Sox2 Is Required to Maintain Cancer Stem Cells in a Mouse Model of High-Grade Oligodendroglioma

• Published in: Cancer research (Chicago, Ill.) Vol. 74; no. 6; pp. 1833 - 1844
• Main Authors: FAVARO, Rebecca, APPOLLONI, Irene, MALATESTA, Paolo, NICOLIS, Silvia K, PELLEGATTA, Serena, SANGA, Alexandra Badiola, PAGELLA, Pierfrancesco, GAMBINI, Eleonora, PISATI, Federica, OTTOLENGHI, Sergio, FOTI, Maria, FINOCCHIARO, Gaetano
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.03.2014
• Subjects: Animals; Antineoplastic agents; Biological and medical sciences; Brain Neoplasms - immunology; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; Brain Neoplasms - therapy; Cancer Vaccines; Cell Line, Tumor; Cell Proliferation; Female; Immunotherapy; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Transgenic; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplastic Stem Cells - physiology; Neurology; Oligodendroglioma - immunology; Oligodendroglioma - metabolism; Oligodendroglioma - pathology; Oligodendroglioma - therapy; Peptide Fragments - immunology; Pharmacology. Drug treatments; SOXB1 Transcription Factors - immunology; SOXB1 Transcription Factors - physiology; Transcriptome; Tumor Cells, Cultured; Tumors; Tumors of the nervous system. Phacomatoses; Animal model; Nervous system diseases; Stem cell; Rodentia; Malignant tumor; High grade; Oligodendroglioma; Malignant glioma; Vertebrata; Mammalia; Mouse; Central nervous system disease; Tumor cell; Cancer; High malignancy
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-13-1942

The stem cell-determining transcription factor Sox2 is required for the maintenance of normal neural stem cells. In this study, we investigated the requirement for Sox2 in neural cancer stem-like cells using a conditional genetic deletion mutant in a mouse model of platelet-derived growth factor-induced malignant oligodendroglioma. Transplanting wild-type oligodendroglioma cells into the brain generated lethal tumors, but mice transplanted with Sox2-deleted cells remained free of tumors. Loss of the tumor-initiating ability of Sox2-deleted cells was reversed by lentiviral-mediated expression of Sox2. In cell culture, Sox2-deleted tumor cells were highly sensitive to differentiation stimuli, displaying impaired proliferation, increased cell death, and aberrant differentiation. Gene expression analysis revealed an early transcriptional response to Sox2 loss. The observed requirement of oligodendroglioma stem cells for Sox2 suggested its relevance as a target for therapy. In support of this possibility, an immunotherapeutic approach based on immunization of mice with SOX2 peptides delayed tumor development and prolonged survival. Taken together, our results showed that Sox2 is essential for tumor initiation by mouse oligodendroglioma cells, and they illustrated a Sox2-directed strategy of immunotherapy to eradicate tumor-initiating cells.