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Glioblastomas (GBM) are lethal brain tumors where poor outcome is attributed to cellular heterogeneity, therapeutic resistance, and a highly infiltrative nature. These characteristics are preferentially linked to GBM cancer stem cells (GSC), but how GSCs maintain their stemness is incompletely understood and the subject of intense investigation. Here, we identify a novel signaling loop that induces and maintains GSCs consisting of an atypical metalloproteinase, ADAMDEC1, secreted by GSCs. ADAMDEC1 rapidly solubilizes FGF2 to stimulate FGFR1 expressed on GSCs. FGFR1 signaling induces upregulation of ZEB1 via ERK1/2 that regulates ADAMDEC1 expression through miR-203, creating a positive feedback loop. Genetic or pharmacologic targeting of components of this axis attenuates self-renewal and tumor growth. These findings reveal a new signaling axis for GSC maintenance and highlight ADAMDEC1 and FGFR1 as potential therapeutic targets in GBM. Significance: Cancer stem cells (CSC) drive tumor growth in many cancers including GBM. We identified a novel sheddase, ADAMDEC1, which initiates an FGF autocrine loop to promote stemness in CSCs. This loop can be targeted to reduce GBM growth.

Glioblastoma (GBM) is the most lethal and aggressive brain cancer in adults with a median survival of approximately 20 months after diagnosis. GBM represents a highly infiltrative and heterogenous tumour, formed by populations of cells harbouring diverse molecular signatures and responses to therapy. Tumour recurrence and poor prognosis have been thought to be a consequence of resident glioblastoma stem cells (GSCs), which are quiescent cells capable of self-renewal, migration and initiation of new tumours. These cells are subject to cell-autonomous factors and extrinsic cues, which are translated into cell responses that promote tumour progression. Particularly, trophic factors from the tumour microenvironment, such as fibroblast growth factor 2 (FGF2), are essential to GBM growth and GSC maintenance. FGF2 and its cognate receptors have been linked to malignancy and progression in GBM as they promote angiogenesis, proliferation and GSC self-renewal. However, the specific mechanisms of how this growth factor contributes to GSC functions remain incompletely understood. Therefore, we analysed expression of FGF receptors (FGFRs) and the effects of FGF2 on patient-derived glioblastoma cells. We found that FGF2 induces expression of the stemness-associated transcription factors ZEB1, SOX2 and OLIG2. Analysis of FGFR1-3 function using knockdown approaches in patient-derived glioblastoma cell lines revealed that FGFR1 was the only FGFR relevant for GSC maintenance. FGFR1 knockdown reduced sphere/colony-formation, invasion and increased survival in xenograft mouse models. On the other hand, serial dilution orthotopic xenografts of FGFR1+ sorted cells revealed higher tumour formation capacity than FGFR1- cells, consistent with a stem cell population. We found that differentiated cancer cells showed a reduction in FGFR1, ZEB1, SOX2 and OLIG2 expression, and that FGFR1 regulated ZEB1 function through ERK1/2 signalling. Finally, analysis of large-scale gene-expression datasets

Glioblastoma (GBM) is the most lethal and aggressive brain cancer in adults with a median survival of approximately 20 months after diagnosis. GBM represents a highly infiltrative and heterogenous tumour, formed by populations of cells harbouring diverse molecular signatures and responses to therapy. Tumour recurrence and poor prognosis have been thought to be a consequence of resident glioblastoma stem cells (GSCs), which are quiescent cells capable of self-renewal, migration and initiation of new tumours. These cells are subject to cell-autonomous factors and extrinsic cues, which are translated into cell responses that promote tumour progression. Particularly, trophic factors from the tumour microenvironment, such as fibroblast growth factor 2 (FGF2), are essential to GBM growth and GSC maintenance. FGF2 and its cognate receptors have been linked to malignancy and progression in GBM as they promote angiogenesis, proliferation and GSC self-renewal. However, the specific mechanisms of how this growth factor contributes to GSC functions remain incompletely understood. Therefore, we analysed expression of FGF receptors (FGFRs) and the effects of FGF2 on patient-derived glioblastoma cells. We found that FGF2 induces expression of the stemness-associated transcription factors ZEB1, SOX2 and OLIG2. Analysis of FGFR1-3 function using knockdown approaches in patient-derived glioblastoma cell lines revealed that FGFR1 was the only FGFR relevant for GSC maintenance. FGFR1 knockdown reduced sphere/colony-formation, invasion and increased survival in xenograft mouse models. On the other hand, serial dilution orthotopic xenografts of FGFR1+ sorted cells revealed higher tumour formation capacity than FGFR1- cells, consistent with a stem cell population. We found that differentiated cancer cells showed a reduction in FGFR1, ZEB1, SOX2 and OLIG2 expression, and that FGFR1 regulated ZEB1 function through ERK1/2 signalling. Finally, analysis of large-scale gene-expression datasets