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Cytokine Receptor Laboratory

Cytokine Receptor Laboratory

Research Program Overview:

Cancer is primarily a signalling disease that arises as a consequence of errors in the signalling road maps used by cells in the different organs of the human body.  Our laboratory focusses on identifying the signalling mistakes responsible for causing some blood cell diseases such as acute myeloid leukaemia and myeloproliferative neoplasms, and some solid cancers such as breast cancer. As one of the processes underpinning cancer is chronic inflammation, our lab also focusses on how blood cell activation can be restrained, particularly in the lung (asthma) and the upper respiratory tract (nasal polyposis).

Our work is made possible thanks to our established close collaborations with our pathology consultant colleagues and scientists in SA Pathology, clinical colleagues at the Royal Adelaide Hospital, and colleagues at the University of Adelaide, UniSA and SAHMRI.

As we generate new insights into the causes of cancer and the underlying inflammatory processes, we continue to translate these into the development of new diagnostics and potential new treatments in collaboration with the international pharmaceutical industry such as CSL.

Our vision is that a deep understanding of the errors of cell signalling in cancer and in chronic inflammation is the key to optimal long term clinical management of disease and potentially the development of cures.

Current Research Projects:

  • Biasing cell signalling by the engineering of novel biologics;
  • Structural, molecular and signalling characterisation of the IL-5 receptor and it’s function in the upper and lower respiratory tracts;
  • Establishing the transcriptional programs that determine cell fate in haemopoiesis and leukaemia;
  • A novel, neoepitope-directed strategy to selectively eliminate pathogenic clones in young adults with myelofibrosis;
  • Harnessing the tumour microenvironment to better diagnose and treat breast cancer.

Recent Publications:

  1. Tvorogov D, Thomas D, Liau NPD, Dottore M, Barry E, Lathi M, Kan W, Hercus TR, Stomski F, Hughes TP, Tergaonkar V, Parker MW, Ross DM, Majeti R, Babon JJ, LOPEZ AF. Accumulation of JAK activation-loop phosphorylation is linked to Type I JAK inhibitor withdrawal syndrome in myelofibrosis. Science Advances, 4(11), 2018 Nov 28;4(11):eaat3834 DOI: 1126/sciadv.aat3834
  2. Cildir G, Toubia J, Yip KH, Zhou M, Pant H, Hissaria P, Zhang J, Hong W, Robinson, N, Grimbaldeston M, LOPEZ AF, Tergaonkar V. “Genome-wide analyses of chromatin state in human mast cells reveals molecular drivers and mediators of allergic and inflammatory diseases”. Immunity, 2019 Nov 19;51(5):949-965.e6 1016/j.immuni.2019.09.021
  3. Yip KH, Wilson NJ, Pant H, Brown CL, Busfield S, Ng M, Alhamdoosh M, Woodman N, Schembri M, Tumes DJ, Vairo G, LOPEZ AF, Nash AD, Wilson MJ, Grimbaldeston MA, Owczarek CM. “Anti-βc mAb CSL311 inhibits human nasal polyp pathophysiology in a humanized mouse xenograft model”. Allergy, 2020 Feb;75(2):475-478
  4. Boyle ST, Poltavets V, Kular J, Pyne NT, Sandow JJ, Lewis AC, Murphy KJ, Kolesnikoff N, Moretti PAB, Tea MN, Tergaonkar V, Timpson P, Pitson SM, Webb AI, Whitfield RJ, LOPEZ AF, Kochetkova M, Samuel MS. “ROCK-mediated Selective Activation of PERK Signalling Causes Fibroblast Reprogramming and Tumour Progression Through a CRELD2-dependent Mechanism”. Nature Cell Biology, 2020 Jul;22(7):882-895 org/10.1038/s41556-020-0523-y
  5. Kan, Winnie L. and Dhagat, Urmi and Hercus, Timothy R. and Kaufmann, Kerstin B. and Nero, Tracy L. and Zeng, Andy G. X. and Toubia, John and Barry, Emma F. and Broughton, Sophie E. and Gomez, Guillermo A. and Dottore, Mara and Cheung Tung Shing, Karen S. and Thomas, Daniel and Benard, Brooks and Simpson, Kaylene J. and Schoof, Erwin and Goodall, Gregory J. and Begley, C. Glenn and Ekert, Paul G. and Tvorogov, Denis and D'Andrea, Richard J. and Dick, John E. and Parker, Michael W. and LOPEZ, AF, “Distinct Assemblies of Heterodimeric Cytokine Receptors Govern Stemness Programs in Leukemia”. SSRN-id3707264, Cell Press, Sneak Peak, Posted 2020, 20 October
  6. Baroni ML, Sánchez-Martínez, D, Gutierrez-Agüera, F, Roca-Ho, H, Castella M, Zanetti SR, Velasco-Hernández T, Diaz de la Guardia R, Castaño J, Anguita E, Vives S, Nomdedeu JF, Lapillonne H, Bras AE, van der Velden VHJ, Junca J, LOPEZ AF, Sorigue M, Bueno C, Menéndez P. “41BB-based and CD28-based CD123 - redirected T-cells ablate human normal hematopoiesis in vivo”. Journal of Immunotherapy in Cancer, 2020 Jun;8(1):e000845 org/10.1136/jitc-2020-000845
  7. Cildir G, Yip K H, Pant H, Tergaonkar V, LOPEZ AF, and Tumes D, “Understanding mast cell heterogeneity at single cell resolution”, Trends in Immunology, 2021 Jun;42(6):523-535 1016/
  8. Begley G, Aston M, Baell J, Bettess M, Brown MP, Carter B, Charman WN, Davis C, Fisher S, Frazer I, Gautam A, Jennings MP, Kearney P, Keeffe E, Kelly D, LOPEZ AF, McGuckin M, Parker MW, Rayner C, Roberts B, Rush JS, Sullivan M, “Drug Repurposing: Misconceptions, Challenges and Opportunities facing Academic Researches”, Science Translational Medicine Manuscript, 2021 Sep 22;13(612):eabd5524. 1126/scitranslmed.abd5524
  9. Kan W, Cheung Tung Shing KS, Nero TL, Hercus TR, Tvorogov D, Parker MW, LOPEZ AF, “Messing with βc: a unique receptor with many goals”, Seminars in Immunology, 2021 Apr;54:101513. 1016/j.smim.2021.101513  
  10. Khawanky N, HughesA, Yu W, Myburgh R, Matschulla T, Taromi S, Aumann K, Clarson J, Vinnakota JM, Shoumariyeh K, Miething C, LOPEZ AF, Brown MP, Duyster J, Hein L, Manz, MG, Hughes TP, White DL, Yong ASM, Zeiser R, "Demethylating therapy increases anti-CD123 CAR T cell cytotoxicity against acute myeloid leukemia " Nature Communications, 2021 Nov 8;12(1):6436 1038/s41467-021-26683-0
  11. Yip KH, McKenzie D, Ramshaw HS, Chao J, McClure BJ, Raquet E, Kraushaar T, Röder J, Maxwell M, Alhamdoosh M, Hammet A, Fong JH, Zeglinski K, Monaghan K, Pant H, Grimbaldeston MA, Vairo G, Wilson NJ, Owczarek CM, Hercus TR, LOPEZ AF, Tumes DJ, “Targeting the human βc receptor inhibits contact dermatitis in a transgenic mouse model”, The Journal of Investigative Dermatology, 2022 Apr;142(4):1103-1113.e11 1016/j.jid.2021.07.183
  12. Tvorogov D, Thompson-Peach C, Foßelteder J, Dottore M, Stomski F, Onnesha S, Lim K, Moretti P, Pitson S, Ross D, Reinisch A, Thomas D, and LOPEZ AF, "Targeting human CALR mutated MPN progenitors with a neoepitope-directed monoclonal antibody", EMBO reports 2022 Apr 5;23(4):e52904 15252/embr.202152904
  13. Wang H, Tumes D, Hercus T, Yip K, Aloe C, Vlahos R, LOPEZ AF, Wilson N, Owczarek C, and Bozinovski S, "Blocking the human common β subunit of the GM-CSF, IL-5 and IL-3 receptors markedly reduces hyperinflammation in ARDS models", Cell Death and Disease 2022 Feb 10;13(2):137 1038/s41419-022-04589-z
  14. Brown G, Medhavy A, Canete P, Ellyard J, Bassett K, Burgio G, Zhang Y, Turnbull C, Meng X, Wu P, Cho V, Miosge L, Capello J, Andrews T, Field M, Tvorogov D, LOPEZ AF, He Y, Babon J, Lopez CA, Gonzalez-Murillo A, Pascual V, Levy T, Ding H, Shen N, Cook M, Mallack E, Collantes CL,  Athanasopoulos V, Wang H, Bones J, Shen Q, Roco J, Calame D, Lotze T, Lupski J, Ullah T, Gantier M,  Corry B, Qin Y, Vinuesa CG, “TLR7 gain-of-function genetic variation causes human lupus”, Biological Sciences – Article, Nature, 2022 May;605(7909):349-356 1038/s41586-022-04642-z