Consistent with results from conventional knockout GEMMs16,18–20, Smad4 depletion (by continuous Dox administration starting at 5 weeks of age) promoted tumor initiation, shortened survival and led to the development of tumors that metastasize to the liver and, less frequently, to the lungs (Fig. 1b,c and Extended Data Fig. 1a). This evidence concerns the gene SMAD4 and neoplasm.