Using genetically defined mouse models of pancreatic cancer in a KRAS and TP53 mutant background, Whittle et al. showed that a heterozygous deletion of SMAD4 leads to locally aggressive disease when tumoral expression levels of runt-related transcription factor 3 (RUNX3) are low, but to extensive metastatic spread when RUNX3 levels are high, similarly as in the situation of SMAD4 homozygous deletion [22]. Here, KRAS is linked to familial pancreatic carcinoma.