An NFATc1/SMAD3/cJUN Complex Restricted to SMAD4-Deficient Pancreatic Cancer Guides Rational Therapies.

MEK inhibition NFATc1 Pancreatic Cancer RRM1/2 Stratification

Journal

Gastroenterology
ISSN: 1528-0012
Titre abrégé: Gastroenterology
Pays: United States
ID NLM: 0374630

Informations de publication

Date de publication:
31 Oct 2023
Historique:
received: 13 02 2023
revised: 19 09 2023
accepted: 21 10 2023
pubmed: 2 11 2023
medline: 2 11 2023
entrez: 1 11 2023
Statut: aheadofprint

Résumé

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 Transcriptomic and clinical data were analyzed to determine the prognostic relevance of SMAD4 Our findings determined the tumor biology of an aggressive and chemotherapy-resistant SMAD4 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.

Sections du résumé

BACKGROUND & AIMS OBJECTIVE
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
METHODS METHODS
Transcriptomic and clinical data were analyzed to determine the prognostic relevance of SMAD4
RESULTS RESULTS
Our findings determined the tumor biology of an aggressive and chemotherapy-resistant SMAD4
CONCLUSIONS 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.

Identifiants

DOI: 10.1053/j.gastro.2023.10.026 PMID: 37913894
pubmed: 37913894
pii: S0016-5085(23)05202-2
doi: 10.1053/j.gastro.2023.10.026
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Informations de copyright

Copyright © 2023 AGA Institute. Published by Elsevier Inc. All rights reserved.

Auteurs

Marie C 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, New York; Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, New York.

Denise Schlösser (D)

Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Goettingen, Goettingen, Germany.

Lennart Versemann (L)

Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Goettingen, Goettingen, Germany.

Geske E 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.

Maria 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.

Joana 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.

Zhe 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.

Feda Hamdan (F)

Gene Regulatory Mechanisms and Molecular Epigenetics Laboratory, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.

Harry 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.

Waltraut 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.

Jessica 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.

Christin 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.

Carolin Schneider (C)

Department of General, Visceral and Pediatric Surgery, University Medical Center Goettingen, Goettingen, Germany.

Kristina Reutlinger (K)

Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Goettingen, Goettingen, Germany.

Sankari 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, UK.

Benjamin Steuber (B)

Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Goettingen, Goettingen, Germany.

Stephen A 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.

Carmine F 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.

Jennifer Appelhans (J)

Clinical Research Unit KFO5002, University Medical Center Goettingen, Goettingen, Germany; Institute of Pathology, University Medical Center Goettingen, Goettingen, Germany.

Hanibal Bohnenberger (H)

Institute of Pathology, University Medical Center Goettingen, Goettingen, Germany.

Jovan Todorovic (J)

Clinical Research Unit KFO5002, University Medical Center Goettingen, Goettingen, Germany; Institute of Pathology, University Medical Center Goettingen, Goettingen, Germany.

Irina Kostyuchek (I)

Institute of Pathology, University Medical Center Goettingen, Goettingen, Germany.

Philipp Ströbel (P)

Clinical Research Unit KFO5002, University Medical Center Goettingen, Goettingen, Germany; Institute of Pathology, University Medical Center Goettingen, Goettingen, Germany.

Aiko Bockelmann (A)

Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Goettingen, Goettingen, Germany.

Alexander König (A)

Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Goettingen, Goettingen, Germany.

Christoph 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.

Laura 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.

Silke Kaulfuß (S)

Clinical Research Unit KFO5002, University Medical Center Goettingen, Goettingen, Germany; Institute of Human Genetics, University Medical Center Goettingen, Goettingen, Germany.

Bernd 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 Goettingen, Germany.

Stephan A Hahn (SA)

Ruhr University Bochum, Faculty of Medicine, Department of Molecular Gastrointestinal Oncology, Bochum, Germany.

Albrecht 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.

Shiv K 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.

Holger 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.

Maximilian 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 between Deutsches Krebsforschungszentrum and University Hospital Klinikum Rechts der Isar), Munich, Germany; Center for Protein Assemblies, Technical University of Munich, Garching, Germany; Center for Organoid Systems and Tissue Engineering, Technical University Munich, Garching, Germany.

Ulrich Sax (U)

Clinical Research Unit KFO5002, University Medical Center Goettingen, Goettingen, Germany; Department of Medical Informatics, University Medical Center Goettingen, Goettingen, Germany.

Kenneth P 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.

Steven A Johnsen (SA)

Department of General, Visceral and Pediatric Surgery, University Medical Center Goettingen, Goettingen, Germany; Robert Bosch Center for Tumor Diseases, Stuttgart, Germany.

Günter 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, Germany.

Volker 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, Germany.

Elisabeth 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, Germany. Electronic address: elisabeth.hessmann@med.uni-goettingen.de.

Classifications MeSH