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

While 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. [Display omitted] •Glioblastoma survival in mice and humans depends biphasically on CD44 levels•Intermediate CD44 levels are linked to high cell migration rates and poor survival•High levels of CD44 correlate with better patient outcomes•Net proliferation rates are independent of CD44, consistent with a biophysical theory Klank et al. describe a biphasic relationship between CD44 expression levels and survival/cell migration rates in glioma. Intermediate CD44 levels in glioblastoma are linked to high tumor cell migration rates and poor survival, while both low and high CD44 levels were a positive prognostic indicator. These results illustrate the potential importance of non-monotonic relationships between survival and biomarkers associated with cancer progression.