HEY1 and cancer: In LCSCs, MAPK signalling was shown to be activated by intrinsic genetic alterations of tumour-suppressor proteins such as apoptosis-stimulating protein of p53 (ASPP2)68 or by extrinsic stimulation by growth factors such as hepatocyte growth factor (HGF) secreted by stromal cells.69 HGF secreted by cancer-associated fibroblasts (CAFs) transactivates the c-MET receptor and induces downstream MAPK signalling to activate FRA1-mediated transcription of hairy/enhancer-of-split related with YRPW motif 1 (HEY1) to support the cancer initiation properties in LCSCs.