Circadian Dysregulation of the TGFβ/SMAD4 Pathway Modulates Metastatic Properties and Cell Fate Decisions in Pancreatic Cancer Cells
Yin Li,
Alireza Basti,
Müge Yalçin,
Angela Relógio
Affiliations
Yin Li
Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt - Universität zu Berlin, and Berlin Institute of Health, Institute for Theoretical Biology, Berlin, Germany; Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt - Universität zu Berlin, and Berlin Institute of Health, Medical Department of Hematology, Oncology, and Tumour Immunology, Molecular Cancer Research Centre, Berlin, Germany
Alireza Basti
Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt - Universität zu Berlin, and Berlin Institute of Health, Institute for Theoretical Biology, Berlin, Germany; Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt - Universität zu Berlin, and Berlin Institute of Health, Medical Department of Hematology, Oncology, and Tumour Immunology, Molecular Cancer Research Centre, Berlin, Germany
Müge Yalçin
Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt - Universität zu Berlin, and Berlin Institute of Health, Institute for Theoretical Biology, Berlin, Germany; Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt - Universität zu Berlin, and Berlin Institute of Health, Medical Department of Hematology, Oncology, and Tumour Immunology, Molecular Cancer Research Centre, Berlin, Germany
Angela Relógio
Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt - Universität zu Berlin, and Berlin Institute of Health, Institute for Theoretical Biology, Berlin, Germany; Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt - Universität zu Berlin, and Berlin Institute of Health, Medical Department of Hematology, Oncology, and Tumour Immunology, Molecular Cancer Research Centre, Berlin, Germany; MSH Medical School Hamburg GmbH–University of Applied Sciences and Medical University, Department of Human Medicine, Institute for Systems Medicine and Bioinformatics, Hamburg, Germany; Corresponding author
Summary: Impairment of circadian rhythms impacts carcinogenesis. SMAD4, 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 in vitro 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 TGFβ1, SMAD3, SMAD4, and SMAD7 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 DEC1, DEC2, and CRY1 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 SMAD3, SMAD4, DEC1, and CRY1 involved in this cross-talk affect PDA patient survival.
