Journal article

Deep profiling of apoptotic pathways with mass cytometry identifies a synergistic drug combination for killing myeloma cells

Charis E Teh, Jia-Nan Gong, David Segal, Tania Tan, Cassandra J Vandenberg, Pasquale L Fedele, Michael SY Low, George Grigoriadis, Simon J Harrison, Andreas Strasser, Andrew W Roberts, David CS Huang, Garry P Nolan, Daniel HD Gray, Melissa E Ko

Cell Death & Differentiation | NATURE PUBLISHING GROUP | Published : 2020

Abstract

Multiple myeloma is an incurable and fatal cancer of immunoglobulin-secreting plasma cells. Most conventional therapies aim to induce apoptosis in myeloma cells but resistance to these drugs often arises and drives relapse. In this study, we sought to identify the best adjunct targets to kill myeloma cells resistant to conventional therapies using deep profiling by mass cytometry (CyTOF). We validated probes to simultaneously detect 26 regulators of cell death, mitosis, cell signaling, and cancer-related pathways at the single-cell level following treatment of myeloma cells with dexamethasone or bortezomib. Time-resolved visualization algorithms and machine learning random forest models (RFM..

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Grants

Awarded by Australian NHMRC Early Career Fellowship


Awarded by NHMRC/RACP Gus Nossal PhD scholarship


Awarded by Australian NHMRC Fellowships


Awarded by Australian NHMRC Senior Principal Research Fellowship


Awarded by National Cancer Institute of the National Institutes of Health


Awarded by Northrop-Grumman Corporation


Awarded by Cancer Council of Victoria


Awarded by NHRMC


Awarded by Leukemia and Lymphoma Society



Funding Acknowledgements

CET is supported by an Australian NHMRC Early Career Fellowship (1089072) and a Fulbright Australia-America Postdoctoral Fellowship. PLF is supported by a Leukaemia Foundation of Australia Clinical PhD Scholarship. MSYL is supported by a NHMRC/RACP Gus Nossal PhD scholarship (1075151). GPN is supported by the Rachford and Carlotta A. Harris Endowed Chair. DHDG is supported by Australian NHMRC Fellowships (1090236 and 1158024). AS is supported by an Australian NHMRC Senior Principal Research Fellowship (1020363). MEK is supported by the National Cancer Institute of the National Institutes of Health under Award Number F99CA212231 and Stanford University's Diversifying Academia, Recruiting Excellence Fellowship. This work was supported by grants to GPN: U19 AI057229, 1U19AI100627, Department of Defense (CDMRP), Northrop-Grumman Corporation, R01CA184968, 1R33CA183654-01, R33CA183692, R01CA184968, 1R21CA183660, 1R01NS08953304, OPP1113682, 5UH2AR067676, 1R01CA19665701, R01HL120724; grants to DHDG: Cancer Council of Victoria Grants-in-Aid (1146518 and 1102104); grants to AWR/DCSH: NHRMC (1113577, 1016701, 1079560); grants to AS: Leukemia and Lymphoma Society SCOR 7001-13, NHMRC program grant 1016701. This work was made possible through Victorian State Government Operational Infrastructure Support and Australian Government NHMRC IRIISS. The authors thank Prof. Silvia Plevritis (Stanford University) for advice and critical discussions, Dr Andrew Mitchell (University of Melbourne) for assistance with mass cytometry maintenance/operation, Chris Riffkin (WEHI) for assistance with cell culture and Assoc. Prof Grant Dewson for assistance with densitometric analysis of western blot data. This work was performed in part at the Materials Characterization and Fabrication Platform (MCFP) at the University of Melbourne and the Victorian Node of the Australian National Fabrication Facility (ANFF) with support from the Victorian Comprehensive Cancer Centre.