SMAD4 and neoplasm: However, studies using genetically engineered mice show that pancreas-specific SMAD4 deficiency does not initiate either PanIN or invasive PDAC; SMAD4 loss markedly promotes tumor progression initiated by KRASG12D activating mutation, indicating that blockade of TGF-β signaling and activation of Ras signaling cooperate to promote PDAC progression [135,136].