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.
View: Text | PDF
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

×

Figure 4

SCCC signature includes genes related to several biological functions.

Options: View larger image (or click on image) Download as PowerPoint
SCCC signature includes genes related to several biological functions. (...
(A) Single-sample GSEA projections for each indicated MT cancer model. Colored boxes correspond to general functions grouping differentially enriched gene sets. Color bar legend: blue, downregulated expression; red, upregulated expression. ECM, extracellular matrix. (B) Venn diagrams comparing genes lowly (top) or highly (bottom) expressed in SCCCs versus RCCCs. (C) Genes more highly expressed in SCCCs were grouped depending on their function following the Broad Institute’s ontology. Bars represent the percentage of genes related to a particular function with respect to all genes more highly expressed in SCCCs that are exclusive or common to models of each cancer type as defined in the Venn diagram shown in B, bottom. (D and E) Normalized PanC-SCCC signature score of The Cancer Genome Atlas (TCGA) CRC (D) and GBM (E) cohorts with intrinsic gene expression classifier labels. Significantly higher scores in the upper quartile are marked in green dots. *P < 0.001, Kruskal-Wallis test.