Self-Assembly of Integrin Ligands on the Apical Membrane Inhibits the Migration of Glioma Cells

Abstract

Malignant brain cancer remains challenging in treatment due to the highly invasive quality of gliomas. Inspired by the upregulated expression of integrin β1 subunits in tumors, we designed and synthesized an integrin-targeting self-assembling ligand based on a laminin-derived peptide that selectively forms nanofibrous microdomains on the apical membrane of glioma cells, inhibiting their migration and invasion.

Above the Matrix: Functional Roles for Apically Localized Integrins

“…Consistent with this observation, when apical pools of β1 integrins on F98 cells are in the closed conformation, the cells are highly migratory (Mang et al, 2020). However, when cells are treated with ligand that both clusters and activates the apical β1 subunits there is a reduction of focal adhesions and cell elongation that in turn inhibits migration (Mang et al, 2020).…”

“…Clustering of apical integrins, particularly activated integrins, appears to be a key component in inducing cell responses ranging from cell migration to increases in permeability (Ojakian and Schwimmer, 1994;Garbi et al, 1996;Zuk and Matlin, 1996;Kam et al, 2013;Walsh et al, 2015;Grassme et al, 2017;Stewart et al, 2017;Badaoui et al, 2020;Mang et al, 2020;Turner et al, 2020). Apical integrin clustering can also drive endocytosis which can be physiological, in the case of integrin turnover during cell migration, but also has the pathological consequences of facilitating infection by bacteria using apical integrins as receptors.…”

“…How clustering of apical integrins is linked to integrin conformation and activation is not well defined. Several studies have demonstrated that integrin activation, usually through ligand binding (Ojakian and Schwimmer, 1994;Garbi et al, 1996;Zuk and Matlin, 1996;Grassme et al, 2017;Badaoui et al, 2020;Mang et al, 2020;Turner et al, 2020), but not necessarily clustering (Xu et al, 2016) were necessary to cause cells to respond. Recent evidence demonstrates that β1 integrins associated with focal adhesions contain nanoclusters with distinct populations of both active and inactive integrins suggesting two independent pools depending on activation state (Spiess et al, 2018).…”

“…Much like their basolaterally localized counterparts, apically localized integrins interact with the actin cytoskeleton (Tafazoli et al, 2000;Li et al, 2009;Yang and Rizzo, 2013;Uehara and Uehara, 2014;Walsh et al, 2015;Badaoui et al, 2020;Mang et al, 2020). One possible explanation for the differential roles for apical and basal integrins is that the apical integrins access unique pools of actin that are distinct from actin interacting with integrins associated with focal adhesions.…”

Control Cell Migration by Engineering Integrin Ligand Assembly

“…To promote a wide application of the technique, we randomly selected peptide sequences derived from ECM components possessing different binding interests to integrin isoforms for extracellular constructs. (26,27) Fibronectinderived GRGDSP, LRGDN, and synergy peptide PHSRN, laminin b1 chain-derived YIGSR, (28) and a1 chain-derived IKVAV, targeting integrin a5b1, avb3, a3b1, or a6b1, were coupled with FFF obtaining a series of assembling ligands. Upon the treatment of these assembling ligands, cells phenocopied the morphology and motility of FFFIKLLI-treated cells indicating that the design strategy could be applied as generalized tool to fabricate biomaterials with therapeutic potentials in targeting subtype malignant tumor associated with different integrin expression pattern.…”