Contribution of proteases to oral cancer pain and metastasis

Researcher

Project Details

Oral squamous cell carcinoma is the most common head and neck cancer. Many patients with oral cancer experience severe pain that profoundly interferes with their quality of life. Treatments for this pain are currently limited to opioid drugs, which are not suitable for long-term use due to side effects such as sedation and constipation.

Oral cancer often spreads to cervical lymph nodes, and once this metastasis occurs, patient survival rates drop below 40%. Current methods to predict the spread of oral cancer are ineffective; thus, most patients undergo radical elective neck dissection to remove all cervical lymph nodes prior to the appearance of metastatic lesions.

In collaboration with Professor Brian Schmidt, an oral cancer surgeon at the New York University College of Dentistry, our group is investigating the mechanisms by which proteases mediate oral cancer pain and metastasis.  Our approach is multifaceted, and examines protease function in tumour and associated immune cells in vitro, in mouse models of oral cancer, and in clinical samples derived from oral cancer patients.

The overarching goals of this project are to establish proteases as biomarkers for diagnosing oral cancer, as prognostic markers for cervical metastasis, and as drug targets for the treatment of oral cancer pain and prevention of metastasis.

histology section showing elevated protease in murine oral squamous cell carcinoma
Figure 1: Protease expression is elevated in murine oral squamous cell carcinoma.

Researchers

Bethany Anderson, PhD Student

Bangyan Xu, Honours Student

Collaborators

Professor Brian Schmidt, New York University College of Dentistry, USA

Professor Nigel Bunnett, Columbia University, USA

Funding

NHMRC Peter Doherty Early Career Fellowship (2015-2018)

Grimwade Research Fellowship (2018-2022)

ARC DECRA Fellowship (2019-2021)

Research Publications

  1. Edgington-Mitchell LE, Bogyo M, Verdoes M.  Live cell imaging and profiling of cysteine cathepsin activity using a quenched activity-based probe. Methods in Molecular Biology 2017; In Press.
  2. Duivenvoorden HM, Rautela J, Edgington-Mitchell LE, Spurling A, Greening DW, Nowell CJ, Lolloy TJ, Robbins E, Huang P, Brockwell NK, Faou P, Lee CS, Chen M, Holliday A, Selinger CI, Hu M, Britt KL, Stroud DA, Bogyo M, Moller A, Polyak K, Sloane BF, O’Toole SA, Parker BS.  Myoepithelial cell-specific expression of stefin A as a suppressor of early breast cancer invasion. J Path 2017; 243(4): 496-509.
  3. Edgington-Mitchell LE, Barlow N, Aurelio L, Samha A, Szabo M, Graham B, Bunnett NW.  Fluorescent diphenylphosphonate-based probes for detection of serine protease activity during inflammation. Bioorg Med Chem Lett 2017; 27(2): 254-260.
  4. Edgington-Mitchell LE, Wartmann T, Fleming AK, Gocheva V, van der Linden WA, Withana NP, Verdoes M, Aurelio L, Edgington-Mitchell D, Lieu T, Parker BS, Graham B, Reinheckel T, Furness JB, Joyce JA, Storz P, Halangk W, Bogyo M, Bunnett NW.  Legumain is activated in macrophages during pancreatitis. Am J Physiol Gastrointest Liver Physiol 2016; 311(3): G548-60.
  5. Lieu TM, Savage E, Zhao P, Edgington-Mitchell LE, Barlow N, Bron R, Poole D, McLean P, Lohman R, Fairlie D, Bunnet NW. Antagonism of the proinflammatory and pronociceptive actions of canonical and biased agonists of protease-activated receptor 2. British J Pharmacol 2016; 173(18): 2752-65.
  6. Edgington-Mitchell LE.  Pathophysiological roles for proteases in gastrointestinal disease. Am J Physiol Gastrointest Liver Physiol 2016; 310(4): G234-9.
  7. Edgington-Mitchell LE, Rautela J, Duivenvoorden HM, Jayatilleke KM, van der Linden W, Verdoes M, Bogyo M, Parker BS.  Cysteine Cathepsin Activity Suppresses Osteoclastogenesis of Myeloid-Derived Suppressor Cells in Breast Cancer. Oncotarget 2015; 6(29): 27008-22.
  8. Edgington LE, Verdoes M, Ortega A, Withana NP, Lee J, Syed S, Bachmann MH, Blum G, Bogyo M. Functional imaging of legumain in cancer using a new quenched activity-based probe. J Am Chem Soc 2013; 135(1): 174-82.
  9. Edgington LE, Bogyo M.  In vivo imaging and biochemical characterization of protease function using fluorescent activity-based probes. Curr Protoc Chem Biol  2013; 5(1): 25-44.
  10. Edgington LE, van Raam BJ, Verdoes M, Wierschem C, Salvesen GS, Bogyo M.  An optimized activity-based probe for the study of caspase-6 activation. Chem Biol  2012; 19: 340-352.
  11. Verdoes M, Edgington LE, Scheeren FA, Leyva M, Blum G, Weiskopf K, Bachmann MH, Ellman JA, Bogyo M.  A nonpeptidic cathepsin s activity-based probe for noninvasive optical imaging of tumor-associated macrophages. Chem Biol  2012; 19: 619-628. 22.25.
  12. Edgington LE, Verdoes M, Bogyo M.  Functional imaging of proteases: recent advances in the design and application of substrate-based and activity-based probes. Curr Opin Chem Biol 2011; 15: 798-805.
  13. Edgington LE, Berger AB, Blum G, Albrow VE, Paulick MG, Lineberry N, Bogyo M.  Noninvasive optical imaging of apoptosis by caspase-targeted activity-based probes. Nat Med 2009; 15: 967-973.

Research Group

Edgington-Mitchell laboratory: Protease Pathophysiology



Faculty Research Themes

Infection and Immunology, Cancer

School Research Themes

Infection & Immunity, Cancer in Biomedicine, Molecular Mechanisms of Disease, Therapeutics & Translation



Key Contact

For further information about this research, please contact the research group leader.

Department / Centre

Biochemistry and Molecular Biology

Unit / Centre

Edgington-Mitchell laboratory: Protease Pathophysiology


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