Introduction: Despite therapeutic advances, disease recurrence and tumour progression in patients with glioblastoma remain universal (1). Tumour resistance is thought to be due in part to cell-intrinsic heterogeneity in these cancers. In particular, glioblastoma is thought to harbour a population of stem-like cells called glioma stem cells (GSCs), that appear to be responsible for tumor recurrence (2). Given their import in normal stem cell microenvironments, we have examined the role of cell-extrinsic signaling in glioma stem cell biology and resistance. We have focused on two signaling pathways known to be relevant to neural and glioma stem cells, TGF-ß (3) and BMP (4,5).
Methods: The role of TGF-ß and BMP signaling in glioblastoma progression was examined using IHC in patient tumor samples and in vitro
studies of glioma stem cells. Our results were then analyzed against clinical and gene expression data from the TCGA and Rembrant datasets.
Results: We identified intratumoural heterogeneity in glioma stem cell phenotype driven by cell-extrinsic TGF-ß and BMP signaling. Activation of the TGF-ß pathway gives rise to a GSC that is highly proliferative and motile, but also sensitive to radiation- and chemotherapy-induced cell death. Conversely, BMP-acticated GSCs are relatively quiescent and sedentary, but are resistant to radiation and chemotherapy. These findings correlate with the mesenchymal and proneural glioblastoma subtypes, in which TGF- ß and BMP signaling predominate, respectively.
Conclusions: Cell-extrinsic signaling via the TGF-ß and BMP pathways has profound effects on glioma stem cell phenotype and on outcomes
in patients with glioblastoma. Modification of GSC phenotype through extrinsic manipulation of these signaling factors could be relevant to the care of patients with glioblastoma.
Patient Care: In our studies, activation of the TGF- pathways in GSCs resulted in increased cell proliferation but rendered this population more susceptible to chemotherapy- and radiation-induced cell death. Conversely, BMP activation in GSCs conferred these cells with greater resistance to chemotherapy and radiation, but also resulted in relative quiescence. We are currently performing studies in a mouse xenotransplant model to determine whether treatment with a TGF- agonist during adjuvant therapy followed by treatment with a BMP agonist results in improved survival.
Learning Objectives: By the conclusion of this session, participants should understand 1) the importance of cell-extrinsic signaling as a mechanism for
tumor heterogeneity and treatment resistance; and 2) the role of epigenetics in glioblastoma progression.