Associate Professor Matthias Ernst

Details

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Division: Cell Signalling and Cell Death

Research Overview

The major focus of the laboratory is to dissect molecular mechanisms linking inflammation to tumour development.

The premise is that tumour promotion is often facilitated through interactions between tumour cells and the highly abundant inflammatory molecules and cells within the tumour microenvironment.

Although the molecular mechanisms that drive this tumour promotion may vary among different solid cancers, these mechanisms converge in tumour cells on the shared transcription factors NFκB and Stat3 to promote survival and, in the case of the Stat3, to also facilitate tumour proliferation, invasion, blood vessel growth and metabolic switches.

The cytokine and cell signalling molecule interleukin (IL)-11 is readily detected in many inflammation-associated diseases, including colon and gastric cancers. The lab recently established a novel link whereby IL-11, through its shared gp130 receptor and Stat3 signaling, promotes tumourigenesis. Gastric and colitis-associated colon cancers are exaggerated in models where excessive Stat3 activation mimics the smoldering inflammation observed in corresponding human diseases.

These molecules are potential therapeutic targets for inflammation-associated cancers. Tumour maintenance is susceptible to treatment with Stat3 or IL-11 antagonists. The physical proximity between IL-11-producing cells and the responding neoplastic epithelium makes IL-11 an attractive target for novel therapeutic targets in inflammation-associated (gastrointestinal) cancers. Our recent findings also reveal that tumours ‘addicted’ to continuous gp130 signalling become susceptible to orthogonal intervention with inhibitors of the PI3K/mTorc1 pathway, suggesting a gate-keeper role for the latter in inflammation-associated malignancies.

The laboratory is also therapeutically exploiting differences in signalling threshold requirements between normal and neoplastic cells. For instance, oncogenic activation of the Wnt/beta-catenin signaling cascade, which often comprises cooperating genetic and/or epigenetic events, is the most common tumour-initiating hallmark in neoplastic intestinal stem cells for sporadic colorectal cancer. Since interference with the gp130/Stat3 signalling cascades limits the expansion of such intestinal (cancer) stem cells, the Stat3-mediated non-oncogene addiction dependency can be therapeutically targeted in Wnt-dependent tumorigenesis or in regenerative medicine.

Research Interests

  • Stat3 and NFkB-dependent molecular mechanisms that link inflammation to tumour progression
  • Permissive signalling thresholds in tissue homeostasis and disease
  • Therapeutic exploiting of non-oncogene addiction pathways in gastrointestinal cancer

Selected Publications

  1. Jenkins BJ, Grail D, Nheu T, Najdovska M, Wang B, Waring P, Inglese M, McLoughlin RM, Simon A. Jones SA, Topley N, Baumann H, Judd LM, Giraud AS, Boussioutas A, Zhu, H-J and Ernst M. Hyperactivation of Stat3 in gp130 mutant mice promotes gastric hyperproliferation and desensitizes TGF-β signaling. Nature Medicine 2005 Aug;11(8):845-52. PMID 16041381
  2. Stumhofer JS, Laurence A, Wilson EH, Huang E, Tato CM, Johnson LM, Villarino AV, Huang Q, Yoshimura A, Sehy D, Saris CJM, O’Shea JJ, Hennighausen L, Ernst M and Hunter CA. Interleukin 27 negatively regulates development of interleukin 17-producing T helper 17 cells during chronic CNS inflammation. Nature Immunology 2006 Sep;7(9):937-45. PMID 16906166
  3. Stumhofer JS, Silver J, Laurence A, Porrett PM, Turka LA, Saris CJM, Hennighausen L, Ernst M, O′Shea JJ and Hunter CA. A central role for Interleukin 27 mediated activation of STAT1 and STAT3 in T cell production of IL-10. Nature Immunology 2007 Dec;8(12):1363-71. PMID 17994025
  4. Ernst M, Najdovska M, Grail D, Lundgren-May T, Matthews VB, Buchert M, Armes J, Bhathal PS, Hughes NR, Marcusson EG, Na S, Sedgwick JD, Hertzog PJ and Jenkins BJ. Functional cooperation between Stat1 and Stat3 in IL-11-dependent gastric tumourigenesis in gp130 mutant mice. The Journal of Clinical Investigation 2008 May;118(5):1727-38. PMID 18431520
  5. Bollrath J, Phesse TJ, Daerr VA, Putoczki T, Bennecke M, Bateman T, Nebelsiek T, Lundgren-May T, Canli Ö, Schwitalla S, Matthews V, Schmid RM, Kirchner T, Arkan MC, Ernst M and Greten FR. gp130-mediated Stat3 activation in enterocytes regulates cell survival and cell cycle progression during colitis-associated tumorigenesis. Cancer Cell 2009 Feb 3;15(2):91-102. PMID 19185844
  6. Samuel MS, Suzuki H, Buchert M, Putoczki TL, Tebbutt NC, Lundgren-May T, Christou A, Inglese M, Toyota M, Heath JK, Ward RL, Waring PM and Ernst M. Elevated Dnmt3a activity promotes polyposis in ApcMin mice by relaxing extracellular restraints on Wnt signaling. Gastroenterology 2009 Sep;137(3):902-13, 913.e1-11. PMID 19454286
  7. Buchert M, Athineos D, Abud HE, Burke ZD, Faux MC, Samuel MS, Jarnicki AG, Winbanks CE, Newton I, Meniel VS, Suzuki H, Stacker SA, Näthke IS, Tosh D, Huelsken J, Clarke AR, Heath JK, Sansom OJ and Ernst M. Genetic dissection of differential signaling threshold requirements for the Wnt/β-catenin pathway in vivo. PLoS Genetics 2010 Jan 15;6(1):e1000816. PMID 20084116
  8. Jarnicki A, Putoczki T and Ernst M. Stat3: linking inflammation to epithelial cancer – more than a “gut” feeling? Cell Division 2010 May 17;5:14. PMID 20478049
  9. Cao Y, DePinho R, Ernst M and Vousden K. Cancer research: past, present and future. Nature Reviews Cancer 2011 Sep 15;11(10):749-54. PMID 21918542
  10. O’Donoghue RJJ, Knight DA, Lau HL, Jarnicki AG, Richards CD, Prêle CM, Jones J, Bozinovski S, Vlahos R, Thiem S, McKenzie BS, Wang B, Stumbles P, Laurent GJ, McAnulty RJ, Rose-John S, Zhu HJ, Anderson GP, Ernst M and Mutsaers SE. Genetic partitioning of interleukin-6 signalling in mice dissociates Stat3 from Smad3 mediated lung fibrosis. EMBO Molecular Medicine 2012 Sep;4(9):939-51. PMID 22684844

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Current Laboratory Members

Faculty Member: Matthias Ernst BSc(Hons) Zurich PhD Zurich

Senior Postdoctoral Fellow: Tracy Putoczki BSc(Hons) Toronto PhD Canterbury

Senior Postdoctoral Fellow: Michael Buchert PhD Zurich

Senior Postdoctoral Fellow: Toby Phesse BSc(Hons) Portsmouth PhD Warwick

Postdoctoral Fellow: Robert O’Donoghue BSc(Hons) Murdoch BCom UWA PhD UWA

Postdoctoral Fellow: Emma Stuart BSc(Hons) Otago PhD Otago

Postdoctoral Fellow: Moritz Eissmann MSc Technical PhD Frankfurt

Postdoctoral Fellow: Tom Pierce BSc(Hons) Melbourne PhD Melbourne

Postdoctoral Fellow: Stefan Thiem MB Cologne BBiology Darmstadt PhD Melbourne

Postgraduate Student: Ashleigh Poh BSc(Hons) Melbourne

Postgraduate Student: Paul Nguyen BBiomedSc(Hons) Melbourne

Research Technician: Adele Preaudet ASc VUT

Research Technician: Ryan Farid BCh UWA