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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 10

TET2 controls SCCC survival by modulating TNF-α signaling.

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TET2 controls SCCC survival by modulating TNF-α signaling.
(A) Venn dia...
(A) Venn diagrams comparing genes highly (top) or lowly (bottom) expressed in SCCCs versus RCCCs isolated from the indicated cell lines. (B) Gene ontology analyses of TET2-induced (green) and TET2-repressed (blue) genes in SCCCs versus RCCCs. (C) GSEA plots showing enrichment of the indicated gene sets in SCCC versus RCCC expression profiles from the indicated cell lines. 1-way ANOVA P value. (D) Genes related to apoptosis were selected from the Molecular Signatures Database (Broad Institute). Venn diagram showing genes related to apoptosis and highly expressed in SCCCs versus RCCCs from the indicated cell lines. Proapoptotic (red) and antiapoptotic (black) genes are shown. The gene of interest is indicated in white (TNF). (E) Expression of the indicated genes was measured by qPCR. TNF mRNA measurements: shCTRL RCCC vs. shTET2 RCCC/SCCC (P ≤ 0.0001); shCTRL SCCC vs. shTET2 RCCC (P ≤ 0.01). TNFRSF1B mRNA measurements: shCTRL RCCC vs. shTET2 RCCC (P ≤ 0.0001); shCTRL SCCC vs. shTET2 RCCC (P ≤ 0.05); shTET2 RCCC vs. shTET2 SCCC (P ≤ 0.0001). (F) Evaluation of apoptosis by flow cytometry in RCCCs and SCCCs of the indicated cell lines after vehicle or pomalidomide (POM) treatment. Apoptosis measurements: shCTRL SCCC/RCCC VEH vs. shTET2 SCCC VEH/POM (P ≤ 0.0001); shTET2 RCCC VEH vs. shTET2 VEH/POM SCCC (P ≤ 0.0001); shTET2 SCCC VEH vs. shCTRL/shTET2 RCCC/SCCC POM (P ≤ 0.0001); shCTRL RCCC/SCCC POM vs. shTET2 SCCC POM (P ≤ 0.0001); shTET2 RCCC POM vs. shTET2 SCCC POM (P ≤ 0.0001). (E and F) Blue bars, RCCCs; green bars, SCCCs. Data are represented as mean ± SD (E) or ± SEM (F) of triplicates from 3 independent experiments. 1-way ANOVA. **P ≤ 0.01; ****P ≤ 0.0001. All analyses were performed in the indicated SW1222-H2BeGFP cell lines growing as MTs.
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