TY - JOUR
T1 - Elucidating the role of matrix porosity and rigidity in glioblastoma type iv progression
AU - Pereira, Rui C.
AU - Santagiuliana, Raffaella
AU - Ceseracciu, Luca
AU - Boso, Daniela P.
AU - Schrefler, Bernhard A.
AU - Decuzzi, Paolo
N1 - Funding Information:
Funding: This research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Number U54CA210181. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This project was further supported by the European Research Council, under the European Union’s Seventh Framework Programme (FP7/2007–2013)/ERC grant agreement no. 616695, the AIRC (Italian Association for Cancer Research) under the individual investigator grant no. 17664 and by the Technical University of Munich— Institute for Advanced Study, funded by the German Excellence Initiative and the TÜV SÜD Foundation. D.P. Boso gratefully acknowledges the support from national funding under Grant DOR1718128.
Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2020/12/2
Y1 - 2020/12/2
N2 - The highly infiltrating nature of glioma cells is the major cause for the poor prognosis of brain malignancies. Motility, proliferation, and gene expression of cells in natural and synthetic gels have been analyzed by several authors, yet quantitative studies elucidating the role of matrix porosity and rigidity in the development of whole malignant masses are missing. Here, an experimental‐computational framework is introduced to analyze the behavior of U87‐MG cells and spheroids in compact hyaluronic acid gels (HA), replicating the brain parenchyma; and fibrous collagen gels (COL), resembling the organized structures of the brain. Experimentally it was observed that individual U87‐MG cells in COL assumed an elongated morphology within a few hours post inclusion (p.i.) and travelled longer distances than in HA. As spheroids, U87‐MG cells rapidly dispersed into COL resulting in infiltrating regions as large as tumor cores (≈600 μm, at 8 days p.i.). Conversely, cells in HA originated smaller and denser infiltrating regions (≈300 μm, at 8 days p.i.). Notably, COL tumor core size was only 20% larger than in HA, at longer time points. Computationally, by introducing for the first time the effects of matrix heterogeneity in our numerical simulations, the results confirmed that matrix porosity and its spatial organization are key factors in priming the infiltrating potential of these malignant cells. The experimental‐numerical synergy can be used to predict the behavior of neoplastic masses under diverse conditions and the efficacy of combination therapies simultaneously aiming at killing cancer cells and modulating the tumor microenvironment.
AB - The highly infiltrating nature of glioma cells is the major cause for the poor prognosis of brain malignancies. Motility, proliferation, and gene expression of cells in natural and synthetic gels have been analyzed by several authors, yet quantitative studies elucidating the role of matrix porosity and rigidity in the development of whole malignant masses are missing. Here, an experimental‐computational framework is introduced to analyze the behavior of U87‐MG cells and spheroids in compact hyaluronic acid gels (HA), replicating the brain parenchyma; and fibrous collagen gels (COL), resembling the organized structures of the brain. Experimentally it was observed that individual U87‐MG cells in COL assumed an elongated morphology within a few hours post inclusion (p.i.) and travelled longer distances than in HA. As spheroids, U87‐MG cells rapidly dispersed into COL resulting in infiltrating regions as large as tumor cores (≈600 μm, at 8 days p.i.). Conversely, cells in HA originated smaller and denser infiltrating regions (≈300 μm, at 8 days p.i.). Notably, COL tumor core size was only 20% larger than in HA, at longer time points. Computationally, by introducing for the first time the effects of matrix heterogeneity in our numerical simulations, the results confirmed that matrix porosity and its spatial organization are key factors in priming the infiltrating potential of these malignant cells. The experimental‐numerical synergy can be used to predict the behavior of neoplastic masses under diverse conditions and the efficacy of combination therapies simultaneously aiming at killing cancer cells and modulating the tumor microenvironment.
KW - Cancer growth
KW - Matrix porosity
KW - Matrix rigidity and heterogeneity
KW - Multi‐physics model
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U2 - 10.3390/app10249076
DO - 10.3390/app10249076
M3 - Article
AN - SCOPUS:85098056643
VL - 10
SP - 1
EP - 29
JO - Applied Sciences (Switzerland)
JF - Applied Sciences (Switzerland)
SN - 2076-3417
IS - 24
M1 - 9076
ER -