An NFATc1/SMAD3/cJUN complex restricted to SMAD4-deficient pancreatic cancer guides rational therapies
AffiliationManchester Breast Centre and Manchester Cancer Research Centre, Division of Molecular and Cellular Function, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK.
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AbstractBackground and aims: The highly heterogeneous cellular and molecular makeup of pancreatic ductal adenocarcinoma (PDAC) not only fosters exceptionally aggressive tumor biology but contradicts the current concept of one size fits all therapeutic strategies to combat PDAC. Therefore, we aimed to exploit the tumor biological implication and the therapeutic vulnerabilities of a clinically relevant molecular PDAC subgroup characterized by SMAD4 deficiency and high expression of the Nuclear Factor of Activated T-cells (SMAD4-/-/NFATc1High). Methods: Transcriptomic and clinical data were analyzed to determine the prognostic relevance of SMAD4-/-/NFATc1High cancers. In vitro and in vivo oncogenic transcription factor complex formation was studied by immunoprecipitation, proximity ligation assays, and validated cross model and species. The impact of the SMAD4 status on therapeutically targeting canonical KRAS signaling was mechanistically deciphered and corroborated by genome-wide gene expression analysis and genetic perturbation experiments, respectively. Validation of a novel tailored therapeutic option was conducted in patient-derived organoids and cells and transgenic as well as orthotopic PDAC models. Results: Our findings determine the tumor biology of an aggressive and chemotherapy-resistant SMAD4-/-/NFATc1High subgroup. Mechanistically, we identify SMAD4 deficiency as a molecular prerequisite for the formation of an oncogenic NFATc1/SMAD3/cJUN transcription factor complex, which drives the expression of RRM1/2. RRM1/2 replenishes nucleoside pools that directly compete with metabolized gemcitabine for DNA strand incorporation. Disassembly of the NFATc1/SMAD3/cJUN complex by mitogen-activated protein kinase signaling inhibition (MEKi) normalizes RRM1/2 expression and synergizes with gemcitabine treatment in vivo to reduce the proliferative index. Conclusion: Our results suggest that PDAC characterized by SMAD4 deficiency and oncogenic NFATc1/SMAD3/cJUN complex formation exposes sensitivity to a MEKi/gemcitabine combination therapy.
CitationHasselluhn MC, Schlösser D, Versemann L, Schmidt GE, Ulisse M, Oschwald J, et al. An NFATc1/SMAD3/cJUN complex restricted to SMAD4-deficient pancreatic cancer guides rational therapies. Gastroenterology. 2023 Oct 30. PubMed PMID: 37913894. Epub 2023/11/02. eng.