SMAD4 and neoplasm: At later stages of carcinogenesis, 2 critical tumour suppressors are inactivated, TP53 and SMAD4. 4,5 However, efforts to decode PDAC heterogeneity and the consequent guiding of therapeutic selection remain a challenge.6, 7, 8, 9 Epigenetic profiling can identify PDAC subtypes and distinguish metastatic lesions from primary tumours, within the same patient.10