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  Integrin subtypes and nanoscale ligand presentation influence drug sensitivity in cancer cells

Young, J. L., Hua, X., Somsel, H., Reichart, F., Kessler, H., & Spatz, J. P. (2020). Integrin subtypes and nanoscale ligand presentation influence drug sensitivity in cancer cells. Nano Letters, 20(2), 1183-1191. doi:10.1021/acs.nanolett.9b04607.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0005-76D0-B Version Permalink: http://hdl.handle.net/21.11116/0000-0006-05BF-E
Genre: Journal Article
Alternative Title : Integrin Subtypes and Nanoscale Ligand Presentation Influence Drug Sensitivity in Cancer Cells

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 Creators:
Young, Jennifer L.1, Author              
Hua, Ximeng1, Author              
Somsel, Heidi2, Author              
Reichart, Florian, Author
Kessler, Horst, Author
Spatz, Joachim P.1, 3, Author              
Affiliations:
1Cellular Biophysics, Max Planck Institute for Medical Research, Max Planck Society, ou_2364731              
2Max Planck Institute for Medical Research, Max Planck Society, ou_1125545              
3Biophysical Chemistry, Institute of Physical Chemistry, University of Heidelberg, 69120 Heidelberg, Germany, ou_persistent22              

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Free keywords: Integrin; chemoresistance; extracellular matrix; nanoparticle; peptidomimetic
 Abstract: Cancer cell-matrix interactions have been shown to enhance cancer cell survival via the activation of pro-survival signaling pathways. These pathways are initiated at the site of interaction, i.e., integrins, and thus, their inhibition has been the target of therapeutic strategies. Individual roles for fibronectin-binding integrin subtypes αvβ3 and α5β1 have been shown for various cellular processes; however, a systematic comparison of their function in adhesion-dependent chemoresistance is lacking. Here, we utilize integrin subtype-specific peptidomimetics for αvβ3 and α5β1, both as blocking agents on fibronectin-coated surfaces and as surface-immobilized adhesion sites, in order to parse out their role in breast cancer cell survival. Block copolymer micelle nanolithography is utilized to immobilize peptidomimetics onto highly ordered gold nanoparticle arrays with biologically relevant interparticle spacings (35, 50, or 70 nm), thereby providing a platform for ascertaining the dependence of ligand spacing in chemoprotection. We show that several cellular properties-morphology, focal adhesion formation, and migration-are intricately linked to both the integrin subtype and their nanospacing. Importantly, we show that chemotherapeutic drug sensitivity is highly dependent on both parameters, with smaller ligand spacing generally hindering survival. Furthermore, we identify ligand type-specific patterns of drug sensitivity, with enhanced chemosurvival when cells engage αvβ3 vs α5β1 on fibronectin; however, this is heavily reliant on nanoscale spacing, as the opposite is observed when ligands are spaced at 70 nm. These data imply that even nanoscale alterations in extracellular matrix properties have profound effects on cancer cell survival and can thus inform future therapies and drug testing platforms.

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Language(s): eng - English
 Dates: 2019-12-092019-11-082020-01-072020-02-12
 Publication Status: Published in print
 Pages: 9
 Publishing info: -
 Table of Contents: -
 Rev. Method: Peer
 Degree: -

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Title: Nano Letters
  Abbreviation : Nano Lett.
Source Genre: Journal
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Publ. Info: Washington, DC : American Chemical Society
Pages: - Volume / Issue: 20 (2) Sequence Number: - Start / End Page: 1183 - 1191 Identifier: ISSN: 1530-6984
CoNE: https://pure.mpg.de/cone/journals/resource/110978984570403