Elucidating the Role of Cancer-Activated Fibroblasts in Regulating Glioblastoma Stem Cells

Glioblastoma (GBM) is the most prevalent and aggressive malignant primary brain tumour with a median survival of approximately 15 months despite standard of care treatment. A major barrier to effective treatment is the extensive genetic and phenotypic heterogeneity, fostering tumor resistance and contributes to its aggressive nature. Thus, GSC’s can recapitulate the tumour mass resulting in tumour recurrence and patient relapse in over 90% of GBM cases. The microenvironment of glioblastoma includes diverse types of stromal cells which co-exist in close association with tumour cells and have been identified as an important source of secreted factors and cell-to-cell signals that regulate the stemness of GSCs. Within GBM, Cancer-Associated Fibroblasts (CAFs) have emerged as key facilitators of these effects. CAFs are known to promote cell cycle dysregulation, enhance tumor vasculature and secrete various growth factors into the extracellular matrix to promote tumorigenesis. YKL-40 (also known as CHI-3L1) is an abundant glycoprotein that binds to the interleukin-13 receptor 2 (IL-13Rα2) and has been shown to promote growth, angiogenesis, metastasis, and resistance to therapy in diverse types of cancer. Elevated levels of YKL-40 expression have been associated with a poorer prognosis in GBM. Whether CAFs can enhance GBM tumor aggressiveness and support GSC survival through increasing the expression of YKL-40 is not known. We hypothesize that the increased expression of YKL-40, in response to CAFs, plays a pivotal role in GBM aggressiveness and therapy resistance. Understanding these interactions could lead to the development of targeted therapeutic strategies to prevent GBM progression and recurrence.