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Nearly two decades of research confirmed this role and revealed other divergent and cancer\u2010specific functions including paradoxical tumor promotion effects. Although Smad4 is the most potent tumor suppressor, its functions are highly context\u2010specific as exemplified by pancreatic cancer and head\u2010and\u2010neck cancer: in pancreatic cancer, Smad4 loss cannot initiate tumor formation but promotes metastases while in head\u2010and\u2010neck cancer Smad4 loss promotes cancer progression but also initiates tumor formation, likely through effects on genomic instability. 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