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 12

5hmC levels across cancer types.

Options: View larger image (or click on image) Download as PowerPoint
5hmC levels across cancer types. (A and B) 5hmC levels were evaluated by...
(A and B) 5hmC levels were evaluated by immunohistochemistry on a tissue microarray containing 656 patient samples from 19 different tumor types. (A) Representative pictures showing high and low levels of 5hmC from 3 different cancer types. IDC, invasive ductal carcinoma; SCC, squamous cell carcinoma. Arrowheads: 5hmC-positive stromal cells used as internal control staining. Scale bar: 100 μm. (B) Proportion of tumor samples with different amounts of 5hmC for each cancer type. 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 (NEG) tumors did not show any detectable 5HmC signal in cancer cells. Diff, diffuse; int, intestinal; CRC, colorectal cancer; UCC, urothelial carcinoma; GBM, glioblastoma; SC, sebaceous carcinoma. (C and D) Histological quantification of 5hmC in paired primary tumor and liver metastases of CRC patients evaluated by immunofluorescence on formalin-fixed, paraffin-embedded sections. (C) Proportion of 5hmC-positive (green) and -negative (blue) cases (n = 197). (D) Paired comparison of primary tumors and liver metastases from synchronous nontreated patients (n = 96) from the cohort analyzed in C. P value of Wilcoxon paired test.