Integrin Crosstalk Contributes to the Complexity of Signalling and Unpredictable Cancer Cell Fates

Abstract

Integrins are heterodimeric cell surface receptors composed of α and β subunits that control adhesion, proliferation and gene expression. The integrin heterodimer binding to ligand reorganises the cytoskeletal networks and triggers multiple signalling pathways that can cause changes in cell cycle, proliferation, differentiation, survival and motility. In addition, integrins have been identified as targets for many different diseases, including cancer. Integrin crosstalk is a mechanism by which a change in the expression of a certain integrin subunit or the activation of an integrin heterodimer may interfere with the expression and/or activation of other integrin subunit(s) in the very same cell. Here, we review the evidence for integrin crosstalk in a range of cellular systems, with a particular emphasis on cancer. We describe the molecular mechanisms of integrin crosstalk, the effects of cell fate determination, and the contribution of crosstalk to therapeutic outcomes. Our intention is to raise awareness of integrin crosstalk events such that the contribution of the phenomenon can be taken into account when researching the biological or pathophysiological roles of integrins.

Site-Specific and Common Prostate Cancer Metastasis Genes as Suggested by Meta-Analysis of Gene Expression Data

“…This indicates that bone and lymph node metastasis highly rewire the expression of adhesion molecules and related pathways, while for liver metastasis this change is much less prominent. Taken together, these results suggest that there are parts of focal adhesion (integrin) network that are commonly changed in prostate cancer metastasis from all analyzed sites, but also a part that is specific to metastasis from each site, giving them an integrin code that is, apparently, important during every step of the metastatic cascade [ 42 ] and a subject to a frequent change [ 43 ].…”

Recent Advances and Prospects in the Research of Nascent Adhesions

“…As presented in the above discussion, many molecular players contributing to the formation of NAs have been identified, and their mutual interplay have been established, although further investigation of specific interactions is necessary. For example, very little is known about the crosstalk between integrins of the same and different types, recently reported for early adhesions (Bharadwaj et al, 2017;Strohmeyer et al, 2017;Diaz et al, 2020;Samaržija et al, 2020). However, new research avenues in studying molecular interactions in NAs can emerge only from advances in the development of robust quantitative colocalization analysis (Levet et al, 2019).…”

“…Integrin-mediated adhesion of cells and the associated mechanosensing is of monumental importance for the physiology of nearly any cell type (Kechagia et al, 2019;Samaržija et al, 2020). Upon integrin activation, it often proceeds through the maturation of nascent adhesions (NAs) to focal adhesions (FAs) (Figure 1), which are transient supramolecular assemblies, connecting a cell to the extracellular matrix or another cell.…”

Biological Relevance of RGD‐Integrin Subtype‐Specific Ligands in Cancer

“…Alternatively, blocking αvβ3 integrin might activate α5β1 integrin recycling back to membrane and increase cell migration [30] . Distinct mechanisms and/or efficient crosstalk between both integrins have emerged over the years [31] . New insights on focal adhesion maturation have been made possible using ligands specifically designed to target either αvβ3 or α5β1 integrins.…”