SMAD4 and neoplasm: Appearance of other mutations observed in human PDAC, including inactivation of the P16INK4A/P19ARF, TRP53, or SMAD4 tumor suppressors as well as activation of the Hedgehog signaling pathway, significantly accelerates tumor development leading to acquisition of a metastatic phenotype (Hingorani et al, 2005; Bardeesy et al, 2006; Ijichi et al, 2006; Pasca di Magliano et al, 2006).