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Integrin Subtypes and Nanoscale Ligand Presentation Influence Drug Sensitivity in Cancer Cells
Jennifer L Young1,2, Ximeng Hua1,2, Heidi Somsel1,2
1Department of Cellular Biophysics , Max Planck Institute for Medical Research , 69120 Heidelberg , Germany.
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.
Insights
Cancer cell survival and chemoresistance depend on integrin subtypes (αvβ3 and α5β1) and their nanoscale spacing on fibronectin. Altering this spacing impacts drug sensitivity, offering new therapeutic strategies.
Area of Science:
- Biomedical Engineering
- Cell Biology
- Materials Science
Background:
- Cancer cell survival is enhanced by interactions with the extracellular matrix through pro-survival signaling pathways.
- Integrins, such as αvβ3 and α5β1, initiate these signaling pathways at the cell-matrix interface, making them therapeutic targets.
- A systematic comparison of integrin subtypes αvβ3 and α5β1 in adhesion-dependent chemoresistance is lacking.
Purpose of the Study:
- To systematically compare the roles of integrin subtypes αvβ3 and α5β1 in breast cancer cell survival and chemoresistance.
- To investigate the influence of nanoscale ligand spacing on integrin-mediated cellular responses and drug sensitivity.
Main Methods:
- Utilized integrin subtype-specific peptidomimetics for αvβ3 and α5β1 as blocking agents and surface-immobilized adhesion sites.
- Employed block copolymer micelle nanolithography to immobilize peptidomimetics onto gold nanoparticle arrays with controlled interparticle spacings (35, 50, 70 nm).
- Assessed cellular properties including morphology, focal adhesion formation, migration, and chemotherapeutic drug sensitivity.
Main Results:
- Cellular properties like morphology, focal adhesion formation, and migration are dependent on both integrin subtype and nanospacing.
- Chemotherapeutic drug sensitivity is significantly influenced by integrin subtype and ligand nanospacing, with smaller spacings generally reducing survival.
- Specific ligand-receptor interactions (αvβ3 vs. α5β1) dictate drug sensitivity patterns, which are modulated by nanoscale spacing.
Conclusions:
- Nanoscale alterations in extracellular matrix properties profoundly affect cancer cell survival and chemoresistance.
- Understanding integrin subtype and spacing-dependent responses can inform the development of novel cancer therapies and drug testing platforms.
- Targeting integrin-ligand interactions at the nanoscale offers a promising avenue for overcoming chemoresistance in breast cancer.
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