Compressive Stimulation Enhances Ovarian Cancer Proliferation, Invasion, Chemoresistance, and Mechanotransduction via CDC42 in a 3D Bioreactor
Open accessAbstract
This report investigates the role of compressive stress on ovarian cancer in a 3D custom built bioreactor. Cells within the ovarian tumor microenvironment experience a range of compressive stimuli that contribute to mechanotransduction. As the ovarian tumor expands, cells are exposed to chronic load from hydrostatic pressure, displacement of surrounding cells, and growth induced stress. External dynamic stimuli have been correlated with an increase in metastasis, cancer stem cell marker expression, chemoresistance, and proliferation in a variety of cancers. However, how these compressive stimuli contribute to ovarian cancer progression is not fully understood. In this report, high grade serous ovarian cancer cell lines were encapsulated within an ECM mimicking hydrogel comprising of agarose and collagen type I, and stimulated with confined cyclic or static compressive stresses for 24 and 72 h. Compression stimulation resulted in a significant increase in proliferation, invasive morphology, and chemoresistance. Additionally, CDC42 was upregulated in compression stimulated conditions, and was necessary to drive increased proliferation and chemoresistance. Inhibition of CDC42 lead to significant decrease in proliferation, survival, and increased chemosensitivity. In summary, the dynamic in vitro 3D platform developed in this report, is ideal for understanding the influence of compressive stimuli, and can be widely applicable to any epithelial cancers. This work reinforces the critical need to consider compressive stimulation in basic cancer biology and therapeutic developments.
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This work identified CDC42 as a driver of chemoresistance and proliferation under compressive stimuli.
“This work identified CDC42 as a driver of chemoresistance and proliferation under compressive stimuli.”
From Three-dimensional modelling of ovarian cancer: from cell lines to organoids for discovery and personalized medicine (2022) · cites this paper as Novak et al., 2020
Novak and colleagues created a custom bioreactor to mimic the hydrostatic compression pressures on ovarian cancer metastasis from the primary tumor.
“Novak and colleagues created a custom bioreactor to mimic the hydrostatic compression pressures on ovarian cancer metastasis from the primary tumor (Novak et al., 2020).”
From Three-dimensional modelling of ovarian cancer: from cell lines to organoids for discovery and personalized medicine (2022) · cites this paper as Novak et al., 2020
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Cites
Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT Method
Livak, K. J., & Schmittgen, T. D. (2001) · Methods · doi:10.1006/meth.2001.1262 · Cited by 180,860 · see citing works
Rho GTPases and the Actin Cytoskeleton
Hall, A. (1998) · Science · doi:10.1126/science.279.5350.509 · Cited by 6,138 · see citing works
Role of YAP/TAZ in mechanotransduction
Dupont, S., Morsut, L., Aragona, M., Enzo, E., Giulitti, S., Cordenonsi, M., Zanconato, F., Le Digabel, J., Forcato, M., Bicciato, S., et al. (2011) · Nature · doi:10.1038/nature10137 · Cited by 5,979 · see citing works
Mutation of the mouse klotho gene leads to a syndrome resembling ageing
Kuro-o, M., Matsumura, Y., Aizawa, H., Kawaguchi, H., Suga, T., Utsugi, T., Ohyama, Y., Kurabayashi, M., Kaname, T., Kume, E., et al. (1997) · Nature · doi:10.1038/36285 · Cited by 3,837 · see citing works
Tumour-cell invasion and migration: diversity and escape mechanisms
Friedl, P., & Wolf, K. (2003) · Nature reviews. Cancer · doi:10.1038/nrc1075 · Cited by 3,225 · see citing works
Mammalian Rho GTPases: new insights into their functions from in vivo studies
Heasman, S. J., & Ridley, A. J. (2008) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2476 · Cited by 1,871 · see citing works
Mechanotransduction in vascular physiology and atherogenesis
Hahn, C. S., & Schwartz, M. A. (2008) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2596 · Cited by 1,219 · see citing works
The Role of Mechanical Forces in Tumor Growth and Therapy
Jain, R. K., Martin, J. D., & Stylianopoulos, T. (2014) · Annual Review of Biomedical Engineering · doi:10.1146/annurev-bioeng-071813-105259 · Cited by 1,044 · cited 2× · see citing works
“9 kPa—albeit these measurements omit the impact of the surrounding extracellular matrix (ECM), and are likely higher in situ [12].”
BackgroundRho‐kinase/ROCK: A key regulator of the cytoskeleton and cell polarity
Amano, M., Nakayama, M., & Kaibuchi, K. (2010) · Cytoskeleton · doi:10.1002/cm.20472 · Cited by 994 · see citing works
Mechanical compression drives cancer cells toward invasive phenotype
Tse, J. M., Cheng, G., Tyrrell, J. A., Wilcox-Adelman, S. A., Boucher, Y., Jain, R. K., & Munn, L. L. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1118910109 · Cited by 631 · see citing works
Cheng, G., Tse, J. M., Jain, R. K., & Munn, L. L. (2009) · PLoS ONE · doi:10.1371/journal.pone.0004632 · Cited by 474 · see citing works
Tensegrity-based mechanosensing from macro to micro
Ingber, D. E. (2008) · Progress in Biophysics and Molecular Biology · doi:10.1016/j.pbiomolbio.2008.02.005 · Cited by 436 · see citing works
Compression-induced changes in the shape and volume of the chondrocyte nucleus
Guilak, F. (1995) · Journal of Biomechanics · doi:10.1016/0021-9290(95)00100-x · Cited by 405 · see citing works
Removal of the MDCK Cell Primary Cilium Abolishes Flow Sensing
Prætorius, H. A., & Spring, K. R. (2003) · The Journal of Membrane Biology · doi:10.1007/s00232-002-1042-4 · Cited by 345 · see citing works
Compressive Stress Inhibits Proliferation in Tumor Spheroids through a Volume Limitation
Delarue, M., Montel, F., Vignjevic, D. M., Prost, J., Joanny, J., & Cappello, G. (2014) · Biophysical Journal · doi:10.1016/j.bpj.2014.08.031 · Cited by 287 · see citing works
Mechanotransduction in endothelial cell migration
Li, S., Huang, N. F., & Hsu, S. H.-L. (2005) · Journal of Cellular Biochemistry · doi:10.1002/jcb.20614 · Cited by 260 · see citing works
Defining the Role of Solid Stress and Matrix Stiffness in Cancer Cell Proliferation and Metastasis
Kalli, M., & Stylianopoulos, T. (2018) · Frontiers in Oncology · doi:10.3389/fonc.2018.00055 · Cited by 255 · see citing works
MAPK-Mediated YAP Activation Controls Mechanical-Tension-Induced Pulmonary Alveolar Regeneration
Liu, Z., Wu, H., Jiang, K., Wang, Y., Zhang, W., Chu, Q., Li, J., Huang, H., Cai, T., Ji, H., et al. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.07.020 · Cited by 239 · see citing works
Targeting Rac and Cdc42 GTPases in Cancer
Maldonado, M. D. M., & Dharmawardhane, S. (2018) · Cancer Research · doi:10.1158/0008-5472.can-18-0619 · Cited by 236 · see citing works
Hunter, C., Imler, S. M., Malaviya, P., et al. (2002) · Biomaterials · doi:10.1016/s0142-9612(01)00245-9 · Cited by 180 · see citing works
Bourguignon, L., Gilad, E., Rothman, K., & Peyrollier, K. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m411985200 · Cited by 161 · see citing works
Stemness and chemoresistance in epithelial ovarian carcinoma cells under shear stress
Ip, C. K. M., Li, S.-S., Tang, M. Y. H., Sy, S. K. H., Ren, Y., Shum, H. C., & Wong, A. S. T. (2016) · Scientific Reports · doi:10.1038/srep26788 · Cited by 128 · see citing works
Liu, Y., Lv, J., Liang, X., Yin, X., Zhang, L., Chen, D., Jin, X., Fiskesund, R., Tang, K., Ma, J., et al. (2018) · Cancer Research · doi:10.1158/0008-5472.can-17-3719 · Cited by 120 · see citing works
Guo, Y., Kenney, S. R., Muller, C. Y., Adams, S. F., Rutledge, T. L., Romero, E., Murray-Krezan, C. M., Prekeris, R., Sklar, L. A., Hudson, L. G., et al. (2015) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-15-0419 · Cited by 115 · see citing works
McGrail, D. J., Kieu, Q. M. N., & Dawson, M. (2014) · Journal of Cell Science · doi:10.1242/jcs.144378 · Cited by 115 · see citing works
Solid Stress Facilitates Fibroblasts Activation to Promote Pancreatic Cancer Cell Migration
Kalli, M., Papageorgis, P., Gkretsi, V., & Stylianopoulos, T. (2018) · Annals of Biomedical Engineering · doi:10.1007/s10439-018-1997-7 · Cited by 95 · see citing works
Clinical Characteristics of Metastatic Tumors to the Ovaries
Lee, S. J., Bae, J.-H., Lee, A.-W., et al. (2009) · Journal of Korean Medical Science · doi:10.3346/jkms.2009.24.1.114 · Cited by 88 · see citing works
Integrated cancer tissue engineering models for precision medicine
Bregenzer, M. E., Horst, E. N., Mehta, P., Novak, C. M., Raghavan, S. A., Snyder, C. S., & Mehta, G. (2019) · PLoS ONE · doi:10.1371/journal.pone.0216564 · Cited by 83 · see citing works
Self-citationFerraro, J. T., Daneshmand, M. A., Bizios, R., & Rizzo, V. (2004) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00224.2003 · Cited by 81 · see citing works
Arias‐Romero, L. E., & Chernoff, J. (2013) · Expert Opinion on Therapeutic Targets · doi:10.1517/14728222.2013.828037 · Cited by 79 · see citing works
Kalli, M., Minia, A., Pliaka, V., Fotis, C., Alexopoulos, L. G., & Stylianopoulos, T. (2019) · Scientific Reports · doi:10.1038/s41598-018-37425-6 · Cited by 78 · see citing works
Novak, C. M., Horst, E. N., Taylor, C. C., Liu, C. Z., & Mehta, G. (2019) · Biotechnology and Bioengineering · doi:10.1002/bit.27119 · Cited by 74 · see citing works
Self-citationFluid-Flow Induced Wall Shear Stress and Epithelial Ovarian Cancer Peritoneal Spreading
Avraham-Chakim, L., Elad, D., Zaretsky, U., Kloog, Y., Jaffa, A. J., & Grisaru, D. (2013) · PLoS ONE · doi:10.1371/journal.pone.0060965 · Cited by 67 · see citing works
The Role of Cancer Stem Cells and Mechanical Forces in Ovarian Cancer Metastasis
Bregenzer, M. E., Horst, E. N., Mehta, P., Novak, C. M., Repetto, T., & Mehta, G. (2019) · Cancers · doi:10.3390/cancers11071008 · Cited by 64 · see citing works
Self-citationReview: Mechanotransduction in ovarian cancer: Shearing into the unknown
Novak, C. M., Horst, E. N., & Mehta, G. (2018) · APL Bioengineering · doi:10.1063/1.5024386 · Cited by 62 · see citing works
Self-citationA Potent and Selective Inhibitor of Cdc42 GTPase
Surviladze, Z., Waller, A., Strouse, J. J., Bologa, C., Ursu, O., Salas, V. M., Parkinson, J. F., Phillips, G. K., Romero, E., Wandinger‐Ness, A., et al. (2010) · DigitalCommons-Cedarville (Cedarville University) · Cited by 57 · see citing works
Munkarah, A. R., Genhai, Z., Morris, R. T., et al. (2003) · Gynecologic Oncology · doi:10.1016/s0090-8258(03)00084-2 · Cited by 53 · see citing works
Kalli, M., Voutouri, C., Minia, A., Pliaka, V., Fotis, C., Alexopoulos, L. G., & Stylianopoulos, T. (2019) · Frontiers in Oncology · doi:10.3389/fonc.2019.00992 · Cited by 52 · see citing works
Mechanisms of Cdc42-mediated rat MSC differentiation on micro/nano-textured topography
Li, G., Song, Y., Shi, M., Du, Y., Wang, W., & Zhang, Y. (2016) · Acta Biomaterialia · doi:10.1016/j.actbio.2016.11.057 · Cited by 44 · see citing works
Rac1 and Cdc42 GTPases regulate shear stress-driven β-catenin signaling in osteoblasts
Wan, Q., Cho, E., Yokota, H., et al. (2013) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2013.03.020 · Cited by 38 · see citing works
Modeling the effect of ascites-induced compression on ovarian cancer multicellular aggregates
Klymenko, Y., Wates, R. B., Weiss‐Bilka, H. E., Lombard, R., Liu, Y., Campbell, L., Kim, O. V., Wagner, D. R., Ravosa, M. J., & Stack, M. S. (2018) · Disease Models & Mechanisms · doi:10.1242/dmm.034199 · Cited by 34 · see citing works
Ma, D., Kou, X., Jin, J., et al. (2016) · International Journal of Molecular Sciences · doi:10.3390/ijms17111847 · Cited by 29 · see citing works
Mechanical stress-induced cell death in breast cancer cells
Takao, S., Taya, M., & Chiew, C. (2019) · Biology Open · doi:10.1242/bio.043133 · Cited by 29 · see citing works
Miniaturized platform with on-chip strain sensors for compression testing of arrayed materials
MacQueen, L. A., Chebotarev, O., Simmons, C. A., et al. (2012) · Lab on a Chip · doi:10.1039/c2lc40670e · Cited by 21 · see citing works
Shyy, J. Y. ‐. (2001) · Biorheology · doi:10.1177/0006355x2001038002003006 · Cited by 17 · see citing works
Mechanical loading promotes Lewis lung cancer cell growth through periostin
Ma, D., Lu, H., Xu, L., Xu, X., & Xiao, W. L. (2009) · In Vitro Cellular & Developmental Biology - Animal · doi:10.1007/s11626-009-9214-5 · Cited by 15 · see citing works
Ho, F. C., Zhang, W., Li, Y. Y., et al. (2015) · Biomaterials · doi:10.1016/j.biomaterials.2015.02.102 · Cited by 15 · see citing works
Bilateral Ovarian Tumors on MRI: How Should We Differentiate the Lesions?
Mukuda, N., Fujii, S., Inoue, C., et al. (2018) · Yonago acta medica · doi:10.33160/yam.2018.06.003 · Cited by 14 · see citing works
Lee, C. S., Kim, Y. J., Jang, E.-R., et al. (2010) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2010.01.004 · Cited by 11 · see citing works
Hayakawa, K., Hirata, H., MIu, S., & Sokabe, M. (2018) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2018.10.192 · Cited by 5 · see citing works
Cancer Suppression by Compression
Frieden, B. R., & Gatenby, R. A. (2014) · Bulletin of Mathematical Biology · doi:10.1007/s11538-014-0051-7 · Cited by 2 · see citing works
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Mierke, C. T. (2024) · Cells · doi:10.3390/cells13010096 · Cited by 146 · see citing works
Yee, C., Dickson, K.-A., Muntasir, M. N., Ma, Y., & Marsh, D. J. (2022) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2022.836984 · Cited by 66 · see citing works
Piezo1 activation facilitates ovarian cancer metastasis via Hippo/YAP signaling axis
Xiong, Y., Dong, L., Bai, Y., Tang, H., Li, S., Luo, D., Liu, F., Bai, J., Yang, S., & Song, X. (2022) · Channels · doi:10.1080/19336950.2022.2099381 · Cited by 48 · see citing works
A Flexible Microdevice for Mechanical Cell Stimulation and Compression in Microfluidic Settings
Onal, S., Alkaisi, M. M., & Nock, V. (2021) · Frontiers in Physics · doi:10.3389/fphy.2021.654918 · Cited by 29 · see citing works
- Authors
- Novak, C. M., Horst, E. N., Lin, E., & Mehta, G.
- Affiliations
- University of Michigan (US)
- Corresponding author
- Mehta, Geeta
- Venue
- Cancers
- Publisher
- MDPI AG
- Published
- 2020-06-10
- Volume
- 12
- Issue
- 6
- Pages
- 1521
- ISSN
- 2072-6694 (ISSN-L)
- PMC
- PMC7352213
- OpenAlex
- W3035285190
- Cited by
- 47
- References
- 51
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 11 · 2023: 11 · 2022: 12 · 2021: 6
- FWCI
- 3.62
- Type
- journal article
- Language
- en
- Open access
- gold
- dx.doi.org
- Licence
- Locations
- Cancers (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- U.S. Department of Defense (DOD Pilot award W81XWH-16-1-0426, DOD OCRP Early Career Investigator Award W81XWH-13-1-0134, DOD Investigator Initiated award W81XWH-18-0346)
- American Cancer Society (Research Scholar Award RSG-19-003-01-CCE)
- Rivkin Center for Ovarian Cancer (Pilot award)
- undefined <span style="color:gray;font-size:10px;">undefined</span> (Michigan Ovarian Cancer Alliance)
- National Cancer Institute (P30CA046592)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
- Health Sciences › Medicine › Reproductive Medicine › Ovarian cancer diagnosis and treatment
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- ovarian cancer, compressive stress, mechanotransduction, Cdc42, chemoresistance, tumor cell proliferation, tumor invasion, high-grade serous ovarian cancer, 3D bioreactor, tumor microenvironment, cyclic compression, chemosensitivity
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