Centre for Regenerative Medicine and Health, Hong Kong Institute of Science & Innovation, Chinese Academy of Sciences Limited
Abstract: TET2 dysfunction has been observed in several types of solid tumours, but the exact role of TET2 in tumour progression is unknown. In this study, via utility of SW480-SW620, which is a unique pair of cell lines derived from the same patient and originated from primary tumour and metastasis tumour respectively, we found by in vivo and in vitro experiments that TET2 translocate from cell cytoplasm to cell nuclear in the late stage of tumour progression. More importantly, nuclear translation of TET2 was associated with increased DNA demethylation activity and tumour suppressor activity. And we found that epithelial-mesenchymal transition (EMT) is a crucial molecular mechanism regulating cell migration and TET2 nuclear translocation. Further sequencing of individual cells revealed a gradual transition of cells from the inside to the outside of the clone. During migration, TET2 forms negative feedback loops with the EMT and WNT pathways, resembling the clinical progression of colorectal cancer (CRC) patients. Finally, pseudotime points were plotted based on the migration process as a measure of TET2 activity and patient survival in different tumours. Taken together, these data suggest that TET2 is an innate brake of cancer progression and serves as an important therapeutic target in the treatment of solid tumours.
