SMAD4 and colorectal adenoma: To improve our understanding of the EGF–LGR5 axis for human colorectal adenoma progression, further studies could be performed in a primary organoid culture system where the stepwise accumulation of genetic mutations essential for colorectal transformation (e.g., APC, KRAS, P53, SMAD4) can be controlled (Drost et al, 2015; Matano et al, 2015).