Biphasic Dependence of Glioma Survival and Cell Migration on CD44 Expression Level

Abstract

SUMMARYWhile several studies link the cell-surface marker CD44 to cancer progression, conflicting results show both positive and negative correlations with increased CD44 levels. Here, we demonstrate that the survival outcomes of genetically induced glioma-bearing mice and of high-grade human glioma patients are biphasically correlated with CD44 level, with the poorest outcomes occurring at intermediate levels. Furthermore, the high-CD44-expressing mesenchymal subtype exhibited a positive trend of survival with increased CD44 level. Mouse cell migration rates in ex vivo brain slice cultures were also biphasically associated with CD44 level, with maximal migration corresponding to minimal survival. Cell simulations suggest that cell-substrate adhesiveness is sufficient to explain this biphasic migration. More generally, these results highlight the potential importance of non-monotonic relationships between survival and biomarkers associated with cancer progression.

Glioma cell migration in confined microchannels via a motor-clutch mechanism

“…In the previously described CMS (24,25), each protrusion module functions as a copy of the motor-clutch model (23) Table S1), the CMS predicts glioma cell migration in environments of varying stiffness and adhesiveness (24,25). However, as these studies used parameter sets calibrated for cells on 2D substrates, it is unclear how well CMS predictions hold for cells migrating in confined channels.…”

“…We generated time-lapse movies of cells moving in channels (Figure 2C and D) and tracked fluorescently labeled nuclei using a previously described semi-automated tracking method (24).…”

“…Given that GBM migration speed correlates inversely with patient survival (24), CMS predictions could inform in silico estimates of tumor progression and response to therapy. However, the CMS has not been rigorously tested on data generated in the mechanical confinement conditions cells encounter in vivo.…”

Tug of War at the Cell-Matrix Interface

“…in a given modeled cell, with full spatial organization to account for focal adhesion area and its changes in space and time, will further propel the field. This appears particularly relevant as recent studies in this area suggest distinct cell-matrix mechanics as a function of the type of adhesion complex (7,9). Likewise, this will be particularly germane as models expand to incorporate multiple extracellular matrices, each with distinct mechanical properties and organization.…”

“…To account for differing mechanical properties in the cell environment, Chan and Odde (6) presented the motor-clutch model for cell traction forces as a major advance to understand mechanical interactions between a cell and the extracellular matrix. Their approach notably employs a force-velocity relationship for actomyosin forces and accounts for elastic deformation in the substrate, while allowing spontaneous cell polarization to emerge (6,7).…”