The Janus kinase 1 is critical for pancreatic cancer initiation and progression

Hridaya Shrestha; Patrick D Rädler; Rayane Dennaoui; Madison N Wicker; Nirakar Rajbhandari; Yunguang Sun; Amy R Peck; Kerry Vistisen; Aleata A Triplett; Rafic Beydoun; Esta Sterneck; Dieter Saur; Hallgeir Rui; Kay-Uwe Wagner

doi:10.1016/j.celrep.2024.114202

The Janus kinase 1 is critical for pancreatic cancer initiation and progression

Cell Rep. 2024 May 10;43(5):114202. doi: 10.1016/j.celrep.2024.114202. Online ahead of print.

Authors

Affiliations

¹ Department of Oncology, Wayne State University School of Medicine and Tumor Biology Program, Barbara Ann Karmanos Cancer Institute, Detroit, MI 48201, USA.
² Department of Oncology, Wayne State University School of Medicine and Tumor Biology Program, Barbara Ann Karmanos Cancer Institute, Detroit, MI 48201, USA; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA.
³ Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA.
⁴ Department of Pathology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
⁵ Department of Pharmacology, Physiology & Cancer Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
⁶ Department of Oncology, Wayne State University School of Medicine and Tumor Biology Program, Barbara Ann Karmanos Cancer Institute, Detroit, MI 48201, USA; Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, USA.
⁷ Laboratory of Cell and Developmental Signaling, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA.
⁸ Division of Translational Cancer Research, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany; Translational Cancer Research and Institute of Experimental Cancer Therapy, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
⁹ Department of Oncology, Wayne State University School of Medicine and Tumor Biology Program, Barbara Ann Karmanos Cancer Institute, Detroit, MI 48201, USA. Electronic address: kuwagner@wayne.edu.

PMID: 38733583
DOI: 10.1016/j.celrep.2024.114202

Abstract

Interleukin-6 (IL-6)-class inflammatory cytokines signal through the Janus tyrosine kinase (JAK)/signal transducer and activator of transcription (STAT) pathway and promote the development of pancreatic ductal adenocarcinoma (PDAC); however, the functions of specific intracellular signaling mediators in this process are less well defined. Using a ligand-controlled and pancreas-specific knockout in adult mice, we demonstrate in this study that JAK1 deficiency prevents the formation of KRAS^G12D-induced pancreatic tumors, and we establish that JAK1 is essential for the constitutive activation of STAT3, whose activation is a prominent characteristic of PDAC. We identify CCAAT/enhancer binding protein δ (C/EBPδ) as a biologically relevant downstream target of JAK1 signaling, which is upregulated in human PDAC. Reinstating the expression of C/EBPδ was sufficient to restore the growth of JAK1-deficient cancer cells as tumorspheres and in xenografted mice. Collectively, the findings of this study suggest that JAK1 executes important functions of inflammatory cytokines through C/EBPδ and may serve as a molecular target for PDAC prevention and treatment.

Keywords: CEBPD; CP: Cancer; Janus kinase 1; PDAC; RNA sequencing; STAT proteins; gene targeting; humans; mice; pancreatic cancer; pancreatic neoplasms; phosphorylation; signal transduction; transcription factor; transgenic; tyrosine kinase.