Project Details
Projekt
Causes and consequences of SMAD4- and TGFβ-regulated PDAC genome instability
Applicant
Professor Dr. Holger Bastians
Subject Area
Gastroenterology
Term
since 2020
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 426671079
Pancreatic ductal adenocarcinoma (PDAC) is characterized by genome instability and shows high levels of chromosomal instability (CIN), which is closely associated with tumour progression and therapy resistance. SMAD4 is a tumour suppressor that is frequently lost in PDAC. In the first funding period of the CRU5002 we found that loss of SMAD4 causes CIN. Mechanistically, we uncovered that SMAD4 acts as part of BMP signaling to induce transcription of ID3, thereby suppressing genome instability. Intriguingly, we found that loss of SMAD4 or ID3 causes impaired homologous recombination (HR) DNA repair and DNA replication stress, conditions frequently seen in human cancer and known to be associated with genome instability. Moreover, we found that replication stress triggers subsequent mitotic errors leading to chromosome missegregation and aneuploidy and this requires non-SMAD TGFβ signaling. Thus, we discovered yet unrecognized functions of SMAD4 important to prevent genome instability and a functional coupling between BMP-SMAD4 and TGFβ signaling important for genome stability. In the second funding period of the CRU5002 we will investigate the mechanisms of how the SMAD4-ID3 axis regulates DNA repair and replication stress and how impairment of this pathway causes mitotic errors via TGFβ signaling. For these studies, we will take advantage of PDAC patient-derived CDX cells and PDOs established by the CRU5002. We will further define the nature and extent of genome instability that is caused by loss of SMAD4-ID3 in PDAC, both on a chromosomal and nucleotide level. Finally, we will investigate the role of the cellular defects and CIN caused by loss of SMAD4/ID3 in determining therapy responses towards conventional treatment regimens and we will explore specific therapeutic vulnerabilities caused by HR repair defects, replication stress and mitotic errors in SMAD4/ID3-deficient PDACs.
DFG Programme
Clinical Research Units
