Multimodal Mass Spectrometry Imaging of an Osteosarcoma Multicellular Tumour Spheroid Model to Investigate Drug-Induced Response
Sophie M. Pearce,
Neil A. Cross,
David P. Smith,
Malcolm R. Clench,
Lucy E. Flint,
Gregory Hamm,
Richard Goodwin,
James I. Langridge,
Emmanuelle Claude,
Laura M. Cole
Affiliations
Sophie M. Pearce
Centre for Mass Spectrometry Imaging, Biomolecular Sciences Research Centre, Sheffield Hallam University, Howard Street, Sheffield S1 1WB, UK
Neil A. Cross
Centre for Mass Spectrometry Imaging, Biomolecular Sciences Research Centre, Sheffield Hallam University, Howard Street, Sheffield S1 1WB, UK
David P. Smith
Centre for Mass Spectrometry Imaging, Biomolecular Sciences Research Centre, Sheffield Hallam University, Howard Street, Sheffield S1 1WB, UK
Malcolm R. Clench
Centre for Mass Spectrometry Imaging, Biomolecular Sciences Research Centre, Sheffield Hallam University, Howard Street, Sheffield S1 1WB, UK
Lucy E. Flint
Imaging and Data Analytics, Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, The Discovery Centre (DISC), Biomedical Campus, 1 Francis Crick Ave, Trumpington, Cambridge CB2 0AA, UK
Gregory Hamm
Imaging and Data Analytics, Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, The Discovery Centre (DISC), Biomedical Campus, 1 Francis Crick Ave, Trumpington, Cambridge CB2 0AA, UK
Richard Goodwin
Imaging and Data Analytics, Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, The Discovery Centre (DISC), Biomedical Campus, 1 Francis Crick Ave, Trumpington, Cambridge CB2 0AA, UK
A multimodal mass spectrometry imaging (MSI) approach was used to investigate the chemotherapy drug-induced response of a Multicellular Tumour Spheroid (MCTS) 3D cell culture model of osteosarcoma (OS). The work addresses the critical demand for enhanced translatable early drug discovery approaches by demonstrating a robust spatially resolved molecular distribution analysis in tumour models following chemotherapeutic intervention. Advanced high-resolution techniques were employed, including desorption electrospray ionisation (DESI) mass spectrometry imaging (MSI), to assess the interplay between metabolic and cellular pathways in response to chemotherapeutic intervention. Endogenous metabolite distributions of the human OS tumour models were complemented with subcellularly resolved protein localisation by the detection of metal-tagged antibodies using Imaging Mass Cytometry (IMC). The first application of matrix-assisted laser desorption ionization–immunohistochemistry (MALDI-IHC) of 3D cell culture models is reported here. Protein localisation and expression following an acute dosage of the chemotherapy drug doxorubicin demonstrated novel indications for mechanisms of region-specific tumour survival and cell-cycle-specific drug-induced responses. Previously unknown doxorubicin-induced metabolite upregulation was revealed by DESI-MSI of MCTSs, which may be used to inform mechanisms of chemotherapeutic resistance. The demonstration of specific tumour survival mechanisms that are characteristic of those reported for in vivo tumours has underscored the increasing value of this approach as a tool to investigate drug resistance.
