Circadian Dysregulation of the TGFβ/SMAD4 Pathway Modulates Metastatic Properties and Cell Fate Decisions in Pancreatic Cancer Cells.

Impairment of circadian rhythms impacts carcinogenesis. a clock-controlled gene and central component of the TGFβ canonical pathway, is frequently mutated in pancreatic ductal adenocarcinoma (PDA), leading to decreased survival. Here, we used an PDA model of SMAD4-positive and SMAD4-negative cells to investigate the interplay between circadian rhythms, the TGFβ canonical signaling pathway, and its impact on tumor malignancy. Our data show that , and oscillate in a circadian fashion in SMAD4-positive PDA cells, whereas altering the clock impairs the mRNA dynamics of these genes. Furthermore, the expression of the clock genes , and varied depending on SMAD4 status. TGFβ pathway activation resulted in an altered clock, cell-cycle arrest, accelerated apoptosis rate, enhanced invasiveness, and chemosensitivity. Our data suggest that the impact of TGFβ on the clock is SMAD4-dependent, and , , and involved in this cross-talk affect PDA patient survival.