We speculate that DTLL seems to act as a module of the SMAD4 driver that normalizes its function as a tumor suppressor according to SMAD4 protein level and genetic status in PDAC, and then adjusts NF-κB, TRIM33, gemcitabine-metabolic enzymes (such as RRM2) and proteomic profiles of PDAC cells, which explains the synergistic effect on tumor growth of DTLL in combination with gemcitabine. The gene discussed is SMAD4; the disease is neoplasm.