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Microchannel stiffness and confinement jointly induce the mesenchymal-amoeboid transition of cancer cell migration Meng Wang, Bo Cheng, Yaowei Yang, Han Liu, Guoyou Huang, Lichun Han, Fei Li, and Feng Xu Nano Lett., Just Accepted Manuscript • DOI: 10.1021/acs.nanolett.9b01597 • Publication Date (Web): 15 Aug 2019 Downloaded from pubs.acs.org on August 16, 2019
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Nano Letters
Microchannel stiffness and confinement jointly induce the mesenchymalamoeboid transition of cancer cell migration Meng Wanga,b, Bo Chenga,b, Yaowei Yanga,b, Han Liua,b, Guoyou Huanga,b, Lichun Hana,b,c, Fei Lia,b,*, Feng Xua,b,* a
The Key Laboratory of Biomedical Information Engineering of Ministry of Education,
School of Life Science and Technology, Xi’an Jiaotong University, Xi’an 710049, P. R. China b
Bioinspired Engineering and Biomechanics Center (BEBC), Xi’an Jiaotong University,
Xi’an 710049, P. R. China c Department
of Anesthesia, Xi’an Daxing hospital, Xi’an 710049, P. R. China
*To whom correspondence may be addressed: Fei Li, Tel: +86-185-9196-9919, Email:
[email protected] Feng Xu, Tel: +86-183-9218-6272, Email:
[email protected] 1
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Abstract: The physical confinement of cell microenvironment could enhance the invasive capability and drug resistance of cancer cells. However, due to the lack of in vitro experimental platform to mimic both stiffness and confinement of the tumor microenvironment, the underlying mechanism remains elusive. Here, we developed a hydrogel-based microchannel platform with independently tunable channel stiffness and width in a physiological range. We found that the migration speed of cancer cell is influenced by the synergistic effect of channel stiffness and width. In addition, the mesenchymal-amoeboid transition has a strong correlation with the channel stiffness. Besides, with a developed computational model, the role of nuclear stiffness on cancer migration speed and thus the mesenchymal-amoeboid transition in microchannels was also revealed. This platform is capable of mimicking the native physical microenvironment during metastasis, providing a powerful tool for high-throughput screening applications and
investigating
the
interaction
between
cancer
migration
and
biophysical
microenvironment.
Keywords:
tumor
microenvironment;
biophysical
mechanobiology
2
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microenvironment;
nucleus;
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Nano Letters
Cellular microenvironment plays a critical role in tumor metastasis, which accounts for the majority of cancer mortality 1. In cellular microenvironment, besides biochemical cues (e.g., oxidative stress 2), biophysical cues have also been proven as the key determinants of tumor metastatic processes 3-7. For example, the stiffness of matrix that cancer cells reside in has been reported to drive tumor metastasis by initialing epithelial-mesenchymal transition (EMT) 8. By degrading extracellular matrix (ECM) through matrix metalloproteinase and depositing new collagen fibers via tumor-associated fibroblast, cancer cells can remodel the native ECM into a stiffer collagen-enriched ECM with aligned collagen fibers and ductal structures to facilitate their invasion
9, 10.
Besides the ductal structures formed by
ECM remodeling, microchannels also exist in native tissues (e.g., interstitial collagen network, fat, muscle and perineural tissue) 11, 12, which are generally with a size of sub-10 μm providing confinement for migrating cancer cell during tumor metastasis 12, 13. Several recent investigations have found that the environmental confinement could boost the cell migration speed
14-16
and induce mesenchymal-amoeboid transition (MAT)
17-20,
which
renders the cancer cell significantly increased invasive capability and resistance to chemotherapy
21.
Therefore, it is of great importance to investigate the role of matrix
stiffness and confinement in the regulation of cancer cell migration and the transition of cancer cell migration mode.
Several strategies have been developed to investigate the effect of matrix stiffness and confinement on cancer cell migration, including microchannel 18, 22-27, grooved substrate 16 and parallel plates
20.
For example, the dependence of cell migration on the decrease of
confinement (i.e., increasing channel width), from 3 μm (nearly the deformation limitation of nucleus
3)
to 50 μm (almost unconfined), has been thoroughly studied in
poly(dimethylsiloxane) (PDMS) microchannels (10 μm height) 28, 29. From the observation results of the PDMS microchannel with 3 μm width (30 μm2 cross section area), a new migration mode (named Osmotic Engine Model) has been established 3
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30.
However, the
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stiffness of PDMS is much higher than that of most mammalian tissues and the effect of matrix stiffness was not considered in these studies. To address this, microchannels and grooved substrates have been fabricated with various hydrogels such as collagen polyacrylamide
16.
22
or
However, the width of the prepared hydrogel microchannels and
grooves are normally >10 μm, which is out of the channel width range in the native physical microenvironment during metastasis (
