Abstract
Glioblastoma multiforme continues to have a dismal prognosis. Even though detailed information on the genetic aberrations in cell signaling and cell-cycle checkpoint control is available, no effective targeted treatment has been developed. Despite the advanced molecular defects, glioblastoma cells may have remnants of normal growth-inhibitory pathways, such as the bone morphogenetic protein (BMP) signaling pathway. We have evaluated the growth-inhibitory effect of BMP4 across a broad spectrum of patient samples, using a panel of 40 human glioblastoma initiating cell (GIC) cultures. A wide range of responsiveness was observed. BMP4 sensitivity was positively correlated with a proneural mRNA expression profile, high SOX2 activity, and BMP4-dependent upregulation of genes associated with inhibition of the MAPK pathway, as demonstrated by gene set enrichment analysis. BMP4 response in sensitive cells was mediated by the canonical BMP receptor pathway involving SMAD1/5/9 phosphorylation and SMAD4 expression. SOX2 was consistently downregulated in BMP4-treated cells. Forced expression of SOX2 attenuated the BMP4 sensitivity including a reduced upregulation of MAPK-inhibitory genes, implying a functional relationship between SOX2 downregulation and sensitivity. The results show an extensive heterogeneity in BMP4 responsiveness among GICs and identify a BMP4-sensitive subgroup, in which SOX2 is a mediator of the response. IMPLICATIONS: Development of agonists targeting the BMP signaling pathway in glioblastoma is an attractive avenue toward a better treatment. Our study may help find biomarkers that predict the outcome of such treatment and enable stratification of patients.
Highlights
Research on the biology of glioblastoma multiforme (GBM) has progressed considerably during the last decade
To get a global view of how long-term BMP4 exposure affects sensitive and resistant cells, RNA sequencing was performed on two sensitive (U3017 and U3065) and two resistant (U3028 and U3019) cell lines cultured in the absence or presence of BMP4 for 14 days (Fig. 1C)
Previous reports on the growth-inhibitory effect of BMP4 on human GBM cells have provided conflicting results
Summary
Research on the biology of glioblastoma multiforme (GBM) has progressed considerably during the last decade. Aberrations in four main signaling pathways (Ras-Erk, pRB, p53, and PI3K-AKT) are common themes [1, 2]. Basic information on the molecular defects in GBM has not been translated into therapy. There are two main reasons why this rather harsh treatment fails in virtually all cases. Tumor growth is fueled by glioma-initiating cells (GIC), which have stem cell characteristics [3, 4] and as such resist therapy [4, 5]. GBM cells are extremely invasive and, at the time of diagnosis, tumor cells have, in principle, invaded the whole brain. There is an urgent need for better therapy
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