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An NFATc1/SMAD3/cJUN Complex Restricted to SMAD4-Deficient Pancreatic Cancer Guides Rational Therapies.
Hasselluhn, Marie C; Schlösser, Denise; Versemann, Lennart; Schmidt, Geske E; Ulisse, Maria; Oschwald, Joana; Zhang, Zhe; Hamdan, Feda; Xiao, Harry; Kopp, Waltraut; Spitalieri, Jessica; Kellner, Christin; Schneider, Carolin; Reutlinger, Kristina; Nagarajan, Sankari; Steuber, Benjamin; Sastra, Stephen A; Palermo, Carmine F; Appelhans, Jennifer; Bohnenberger, Hanibal; Todorovic, Jovan; Kostyuchek, Irina; Ströbel, Philipp; Bockelmann, Aiko; König, Alexander; Ammer-Herrmenau, Christoph; Schmidleitner, Laura; Kaulfuß, Silke; Wollnik, Bernd; Hahn, Stephan A; Neesse, Albrecht; Singh, Shiv K; Bastians, Holger; Reichert, Maximilian; Sax, Ulrich; Olive, Kenneth P; Johnsen, Steven A; Schneider, Günter; Ellenrieder, Volker; Hessmann, Elisabeth.
Afiliação
  • Hasselluhn MC; Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Goettingen, Goettingen, Germany; Department of Medicine, Division of Digestive and Liver Diseases, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, N
  • Schlösser D; Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Goettingen, Goettingen, Germany.
  • Versemann L; Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Goettingen, Goettingen, Germany.
  • Schmidt GE; Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Goettingen, Goettingen, Germany; Clinical Research Unit KFO5002, University Medical Center Goettingen, Goettingen, Germany.
  • Ulisse M; Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Goettingen, Goettingen, Germany; Clinical Research Unit KFO5002, University Medical Center Goettingen, Goettingen, Germany.
  • Oschwald J; Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Goettingen, Goettingen, Germany; Clinical Research Unit KFO5002, University Medical Center Goettingen, Goettingen, Germany.
  • Zhang Z; Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Goettingen, Goettingen, Germany; Clinical Research Unit KFO5002, University Medical Center Goettingen, Goettingen, Germany.
  • Hamdan F; Gene Regulatory Mechanisms and Molecular Epigenetics Laboratory, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
  • Xiao H; Department of Medicine, Division of Digestive and Liver Diseases, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York; Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, New York.
  • Kopp W; Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Goettingen, Goettingen, Germany; Clinical Research Unit KFO5002, University Medical Center Goettingen, Goettingen, Germany.
  • Spitalieri J; Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Goettingen, Goettingen, Germany; Clinical Research Unit KFO5002, University Medical Center Goettingen, Goettingen, Germany.
  • Kellner C; Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Goettingen, Goettingen, Germany; Clinical Research Unit KFO5002, University Medical Center Goettingen, Goettingen, Germany.
  • Schneider C; Department of General, Visceral and Pediatric Surgery, University Medical Center Goettingen, Goettingen, Germany.
  • Reutlinger K; Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Goettingen, Goettingen, Germany.
  • Nagarajan S; Manchester 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, United Kingdom.
  • Steuber B; Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Goettingen, Goettingen, Germany.
  • Sastra SA; Department of Medicine, Division of Digestive and Liver Diseases, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York; Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, New York.
  • Palermo CF; Department of Medicine, Division of Digestive and Liver Diseases, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York; Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, New York.
  • Appelhans J; Clinical Research Unit KFO5002, University Medical Center Goettingen, Goettingen, Germany; Institute of Pathology, University Medical Center Goettingen, Goettingen, Germany.
  • Bohnenberger H; Institute of Pathology, University Medical Center Goettingen, Goettingen, Germany.
  • Todorovic J; Clinical Research Unit KFO5002, University Medical Center Goettingen, Goettingen, Germany; Institute of Pathology, University Medical Center Goettingen, Goettingen, Germany.
  • Kostyuchek I; Institute of Pathology, University Medical Center Goettingen, Goettingen, Germany.
  • Ströbel P; Clinical Research Unit KFO5002, University Medical Center Goettingen, Goettingen, Germany; Institute of Pathology, University Medical Center Goettingen, Goettingen, Germany.
  • Bockelmann A; Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Goettingen, Goettingen, Germany.
  • König A; Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Goettingen, Goettingen, Germany.
  • Ammer-Herrmenau C; Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Goettingen, Goettingen, Germany; Clinical Research Unit KFO5002, University Medical Center Goettingen, Goettingen, Germany.
  • Schmidleitner L; Medical Clinic and Polyclinic II, Klinikum Rechts der Isar, Technical University Munich, Munich, Germany; Translational Pancreatic Research Cancer Center, Medical Clinic and Polyclinic II, Klinikum Rechts der Isar, Technical University Munich, Munich, Germany.
  • Kaulfuß S; Clinical Research Unit KFO5002, University Medical Center Goettingen, Goettingen, Germany; Institute of Human Genetics, University Medical Center Goettingen, Goettingen, Germany.
  • Wollnik B; Clinical Research Unit KFO5002, University Medical Center Goettingen, Goettingen, Germany; Institute of Human Genetics, University Medical Center Goettingen, Goettingen, Germany; Cluster of Excellence Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells, University of Goetti
  • Hahn SA; Ruhr University Bochum, Faculty of Medicine, Department of Molecular Gastrointestinal Oncology, Bochum, Germany.
  • Neesse A; Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Goettingen, Goettingen, Germany; Clinical Research Unit KFO5002, University Medical Center Goettingen, Goettingen, Germany.
  • Singh SK; Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Goettingen, Goettingen, Germany; Clinical Research Unit KFO5002, University Medical Center Goettingen, Goettingen, Germany.
  • Bastians H; Clinical Research Unit KFO5002, University Medical Center Goettingen, Goettingen, Germany; Department of Molecular Oncology, Section for Cellular Oncology, University Medical Center Goettingen, Goettingen, Germany.
  • Reichert M; Medical Clinic and Polyclinic II, Klinikum Rechts der Isar, Technical University Munich, Munich, Germany; Translational Pancreatic Research Cancer Center, Medical Clinic and Polyclinic II, Klinikum Rechts der Isar, Technical University Munich, Munich, Germany; German Cancer Consortium (a partnership
  • Sax U; Clinical Research Unit KFO5002, University Medical Center Goettingen, Goettingen, Germany; Department of Medical Informatics, University Medical Center Goettingen, Goettingen, Germany.
  • Olive KP; Department of Medicine, Division of Digestive and Liver Diseases, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York; Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, New York.
  • Johnsen SA; Department of General, Visceral and Pediatric Surgery, University Medical Center Goettingen, Goettingen, Germany; Robert Bosch Center for Tumor Diseases, Stuttgart, Germany.
  • Schneider G; Clinical Research Unit KFO5002, University Medical Center Goettingen, Goettingen, Germany; Department of General, Visceral and Pediatric Surgery, University Medical Center Goettingen, Goettingen, Germany; Comprehensive Cancer Center, Lower Saxony, Goettingen and Hannover, Germany.
  • Ellenrieder V; Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Goettingen, Goettingen, Germany; Clinical Research Unit KFO5002, University Medical Center Goettingen, Goettingen, Germany; Comprehensive Cancer Center, Lower Saxony, Goettingen and Hannover, Germa
  • Hessmann E; Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Goettingen, Goettingen, Germany; Clinical Research Unit KFO5002, University Medical Center Goettingen, Goettingen, Germany; Comprehensive Cancer Center, Lower Saxony, Goettingen and Hannover, Germa
Gastroenterology ; 166(2): 298-312.e14, 2024 Feb.
Article em En | MEDLINE | ID: mdl-37913894
ABSTRACT
BACKGROUND &

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 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 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 determined 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 normalizes RRM1/2 expression and synergizes with gemcitabine treatment in vivo to reduce the proliferative index.

CONCLUSIONS:

Our results suggest that PDAC characterized by SMAD4 deficiency and oncogenic NFATc1/SMAD3/cJUN complex formation exposes sensitivity to a mitogen-activated protein kinase signaling inhibition and gemcitabine combination therapy.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias Pancreáticas / Carcinoma Ductal Pancreático Idioma: En Ano de publicação: 2024 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias Pancreáticas / Carcinoma Ductal Pancreático Idioma: En Ano de publicação: 2024 Tipo de documento: Article