Contributions of talin-1 to glioma cell–matrix tensional homeostasis

Abstract

The ability of cells to adapt their mechanical properties to those of the surrounding microenvironment (tensional homeostasis) has been implicated in the progression of a variety of solid tumours, including the brain tumour glioblastoma multiforme (GBM). GBM tumour cells are highly sensitive to extracellular matrix (ECM) stiffness and overexpress a variety of focal adhesion proteins, such as talin. While talin has been shown to play critical early roles in integrin-based force-sensing in non-tumour cells, it remains unclear whether this protein contributes to tensional homeostasis in GBM cells. Here, we investigate the role of the talin isoform talin-1 in enabling human GBM cells to adapt to ECM stiffness. We show that human GBM cells express talin-1, and we use RNA interference to suppress talin-1 expression without affecting levels of talin-2, vinculin or phosphorylated focal adhesion kinase. Knockdown of talin-1 strongly reduces both cell spreading area and random migration speed but does not significantly affect overall focal adhesion size distributions. Most strikingly, atomic force microscopy indentation reveals that talin-1 suppression compromises adaptation of cell stiffness to changes in ECM stiffness. Together, these data support a role for talin-1 in the maintenance of tensional homeostasis in GBM and suggest a functional role for enriched talin expression in this tumour.

Comparative multidimensional molecular analyses of pediatric diffuse intrinsic pontine glioma reveals distinct molecular subtypes

“…CLU is a secreted molecular chaperone protein implicated in cancer [15,17,31,42,54,55] that we previously detected in the CSF proteome of DIPG patients [43]. TLN1 is a cytoskeletal protein that controls integrin activation to facilitate cell migration by promoting cell motility and adhesion in glioma [7,40,41,46,56]. Currently, therapeutic agents targeting integrins such as Cilengitide are under investigation as a treatment for adult high-grade astrocytoma (GBM).…”

Engineering strategies to mimic the glioblastoma microenvironment

“…Further, we found that this mechanosensitivity was dependent on non-muscle myosin II-mediated cellular contractility, such that inhibition of contractility using the small-molecule drug blebbistatin rescued invasion on soft substrates. In follow-up studies, we have explored the role of the focal adhesion proteins α-actinin [107] and talin [108] in transducing mechanical cues, as well as the central role of the Rho GTPase RhoA in mediating the resulting contractility-dependent cellular phenotype [109]. As a potential caveat, a recent study suggested that changing the stiffness of the PAA substrate is potentially communicated to cells through alterations in the anchoring density of the tethered ECM protein [110].…”

Molecular Mechanisms of Glioma Cell Motility

“…The resulting structures lead to alterations of the cell morphology and the generation of traction force necessary to move the cell body. Recent reports indicate that focal adhesion protein expression, like talin and alpha-actinin, is related to the invasiveness of glioma cells (111).…”