Cancer and Immune Signalling Research Group
Research Group Head
The projects undertaken in this group combine molecular biological and genetic approaches, together with human translational studies, to identify the mechanisms by which uncontrolled signal transduction from the interleukin (IL)-6 cytokine family, pattern recognition receptors (such as toll-like receptors) and inflammasomes lead to inflammation-associated cancers (stomach, lung, pancreatic) and emphysema/chronic obstructive pulmonary disease (COPD).
The IL-6 cytokine family plays an important role in maintaining homeostasis of various biological systems, including pulmonary function, the gastrointestinal tract, and immune/inflammatory responses. Furthermore, the deregulated over-production of IL-6 family cytokines is implicated in many human cancers, (stomach, lung, pancreatic, colon), inflammatory diseases (arthritis, inflammatory bowel disease), and emphysema/COPD. To identify how IL-6 family cytokines promote disease pathogenesis, Professor Jenkins’ team uses in vivo pre-clinical disease models in which specific signalling pathways downstream of IL-6 family cytokines are over-activated. Using this approach, they have demonstrated the broad pathological consequences of uncontrolled activation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) 3 pathway. While these studies demonstrate that STAT3 activated by specific members of this cytokine family promote cancer and chronic inflammatory responses, they have also uncovered that under certain situations the JAK/STAT3 pathway cross-talks with toll-like receptors and other pattern recognition receptors (including those linked to inflammasome activation) to drive disease.
- Role of Toll-like receptors in gastro-intestinal cancers
- Cross-talk between cytokine signalling pathways and inflammasomes in gastro-intestinal cancers
- Regulation of microRNAs by cytokine signalling pathways in gastro-intestinal cancers
- Role of IL-6 signalling pathways in emphysema (COPD) and lung cancer
Deswaerte V, Nguyen P, West A, Browning AF, Yu L, Ruwanpura SM, Balic J, Livis T, Girard C, Preaude A, Oshima H, Fung KY, Tye H, Najdovska M, Ernst M, Oshima M, Gabay C, Putoczki T, Jenkins BJ (2018) Inflammasome adaptor ASC suppresses apoptosis of gastric cancer cells by an IL-18 mediated inflammation-independent mechanism. Cancer Res 78:1293-1307.
Fielding CA, Jones GW, McLoughlin RM, McLeod L, Hammond VJ, Uceda J, Williams AS, Lambie M, Foster TL, Liao CT, Rice CM, Greenhill CJ, Colmont CS, Hams E, Coles B, Kift-Morgan A, Newton Z, Craig KJ, Williams JD, Williams GT, Davies SJ, Humphreys IR, O’Donnell VB, Taylor PR, Jenkins BJ, Topley N, Jones SA (2014) Interleukin-6 signaling drives fibrosis in unresolved inflammation. Immunity 40:40-50.
Kennedy CL, Najdovska M, Tye H, McLeod L, Yu L, Jarnicki A, Bhathal PS, Putoczki T, Ernst M, Jenkins BJ (2014) Differential role of MyD88 and Mal/TIRAP in TLR2-mediated gastric tumourigenesis. Oncogene 33:2540-2546.
Kennedy CL, Najdovska M, Tye H, McLeod L, Yu L, Jarnicki A, Bhathal PS, Putoczski T, Ernst M, Jenkins BJ (2014) Differential role of MyD88 and Mal/TIRAP in TLR2-mediated gastric tumourigenesis. Oncogene 33:2540-2546.
Yu L, Wu D, Gao H, Balic J, Tsykin A, Han T-S, Liu YD, Kennedy CL, Li JK, Mao JQ, Tan P, Oshima M, Goodall GJ, Jenkins BJ. (2018) Clinical utility of a STAT3-regulated microRNA-200 family signature with prognostic potential in early gastric cancer. Clin Cancer Res 24:1459-1472.
West A, Tang T, Tye H, Yu L, Deng N, Najdovska M, Lin SJ, Balic JJ, Okochi-Takada E, McGuirk P, Keogh B, McCormack W, Bhathal PS, Reilly M, Oshima M, Ushijima T, Tan P, Jenkins BJ (2017) Identification of a TLR2-regulated gene signature associated with tumor cell growth in gastric cancer. Oncogene 36:5134-5144
Berry W, Algar E, Kumar B, Desmond C, Swan M, Jenkins BJ*, Croagh D. (2017) Endoscopic ultrasound-guided fine-needle aspirate-derived preclinical pancreatic cancer models reveal panitumumab sensitivity in KRAS wild-type tumours. Int J Cancer 140:2331-2343. *Corresponding author
Brooks G, McLeod L, Alhayyani S, Miller A, Russell PA, Ferlin W, Rose-John S, Ruwanpura SM, Jenkins BJ. (2016) IL-6 trans-signaling promotes KRAS-driven lung carcinogenesis. Cancer Res 76:866-76.
Ruwanpura SM, McLeod L, Dousha LF, Seow HJ, Alhayyani S, Tate M, Deswaerte V, Brooks G, Bozinovski S, McDonald M, Garbers C, King PT, Bardin PG, Vlahos R, Rose-John S, Anderson GP, Jenkins BJ. (2016) Therapeutic targeting of the IL-6 trans-signaling/mTORC1 axis in pulmonary emphysema. Am J Respir Crit Care Med 194:1494-1505
Tye H, Kennedy CL, Najdovska M, McLeod L, McCormack W, Hughes N, Dev A, Sievert W, Ooi CH, Ishikawa TO, Oshima H, Bhathal PS, Parker AE, Oshima M, Tan P, Jenkins BJ (2012) STAT3-driven upregulation of TLR2 promotes gastric tumorigenesis independent of tumor inflammation. Cancer Cell 22:466-478.
Jenkins BJ, Grail D, Nheu T, Najdovska M, Wang B, Waring P, Inglese M, McLoughlin RM, Jones SA, Topley N, Baumann H, Judd LM, Giraud AS, Boussioutas A, Zhu HJ, Ernst M (2005) Hyperactivation of Stat3 in gp130 mutant mice promotes gastric hyperproliferation and desensitizes TGF-beta signaling. Nat Med 11:845-852.
Jones GW, Bombardieri M, Greenhill CJ, McLeod L, Rocher V, Williams AS, Pitzalis C, Jenkins BJ,* Jones SA* (2015) Interleukin-27 inhibits ectopic lymphoid-like structure development in early inflammatory arthritis. J Exp Med 212:1793-1802. *Equal contribution
Ernst M, Najdovska M, Grail D, Lundgren-May T, Buchert M, Tye H, Matthews VB, Armes J, Bhathal PS, Hughes NR, Marcusson EG, Karras JG, Na S, Sedgwick JD, Hertzog PJ, Jenkins BJ (2008) STAT3 and STAT1 mediate IL-11-dependent and inflammation-associated gastric tumorigenesis in gp130 receptor mutant mice. J Clin Invest 118:1727-1738.