title: Mechanistic adaptability of cancer cells strongly affects anti-migratory drug efficacy.
abstract: Cancer metastasis involves the dissemination of cancer cells from the primary tumour site and is responsible for the majority of solid tumour-related mortality. Screening of anti-metastasis drugs often includes functional assays that examine cancer cell invasion inside a three-dimensional hydrogel that mimics the extracellular matrix (ECM). Here, we built a mechanically tuneable collagen hydrogel model to recapitulate cancer spreading into heterogeneous tumour stroma and monitored the three-dimensional invasion of highly malignant breast cancer cells, MDA-MB-231. Migration assays were carried out in the presence and the absence of drugs affecting four typical molecular mechanisms involved in cell migration, as well as under five ECMs with different biophysical properties. Strikingly, the effects of the drugs were observed to vary strongly with matrix mechanics and microarchitecture, despite the little dependence of the inherent cancer cell migration on the ECM condition. Specifically, cytoskeletal contractility-targeting drugs reduced migration speed in sparse gels, whereas migration in dense gels was retarded effectively by inhibiting proteolysis. The results corroborate the ability of cancer cells to switch their multiple invasion mechanisms depending on ECM condition, thus suggesting the importance of factoring in the biophysical properties of the ECM in anti-metastasis drug screenings.
authors.affiliation: NUS Graduate School for Integrative Sciences and Engineering, Singapore 117456, Republic of Singapore.
authors.forename: Wei
authors.initials: W
authors.lastname: Sun
authors.affiliation: Mechanobiology Institute, National University of Singapore, Singapore 117411, Republic of Singapore Department of Biomedical Engineering, National University of Singapore, Singapore 117576, Republic of Singapore Department of Mechanical Engineering, National University of Singapore, Singapore 117576, Republic of Singapore ctlim@nus.edu.sg.
authors.forename: Chwee Teck
authors.initials: CT
authors.lastname: Lim
authors.affiliation: FOM Institute AMOLF, Science Park 104, 1098XG Amsterdam, The Netherlands kurniawan@amolf.nl.
authors.forename: Nicholas Agung
authors.initials: NA
authors.lastname: Kurniawan
mesh_terms: D000577:Amides; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000503:physiopathology*; D002465:Cell Movement / Q000187:drug effects*; D015638:Cytochalasin D; D004151:Dipeptides; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D006801:Humans; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate; D018613:Microscopy, Confocal; D009361:Neoplasm Invasiveness / Q000503:physiopathology*; D009362:Neoplasm Metastasis / Q000188:drug therapy*; D009360:Neoplastic Cells, Circulating / Q000187:drug effects*; D015739:Nocodazole; D011725:Pyridines; D018709:Statistics, Nonparametric; D059008:Time-Lapse Imaging
chemical_list: D000577:Amides; D000970:Antineoplastic Agents; D004151:Dipeptides; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D011725:Pyridines; C108830:Y 27632; D015638:Cytochalasin D; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate; D015739:Nocodazole
keywords: cancer metastasis; drug assay; extracellular matrix mechanics; three-dimensional cell migration
references.citation: Cancer Metastasis Rev. 2009 Jun;28(1-2):113-27
references.pmid: 19153673
references.citation: Biomech Model Mechanobiol. 2014 Aug;13(4):839-49
references.pmid: 24158353
references.citation: Proc Natl Acad Sci U S A. 2008 Jan 8;105(1):59-63
references.pmid: 18160535
references.citation: Biophys J. 2008 Oct;95(8):4077-88
references.pmid: 18641063
references.citation: J Cell Biol. 1992 Apr;117(1):73-82
references.pmid: 1556157
references.citation: Phys Biol. 2011 Feb;8(1):015009
references.pmid: 21301071
references.citation: Adv Drug Deliv Rev. 2007 Nov 10;59(13):1329-39
references.pmid: 17900747
references.citation: PLoS One. 2009 Jul 24;4(7):e6382
references.pmid: 19629190
references.citation: Lancet. 1996 May 18;347(9012):1377-81
references.pmid: 8637346
references.citation: Cancer Cell. 2005 Sep;8(3):241-54
references.pmid: 16169468
references.citation: Clin Exp Metastasis. 2009;26(4):381-97
references.pmid: 18958576
references.citation: J Cell Biol. 2012 Apr 30;197(3):439-55
references.pmid: 22547408
references.citation: Trends Cell Biol. 2005 Feb;15(2):76-83
references.pmid: 15695094
references.citation: Phys Biol. 2011 Feb;8(1):015010
references.pmid: 21301056
references.citation: J Cell Sci. 2005 Nov 1;118(Pt 21):4917-9
references.pmid: 16254237
references.citation: Integr Biol (Camb). 2009 Sep;1(8-9):506-12
references.pmid: 20023765
references.citation: Proc Natl Acad Sci U S A. 2012 Jun 26;109(26):10334-9
references.pmid: 22689955
references.citation: Antiviral Res. 2006 Sep;71(2-3):96-107
references.pmid: 16844237
references.citation: PLoS One. 2011;6(5):e20355
references.pmid: 21647371
references.citation: J Cell Biol. 2004 Nov 22;167(4):769-81
references.pmid: 15557125
references.citation: Semin Cell Dev Biol. 2009 Oct;20(8):931-41
references.pmid: 19682592
references.citation: Biophys J. 2001 Sep;81(3):1786-92
references.pmid: 11509388
references.citation: Semin Cancer Biol. 2005 Oct;15(5):365-77
references.pmid: 15975824
references.citation: Physiol Res. 2007;56 Suppl 1:S51-60
references.pmid: 17552894
references.citation: Biomaterials. 2010 Mar;31(7):1875-84
references.pmid: 19926126
references.citation: Biophys J. 2005 Aug;89(2):1374-88
references.pmid: 15923238
references.citation: Biomaterials. 2010 Sep;31(25):6425-35
references.pmid: 20537378
references.citation: Biomacromolecules. 2012 Mar 12;13(3):691-8
references.pmid: 22293015
references.citation: Biophys J. 2008 Dec;95(11):5374-84
references.pmid: 18775961
references.citation: Cell. 1995 Apr 7;81(1):53-62
references.pmid: 7536630
references.citation: Cold Spring Harb Symp Quant Biol. 2005;70:343-56
references.pmid: 16869771
references.citation: Nat Cell Biol. 2007 Aug;9(8):893-904
references.pmid: 17618273
references.citation: J Cell Biol. 2003 Jan 20;160(2):267-77
references.pmid: 12527751
references.citation: Nature. 2006 Apr 20;440(7087):1069-72
references.pmid: 16547516
references.citation: Med Res Rev. 2007 Mar;27(2):149-76
references.pmid: 16888756
references.citation: Curr Opin Cell Biol. 2003 Dec;15(6):753-62
references.pmid: 14644202
references.citation: Adv Drug Deliv Rev. 2011 Jul 18;63(8):558-67
references.pmid: 21335038
references.citation: Curr Biol. 2006 Aug 8;16(15):1515-23
references.pmid: 16890527
references.citation: Biophys J. 2013 Mar 5;104(5):1160-9
references.pmid: 23473499
references.citation: Tissue Eng. 2007 Jul;13(7):1443-53
references.pmid: 17518745
references.citation: Biophys J. 2013 Jun 18;104(12):2774-5
references.pmid: 23790386
references.citation: Biomaterials. 2012 Jun;33(16):4157-65
references.pmid: 22405848
references.citation: J Cell Sci. 2011 Jan 1;124(Pt 1):9-18
references.pmid: 21172819
references.citation: Nat Rev Cancer. 2009 Apr;9(4):265-73
references.pmid: 19262571
references.citation: Proc Natl Acad Sci U S A. 2006 Jul 18;103(29):10889-94
references.pmid: 16832052
references.citation: PLoS One. 2010 Sep 23;5(9):e12905
references.pmid: 20886123
references.citation: Cancer Metastasis Rev. 2006 Mar;25(1):35-43
references.pmid: 16680570
references.citation: Nature. 2009 Sep 3;461(7260):99-103
references.pmid: 19693013
references.citation: EMBO J. 2010 Sep 1;29(17):2915-29
references.pmid: 20676060
references.citation: Adv Drug Deliv Rev. 2011 Apr 30;63(4-5):269-76
references.pmid: 21241759
references.citation: Phys Biol. 2011 Feb;8(1):015015
references.pmid: 21301068
references.citation: Am J Physiol Cell Physiol. 2000 Nov;279(5):C1345-50
references.pmid: 11029281