Even for the paradigmatic Wnt‐driven CRC, it has been proposed that while high TCF/Wnt activity sustains tumor initiation, aggressive metastatic CRCs establish a Wnt‐low but Hedgehog‐high gene expression signature, and inhibition of TCF activity is undesirable (Varnat et al., 2010). The gene discussed is HNF4A; the disease is colorectal carcinoma.