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

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 11

TET2/5hmC predicts shorter survival in CRC patients.

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TET2/5hmC predicts shorter survival in CRC patients. (A) GSEA plots show...
(A) GSEA plots showing enrichment of TET2 signature in SCCC versus RCCC expression profiles in the indicated models. 1-way ANOVA P value. (B) Disease-free survival (DFS) of chemo-treated high-risk stage II and stage III colon cancer patients (GSE39582, n = 151) according to TET2 signature score. (C) Histological quantification of 5hmC content in RCCCs and SCCCs per image from the indicated xenografts after vehicle or oxaliplatin treatments (n = 5 to 6 xenografts per group). Between 8 and 30 images per condition were evaluated. Data are represented as mean ± SEM. *P ≤ 0.05; ****P ≤ 0.0001, 1-way ANOVA. 5hmC measurements: shCTRL RCCC VEH vs. shCTRL SCCC OX (P ≤ 0.0001); shCTRL SCCC VEH vs. shTET2 RCCC/SCCC VEH/OX (P ≤ 0.0001); shTET2 RCCC/SCCC VEH vs. shCTRL RCCC/SCCC OX (P ≤ 0.0001); shCTRL RCCC/SCCC OX vs. shTET2 RCCC/SCCC OX (P ≤ 0.0001). (D) Immunofluorescence analysis of 5hmC and the proliferation marker (Ki67) in a colorectal cancer patient sample. Scale bar: 100 μm; high-magnification scale bar: 20 μm. (E) Dot plot correlating the percentage of 5hmC-positive versus Ki67-positive cells quantified by immunofluorescence and immunohistochemistry, respectively, in primary tumors (n = 55) and liver metastases (n = 47) from CRC patients. Red dashed line indicates the cutoff value above which a sample was considered high for 5hmC (5%). (F) DFS of chemo-treated CRC (Vall d’Hebron Institute of Oncology tissue microarray cohort, n = 87) patients. Tumors were considered 5hmC-high when at least 5% of tumor cells presented signal equal to or higher than that of adjacent stroma, and 5hmC-low when fewer than 5% of tumor cells did. Negative tumors did not show any detectable 5hmC signal in cancer cells. Negative tumors are included as 5hmC-low. (B and F) HR, hazard ratio. P values were calculated using Cox proportional hazards model.