SOX2 drives fetal reprogramming and reversible dormancy in colorectal cancer

Abstract Cellular plasticity plays critical roles in tissue regeneration, tumour progression and therapeutic resistance. However, the mechanism underlying this cell state transition remains elusive. Here, we show that the transcription factor SOX2 induces fetal reprogramming and reversible dormancy in colorectal cancer (CRC). SOX2 expression correlates with fetal reprogramming and poor prognosis in human primary and metastatic colorectal adenocarcinomas. In mouse CRC models, rare slow-cycling SOX2 + SCA1 + cells are detected in early Apc -deleted mouse tumours that undergo slow clonal expansion over time. In contrast, the SOX2 + clones were found proliferative in advanced Apc -/- ;Kras G12D/+ ;p53 -/- ;Tgfbr2 -/- (AKPT) tumours, accompanied by dynamic cell state reprogramming from LGR5 + to LGR5 - SCA1 + cells. Using transgenic mouse models, we demonstrate that ectopic expression of SOX2 inhibits intestinal lineage differentiation and induces fetal reprogramming. SOX2+ cells adopt dynamic cell cycle states depending on its expression level. High SOX2 expression results in hyperproliferation, whereas low SOX2 levels induce senescence-mediated dormancy. We find that loss of p53 can reverse SOX2-induced senescence, in line with the dormant cell state exit of the SOX2+ cells observed in advanced tumours. Finally, SOX2 expression is induced by 5-FU treatment in CRC. SOX2-expressing organoids exhibit increased tolerance to chemotherapy treatment, whilst deletion of SOX2 in AKPT tumour organoids sensitises drug responses. We propose that SOX2-induced plasticity and reversible dormancy promotes tumour progression and drug tolerance in CRC.