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Glioblastoma multiforme is a severe form of cancer most likely arising from the transformation of stem or progenitor cells resident in the brain. Although the tumorigenic population in glioblastoma is defined as composed by cancer stem cells (CSCs), the cellular target of the transformation hit remains to be identified. Glioma stem cells (SCs) are thought to have a differentiation potential restricted to the neural lineage. However, using orthotopic versus heterotopic xenograft models and in vitro differentiation assays, we found that a subset of glioblastomas contained CSCs with both neural and mesenchymal potential. Subcutaneous injection of CSCs or single CSC clones from two of seven patients produced tumor xenografts containing osteo-chondrogenic areas in the context of glioblastoma-like tumor lesions. Moreover, CSC clones from four of seven cases generated both neural and chondrogenic cells in vitro …