Role of Jak/Stat Signaling in Pancreas Development and the Initiation and Progression of Pancreatic Cancer

Overview

The project explores the pivotal role of Janus kinase 1 (JAK1) in the initiation and progression of pancreatic cancer. This research utilizes advanced genetic models, including conditional knockout mice, to dissect the contributions of JAK1 to pancreatic ductal adenocarcinoma (PDAC). By employing a combination of genetic, molecular, and cellular techniques, the study aims to elucidate the mechanistic roles of JAK1 in cancer cell signaling and tumor microenvironment interactions.

Overall, the project seeks to validate JAK1 as a therapeutic target in PDAC, offering new insights into its role in cancer biology. By understanding how JAK1 influences various signaling pathways and cellular behaviors in the context of pancreatic cancer, this research could lead to the development of targeted therapies that inhibit JAK1-mediated processes. The ultimate goal is to contribute to the development of more effective treatment strategies that can improve survival and quality of life for patients suffering from this aggressive cancer.

Graphic illustration of the dual recombinase approach to coactivate oncogenic KRAS from its engineered endogenous locus (FSF-Kras^G12D) and tamoxifen-inducible Cre recombinase (Cre^ERT2) in pancreatic cells expressing the Pdx1-Flp transgene. The administration of tamoxifen (Tam) facilitates the conditional knockout of JAK1 in a ligand-inducible and temporally controlled manner. This feature allows the deletion of JAK1 in adolescent and adult mice independent of the initiation of KRAS^G12D-induced tumorigenesis. Expression of GFP from the Cre/lox reporter transgene (CAG-LSL-GFP) can be used to monitor the Flpmediated expression and functionality of CreERT2 following the administration of Tam.

Key Findings

JAK1 deficiency prevents the formation of high-grade preneoplasia and pancreatic tumors.

Pancreatic cancer cells expressing active STAT3 have a higher propensity to metastasize.

JAK1 is a key signaling node for STAT3, STAT1, and STAT6 activation in cancer cells.

CCAAT/enhancer binding protein δ (C/EBPδ) executes pro-tumorigenic functions of JAK1/STAT signaling.

Low-magnification images of H&E-stained histologic sections of pancreata highlighting the widespread differences in the histopathology between a JAK1 conditional knockout (Jak1^fl/fl + Tam) and a JAK1 expressing control animal (Jak1^fl/wt + Tam) at 1 year of age, bars, 500 μm.

Left: representative immunofluorescent (IF) images of normal and pancreatic tumor tissues co-stained for tyrosine phosphorylated STAT3 (pSTAT3) and pan-cytokeratin (panCK). Right: IF staining of C/EBPδ (CEBPD) in the normal human pancreas and pancreatic ductal adenocarcinoma (PDAC).

For a detailed exploration of the role of Jak1 in pancreatic ductal adenocarcinoma (PDAC), please refer to our publication in Cell Reports, where a substantial amount of relevant information is included in the supplementary figures. As part of this project, our research has uncovered significant and noteworthy roles of JAK/STAT signaling in the postnatal development of the exocrine pancreas and in the development of pancreatitis in adult mice. We are in the process of preparing a manuscript to report these findings.

References

2024

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

Hridaya Shrestha, Patrick D Rädler, Rayane Dennaoui, and 8 more authors

Cell Reports, 2024

Abs HTML PDF

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 KRASG12D-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.

2021

Cancer Metastasis R...

Models of pancreatic ductal adenocarcinoma

Rayane Dennaoui, Hridaya Shrestha, and Kay-Uwe Wagner

Cancer and Metastasis Reviews, 2021

Abs HTML PDF

Although pancreatic cancer remains to be a leading cause of cancer-related deaths in many industrialized countries, there have been major advances in research over the past two decades that provided a detailed insight into the molecular and developmental processes that govern the genesis of this highly malignant tumor type. There is a continuous need for the development and analysis of preclinical and genetically engineered pancreatic cancer models to study the biological significance of new molecular targets that are identified using various genome-wide approaches and to better understand the mechanisms by which they contribute to pancreatic cancer onset and progression. Following an introduction into the etiology of pancreatic cancer, the molecular subtypes, and key signaling pathways, this review provides an overview of the broad spectrum of models for pancreatic cancer research. In addition to conventional and patient-derived xenografting, this review highlights major milestones in the development of chemical carcinogen-induced and genetically engineered animal models to study pancreatic cancer. Particular emphasis was placed on selected research findings of ligand-controlled tumor models and current efforts to develop genetically engineered strains to gain insight into the biological functions of genes at defined developmental stages during cancer initiation and metastatic progression.