Multimodal Mechano-Microscopy Reveals Mechanical Phenotypes of Breast Cancer Spheroids in Three Dimensions

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Multimodal Mechano-Microscopy Reveals Mechanical Phenotypes of Breast Cancer Spheroids in Three Dimensions

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Author(s): Alireza Mowla ¹ ^, ² , Liisa M. Hirvonen ³ ^, , Matt S. Hepburn ¹ ^, ² ^, ⁴ , Jiayue Li ¹ ^, ² , Danielle Vahala ⁵ , Sebastian E. Amos ⁵ , Rowan W. Sanderson ¹ ^, ² , Philip Wijesinghe ⁶ , Samuel Maher ⁵ , Yu Suk Choi ⁵ , Brendan F. Kennedy ¹ ^, ² ^, ⁴

Publication date (Electronic): 21 January 2025

Conference name: 13th Asia Pacific Microscopy Congress 2025 (APMC13)

Conference date: 2-7 Febuary 2025

Keywords: multimodal microscopy, mechano-microscopy, breast cancer

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Abstract

Multicellular spheroids are a powerful model to study biochemical and biophysical interactions between cancer cells and the extracellular matrix (ECM). However, these three-dimensional (3D) tumour microenvironment (TME) models remain underutilised, because existing mechanical quantification tools are typically limited to surface measurements, and it is difficult to measure and co-register subcellular-scale elasticity with the morphology and function of living cells in a 3D microenvironment.

Here, we develop a multimodal mechano-microscopy system that integrates optical coherence microscopy-based elasticity imaging with confocal fluorescence microscopy. We use this multimodal microscope to quantify local mechanics of cancer cell spheroids in 3D TMEs.

Our multimodal mechano-microscopy setup integrates high-resolution interferometric detection of optical coherence microscopy (OCM), a high-resolution variant of optical coherence tomography (OCT), with compression elastography and confocal fluorescence microscopy.[ 1] The microscope was implemented as a Michelson interferometer, utilising a supercontinuum laser for OCM illumination, and two laser lines (405 & 488 nm) for fluorescence excitation. A 20X 0.75NA objective lens provides a lateral resolution of 0.5 µm, and OCM axial resolution of 1.4 µm. Scanning was achieved using a 2D galvanometer system. A spectrometer with a 2048-pixel line camera was used to detect the spectral interference for OCM measurements, while the fluorescence from the sample was focused into a multi-modal optical fibre, which also acted as the confocal pinhole, and recorded with a photomultiplier tube.

To test the setup, Young’s modulus of blank, soft and stiff gelatin methacryloyl (GelMA) samples was first measured and was found to be in good agreement with AFM surface measurement ( Fig 1b).

Fig 1:

Multimodal mechano-microscopy. (a) Schematic of the sample setup. (b) Young’s modulus of soft and stiff blank GelMA samples measured using mechano-microscopy (volumetric measurements) and AFM (surface measurements). (c) En face and (d) B-scan Young’s modulus of a non-metastatic cell spheroid over a 120x120 mm ² field-of-view. (e-g) Volumetric maps of non-metastatic cell spheroids acquired by multimodal mechano-microscopy, where (e) OCM SNR, (f) Young’s modulus, and (g) fluorescence labeled with nuclear (cyan) and membrane (red) fluorescent dyes. Yellow arrows indicate the same spheroid in (c), (d), and (f).

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Publication date (Electronic): 21 January 2025

Electronic Location Identifier: e168

Affiliations

[1 ]BRITElab, Harry Perkins Institute of Medical Research, QEII Medical Centre, Perth, WA, Australia

[2 ]Department of Electrical, Electronic & Computer Engineering, School of Engineering, The University of Western Australia, Perth, WA, Australia

[3 ]Centre for Microscopy, Characterisation & Analysis, The University of Western Australia, Perth, WA, Australia

[4 ]Institute of Physics, Faculty of Physics, Astronomy and Informatics, Nicolaus Copernicus University in Toruń, Torun, Poland

[5 ]School of Human Sciences, The University of Western Australia, Perth, WA, Australia

[6 ]Centre of Biophotonics, SUPA, School of Physics and Astronomy, University of St Andrews, St Andrews, UK

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*Corresponding author: liisa.hirvonen@ 123456uwa.edu.au

Article

DOI: 10.14293/APMC13-2025-0168

SO-VID: 57b04328-bf4d-4759-8029-d8d7c27645b9

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Published under Creative Commons Attribution 4.0 International ( CC BY 4.0). Users are allowed to share (copy and redistribute the material in any medium or format) and adapt (remix, transform, and build upon the material for any purpose, even commercially), as long as the authors and the publisher are explicitly identified and properly acknowledged as the original source.

Conference name: 13th Asia Pacific Microscopy Congress 2025

Conference acronym: APMC13

Conference number: 13

Conference location: Brisbane, Australia

Conference date: 2-7 Febuary 2025

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References

A Mowla et al, APL Bioeng 8 (2024), 036113. https://doi.org/10.1101/2024.04.05.588260
A Mowla et al, Opt Lett 47 (2022), 3303-3306. https://doi.org/10.1364/ol.451681

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[1] A Mowla et al, APL Bioeng 8 (2024), 036113. https://doi.org/10.1101/2024.04.05.588260

[2] A Mowla et al, Opt Lett 47 (2022), 3303-3306. https://doi.org/10.1364/ol.451681

Multimodal Mechano-Microscopy Reveals Mechanical Phenotypes of Breast Cancer Spheroids in Three Dimensions

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