The Journal of clinical investigation 2018 06 26() doi 10.1172/JCI96393


Dormant or slow-cycling tumour 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 labelling and isolating slow-cycling cancer cells (SCCC). SCCC showed cancer-initiation potential and enhanced chemoresistance. Cells at this slow-cycling status presented a distinctive non-genetic and cell-autonomous gene expression profile shared across different tumour types. We identified TET2 epigenetic enzyme as key factor controlling SCCC numbers, survival and tumour recurrence. 5-Hydroxymethylcytosine (5hmC), generated by TET2 enzymatic activity, labelled SCCC genome in carcinomas and was a predictive biomarker of relapse and survival in cancer patients. We have shown the enhanced chemoresistance of SCCC, revealed 5hmC as a biomarker for their clinical identification, and TET2 as a potential drug-target for SCCC elimination that could extend patients’ survival.