Although the roles of elastic components in breast cancer progression have been widely studied, the importance of matrix dissipative elements in regulating breast cancer behavior is still poorly understood. In this study, we designed viscosity-tunable fluidic substrates to investigate the effects of matrix viscosity on the alteration of breast cancer cellular fate using a hydrophobic molten polymer of poly(ε-caprolactone-co-D,L-lactide) [P(CL-co-DLLA)] with different levels of fluidity. The high- and low-fluidity substrates used in this study were shown to behave as viscoelastic liquids at physiological temperature. A nonmetastatic breast cancer cell line (MCF-7) was cultured at the interface of the fibronectin-coated substrate, and its behavior towards the substrate fluidity level was thoroughly characterized. Despite fibronectin-mediated cell-substrate interactions, MCF-7 cells show sensitivity to substrate fluidity levels by forming types aggregates of different sizes and structures over time. Accordingly, MCF-7 cells were undergoing senescence on fluidic substrates, as shown by high metabolic activity over time, suppressed proliferation ability, and positive expression of senescence markers. Moreover, senescence implies more resistance towards anticancer drug treatment. This indicates that a fluidic substrate, as a two-dimensional synthetic matrix system, could demonstrate the importance of mechanical cues in redefining cellular function and cellular fate by changing the viscosity of the pure substrate.
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Oskarsson T. Extracellular matrix components in breast cancer progression and metastasis. Breast. 2013;22:566–72. https://doi.org/10.1016/j.breast.2013.07.012.
Lee J, Chaudhuri O. Regulation of breast cancer progression by extracellular matrix mechanics: insights from 3D culture models. ACS Biomater Sci Eng.2018;4:302–13. https://doi.org/10.1021/acsbiomaterials.7b00071.
Papalazarou V, Salmeron-Sanchez M, Machesky LM. Tissue engineering the cancer microenvironment-challenges and opportunities. Biophys Rev. 2018;10:1695–711. https://doi.org/10.1007/s12551-018-0466-8.
Walker C, Mojares E, del Río Hernández A. Role of extracellular matrix in development and cancer progression. Int J Mol Sci. 2018;19:3028 https://doi.org/10.3390/ijms19103028.
Muncie JM, Weaver VM. The physical and biochemical properties of the extracellular matrix regulate cell fate. Curr Top Dev Biol. 2018;130:1–37. https://doi.org/10.1016/bs.ctdb.2018.02.002.
Frantz C, Stewart KM, Weaver VM. The extracellular matrix at a glance. J Cell Sci. 2010;123:4195–200. https://doi.org/10.1242/jcs.023820.
Devi CU, Chandran RB, Vasu RM, Sood AK. Measurement of visco-elastic properties of breast-tissue mimicking materials using diffusing wave spectroscopy. J Biomed Opt. 2007;12:034035 https://doi.org/10.1117/1.2743081.
Chaudhuri PK, Low BC, Lim CT. Mechanobiology of tumor growth. Chem Rev. 2018;118:6499–515. https://doi.org/10.1021/acs.chemrev.8b00042.
Charrier EE, Pogoda K, Wells RG, Janmey PA. Control of cell morphology and differentiation by substrates with independently tunable elasticity and viscous dissipation. Nat Commun. 2018;9:449 https://doi.org/10.1038/s41467-018-02906-9.
Murrell M, Kamm R, Matsudaira P. Substrate viscosity enhances correlation in epithelial sheet movement. Biophys J. 2011;101:297–306. https://doi.org/10.1016/j.bpj.2011.05.048.
Gonzalez-Molina J, Zhang X, Borghesan M, da Silva JM, Awan M, Fuller B. et al. Extracellular fluid viscosity enhances liver cancer cell mechanosensing and migration. Biomaterials . 2018;177:113–24. https://doi.org/10.1016/j.biomaterials.2018.05.058.
Cantini M, Donnelly H, Dalby MJ, Salmeron‐Sanchez M. The plot thickens: the emerging role of matrix viscosity in cell mechanotransduction. Adv Healthcare Mater. 2019. https://doi.org/10.1002/adhm.201901259.
Poh PSP, Hege C, Chhaya MP, Balmayor ER, Foehr P, Burgkart RH, et al. Evaluation of polycaprolactone−poly-D,L-lactide copolymer as biomaterial for breast tissue engineering. Polym Int. 2017;66:77–84. https://doi.org/10.1002/pi.5181.
Mano SS, Uto K, Aoyagi T, Ebara M. Fluidity of biodegradable substrate regulates carcinoma cell behavior: a novel approach to cancer therapy. AIMS Mater Sci. 2016;3:66–82. https://doi.org/10.3934/matersci.2016.1.66.
Mano SS, Uto K, Ebara M. Material-induced senescence (MIS): fluidity induces senescent type cell death of lung cancer cells via insulin-like growth factor binding protein 5. Theranostics. 2017;7:4658–70. https://doi.org/10.7150/thno.20582.
Uto K, Mano SS, Aoyagi T, Ebara M. Substrate fluidity regulates cell adhesion and morphology on poly (ε-caprolactone)-based materials. ACS Biomater Sci Eng. 2016;2:446–53. https://doi.org/10.1021/acsbiomaterials.6b00058.
Uto K, Muroya T, Okamoto M, Tanaka H, Murase T, Ebara M, et al. Design of super-elastic biodegradable scaffolds with longitudinally oriented microchannels and optimization of the channel size for Schwann cell migration. Sci Technol Adv Mater. 2012;13:064207. https://doi.org/10.1088/1468-6996/13/6/064207.
Dzhoyashvili NA, Thompson K, Gorelov AV, Rochev YA. Film thickness determines cell growth and cell sheet detachment from spin-coated poly(N‑Isopropylacrylamide) substrates. ACS Appl Mater Interfaces. 2016;8:27564–572. https://doi.org/10.1021/acsami.6b09711.
Buxboim A, Rajagopal K, Brown AE, Discher DE. How deeply cells feel: methods for thin gels. J Condens. 2010;22:194116. https://doi.org/10.1088/0953-8984/22/19/194116.
Chaudhuri PK, Pan CQ, Low BC, Lim CT. Differential depth sensing reduces cancer cell proliferation via rho-rac-regulated invadopodia. ACS Nano. 2017;11:7336–48. https://doi.org/10.1021/acsnano.7b03452.
Chester D, Kathard R, Nortey J, Nellenbach K, Brown AC. Viscoelastic properties of microgel thin films control fibroblast modes of migration and pro-fibrotic responses. Biomaterials. 2018;185:371–82. https://doi.org/10.1016/j.biomaterials.2018.09.012.
Bennett M, Cantini M, Reboud J, Cooper JM, Roca-Cusachs P, Salmeron-Sanchez M. Molecular clutch drives cell response to surface viscosity. PNAS. 2018;115:1192–7. https://doi.org/10.1073/pnas.1710653115.
Kourouklis AP, Lerum RV, Bermudez H. Cell adhesion mechanisms on laterally mobile polymer films. Biomaterials. 2014;35:4827–34. https://doi.org/10.1016/j.biomaterials.2014.02.052.
Zheng JY, Han SP, Chiu YJ, Yip AK, Boichat N, Zhu SW, et al. Epithelial monolayers coalesce on a viscoelastic substrate through redistribution of vinculin. Biophys J. 2017;113:1585–98. https://doi.org/10.1016/j.bpj.2017.07.027.
Bell S, Terentjev EM. Focal adhesion kinase: the reversible molecular mechanosensor. Biophys J. 2017;112:2439–50. https://doi.org/10.1016/j.bpj.2017.04.048.
Gorgoulis V, Adams PD, Alimonti A, Bennett DC, Bischof O, Bishop C, et al. Cellular senescence: defining a path forward. Cell. 2019;179:813–27. https://doi.org/10.1016/j.cell.2019.10.005.
Zhang W, Choi DS, Nguyen YH, Chang J, Qin L. Studying cancer stem cell dynamics on PDMS surfaces for microfluidics device design. Sci Rep. 2013;3:2332. https://doi.org/10.1038/srep02332.
The authors would like to express their gratitude to the Grants-in-Aid for Scientific Research (B) (19H04476) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) Japan. The authors are grateful to Allan S. Hoffman (University of Washington) for continued and valuable discussion.
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Najmina, M., Uto, K. & Ebara, M. Fluidic substrate as a tool to probe breast cancer cell adaptive behavior in response to fluidity level. Polym J 52, 985–995 (2020). https://doi.org/10.1038/s41428-020-0345-6