Subcellular localization of biomolecules and drug distribution by high-definition ion beam imaging

Xavier Rovira-Clavé, Sizun Jiang, Yunhao Bai, Bokai Zhu, Graham Barlow, Salil Bhate, Ahmet F. Coskun, Guojun Han, Chin-Min Kimmy Ho, Chuck Hitzman, Shih-Yu Chen, Felice-Alessio Bava and Garry P. Nolan ()
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Xavier Rovira-Clavé: Stanford University
Sizun Jiang: Stanford University
Yunhao Bai: Stanford University
Bokai Zhu: Stanford University
Graham Barlow: Stanford University
Salil Bhate: Stanford University
Ahmet F. Coskun: Stanford University
Guojun Han: Stanford University
Chin-Min Kimmy Ho: Stanford University
Chuck Hitzman: Stanford University
Shih-Yu Chen: Stanford University
Felice-Alessio Bava: Stanford University
Garry P. Nolan: Stanford University

Nature Communications, 2021, vol. 12, issue 1, 1-18

Abstract: Abstract Simultaneous visualization of the relationship between multiple biomolecules and their ligands or small molecules at the nanometer scale in cells will enable greater understanding of how biological processes operate. We present here high-definition multiplex ion beam imaging (HD-MIBI), a secondary ion mass spectrometry approach capable of high-parameter imaging in 3D of targeted biological entities and exogenously added structurally-unmodified small molecules. With this technology, the atomic constituents of the biomolecules themselves can be used in our system as the “tag” and we demonstrate measurements down to ~30 nm lateral resolution. We correlated the subcellular localization of the chemotherapy drug cisplatin simultaneously with five subnuclear structures. Cisplatin was preferentially enriched in nuclear speckles and excluded from closed-chromatin regions, indicative of a role for cisplatin in active regions of chromatin. Unexpectedly, cells surviving multi-drug treatment with cisplatin and the BET inhibitor JQ1 demonstrated near total cisplatin exclusion from the nucleus, suggesting that selective subcellular drug relocalization may modulate resistance to this important chemotherapeutic treatment. Multiplexed high-resolution imaging techniques, such as HD-MIBI, will enable studies of biomolecules and drug distributions in biologically relevant subcellular microenvironments by visualizing the processes themselves in concert, rather than inferring mechanism through surrogate analyses.

Date: 2021
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DOI: 10.1038/s41467-021-24822-1

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