures were treated with a DOX pulse chase to evaluate SCCCs together with cellular organization (phalloidin) (C) or proliferation (Ki67) (D). (C and D) Arrowheads, SCCCs. Hoechst was used as counterstain. (B–D) Scale bars: 100 μm.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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