Epithelial states in colorectal cancer are co-determined by YAP associated fetal programming and WNT signaling
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In the colonic epithelium, fetal programming is induced by Yes-associated protein (YAP) signaling, which is associated with tumorigenesis and progression in colorectal cancer (CRC). While CRC was long considered a WNT driven disease, here we show that fetal programmed cells with activated YAP signaling can arise independently of WNT activation. Fetal programmed cells, in the presence of hyper- or hypo-activated WNT, have different characteristics and are associated with poor relapse. Furthermore, using various mouse models, we demonstrated the conserved characteristics of two different fetal programmed cell states with different WNT activation, which can be switched from a hyperactivated to hypoactivated WNT state based on genetic alteration, particularly Kras mutation. Taken together, these data redefine the key determinants of epithelial cell states in colorectal cancer and integrate emerging preclinical biology into a robust landscape of states observed in human and mouse.
