Forcing a growth factor response - tissue-stiffness modulation of integrin signaling and crosstalk with growth factor receptors.

Research throughout the 90s established that integrin crosstalk with growth factor receptors stimulates robust growth factor signaling. These insights were derived chiefly from comparing adherent versus suspension cell cultures. Considering the new understanding that mechanosensory inputs tune adhesion signaling, it is now timely to revisit this crosstalk in different mechanical environments. Here, we present a brief historical perspective on integrin signaling against the backdrop of the mechanically diverse extracellular microenvironment, then review the evidence supporting the mechanical regulation of integrin crosstalk with growth factor signaling. We discuss early studies revealing distinct signaling consequences for integrin occupancy (binding to matrix) and aggregation (binding to immobile ligand). We consider how the mechanical environments encountered in vivo intersect with this diverse signaling, focusing on receptor endocytosis. We discuss the implications of mechanically tuned integrin signaling for growth factor signaling, using the epidermal growth factor receptor (EGFR) as an illustrative example. We discuss how the use of rigid tissue culture plastic for cancer drug screening may select agents that lack efficacy in the soft in vivo tissue environment. Tuning of integrin signaling via external mechanical forces in vivo and subsequent effects on growth factor signaling thus has implications for normal cellular physiology and anti-cancer therapies.

Advanced Spheroid, Tumouroid and 3D Bioprinted In-Vitro Models of Adult and Paediatric Glioblastoma.

The life expectancy of patients with high-grade glioma (HGG) has not improved in decades. One of the crucial tools to enable future improvement is advanced models that faithfully recapitulate the tumour microenvironment; they can be used for high-throughput screening that in future may enable accurate personalised drug screens. Currently, advanced models are crucial for identifying and understanding potential new targets, assessing new chemotherapeutic compounds or other treatment modalities. Recently, various methodologies have come into use that have allowed the validation of complex models-namely, spheroids, tumouroids, hydrogel-embedded cultures (matrix-supported) and advanced bioengineered cultures assembled with bioprinting and microfluidics. This review is designed to present the state of advanced models of HGG, whilst focusing as much as is possible on the paediatric form of the disease. The reality remains, however, that paediatric HGG (pHGG) models are years behind those of adult HGG. Our goal is to bring this to light in the hope that pGBM models can be improved upon.