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

• Published in: Cell reports (Cambridge) Vol. 43; no. 5; p. 114202
• Main Authors: Shrestha, Hridaya, Rädler, Patrick D., Dennaoui, Rayane, Wicker, Madison N., Rajbhandari, Nirakar, Sun, Yunguang, Peck, Amy R., Vistisen, Kerry, Triplett, Aleata A., Beydoun, Rafic, Sterneck, Esta, Saur, Dieter, Rui, Hallgeir, Wagner, Kay-Uwe
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 28-05-2024; Elsevier
• Subjects: Animals; Carcinoma, Pancreatic Ductal - genetics; Carcinoma, Pancreatic Ductal - metabolism; Carcinoma, Pancreatic Ductal - pathology; CCAAT-Enhancer-Binding Protein-delta - genetics; CCAAT-Enhancer-Binding Protein-delta - metabolism; CEBPD; Cell Line, Tumor; CP: Cancer; Disease Progression; gene targeting; Humans; Janus kinase 1; Janus Kinase 1 - genetics; Janus Kinase 1 - metabolism; Mice; Mice, Knockout; pancreatic cancer; pancreatic neoplasms; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; PDAC; phosphorylation; RNA sequencing; Signal Transduction; STAT proteins; STAT3 Transcription Factor - metabolism; transcription factor; transgenic; tyrosine kinase; RNA sequencing; transcription factor; CEBPD; signal transduction; pancreatic neoplasms; tyrosine kinase; gene targeting; Janus kinase 1; mice; pancreatic cancer; PDAC; CP: Cancer; transgenic; humans; phosphorylation; STAT proteins
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2024.114202

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.
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•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•C/EBPδ executes pro-tumorigenic functions of JAK1/STAT signaling
Shrestha et al. demonstrate that JAK1 is a key signaling mediator of cytokines that promote mutant KRAS-induced pancreatic cancer initiation and progression. They provide experimental evidence that deficiency in JAK1 prevents tumor formation, and they identified C/EBPδ as a critical downstream effector of the pro-tumorigenic functions of JAK1/STAT signaling.