Fibrin Stiffness Regulates Phenotypic Plasticity of Metastatic Breast Cancer Cells
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A1 Alkuperäisartikkeli tieteellisessä aikakauslehdessä
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Date
2023-12-15
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en
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Advanced Healthcare Materials, Volume 12, issue 31
Abstract
The extracellular matrix (ECM)-regulated phenotypic plasticity is crucial for metastatic progression of triple negative breast cancer (TNBC). While ECM faithful cell-based models are available for in situ and invasive tumors, such as cell aggregate cultures in reconstituted basement membrane and in collagenous gels, there are no ECM faithful models for metastatic circulating tumor cells (CTCs). Such models are essential to represent the stage of metastasis where clinical relevance and therapeutic opportunities are significant. Here, CTC-like DU4475 TNBC cells are cultured in mechanically tunable 3D fibrin hydrogels. This is motivated, as in circulation fibrin aids CTC survival by forming a protective coating reducing shear stress and immune cell-mediated cytotoxicity and promotes several stages of late metastatic processes at the interface between circulation and tissue. This work shows that fibrin hydrogels support DU4475 cell growth, resulting in spheroid formation. Furthermore, increasing fibrin stiffness from 57 to 175 Pa leads to highly motile, actin and tubulin containing cellular protrusions, which are associated with specific cell morphology and gene expression patterns that markedly differ from basement membrane or suspension cultures. Thus, mechanically tunable fibrin gels reveal specific matrix-based regulation of TNBC cell phenotype and offer scaffolds for CTC-like cells with better mechano-biological properties than liquid.Description
Funding Information: N. and J.K. contributed equally to this work. The work was funded by grants from the Academy of Finland's Flagship Program under Projects No. 318890 and 318891 (Competence Center for Materials Bioeconomy, FinnCERES), the Academy of Finland Center of Excellence Program in Life‐Inspired Hybrid Materials (No. 346108, LIBER), the Academy of Finland Project Funding (BioBase, No. 352900), the Academy of Finland Photonics Research and Innovation flagship (No. 320167, PREIN), Business Finland R2B funding (2489/31/2017, Preclinica), and ERC‐Advanced grant (No. 680083, DRIVEN). J. Klefström acknowledges the Academy of Finland, Cancer Foundation Finland, the Sigrid Juselius Foundation, Finnish Cancer Institute (FCI), Jane and Aatos Erkko Foundation, and RESCUER project, which has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No. 847912. This work was also supported by the Office of the Assistant Secretary of Defense for Health Affairs through the Breast Cancer Research Program under Award No. W81XWH2110773. Opinions, interpretations, conclusions, and recommendations are those of the author and are not necessarily endorsed by the Department of Defense. J. Pokki acknowledges funding from Instrumentarium Science foundation and Aalto University Seed Funding. The authors acknowledge the Biomedicum Functional Genomics Unit (FuGU) for their high‐quality genome profiling services and the Biomedicum Imaging Unit (BIU) and OtaNano – Aalto Nanomicroscopy Centre (Aalto‐NMC) facilities for the microscopy support. The authors thank POLYMERS group at University of Helsinki for provision of facilities for bulk rheological measurements, Dr. Peter Engelhardt for technical assistance in SEM sample preparation and Babette Hollmann for technical assistance in RNA extraction. Publisher Copyright: © 2023 The Authors. Advanced Healthcare Materials published by Wiley-VCH GmbH.
Keywords
3D cell culture, circulating tumor cells, fibrin hydrogels, metastasis, phenotypic plasticity, triple negative breast cancer
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Heilala, M, Lehtonen, A, Arasalo, O, Peura, A, Pokki, J, Ikkala, O, Nonappa, Klefström, J & Munne, P M 2023, ' Fibrin Stiffness Regulates Phenotypic Plasticity of Metastatic Breast Cancer Cells ', Advanced Healthcare Materials, vol. 12, no. 31, 2301137 . https://doi.org/10.1002/adhm.202301137