Rare, quiescent SOX2+ cells drive SHH group medulloblastoma propagation and are chemoresistant.

  • Major finding: Rare, quiescent SOX2+ cells drive SHH group medulloblastoma propagation and are chemoresistant.

  • Mechanism: SOX2+ cells express a neuronal stem cell transcriptional program that promotes self-renewal in vivo.

  • Impact: Targeting the SOX2+ cell population may clinically benefit patients with SHH medulloblastoma.

The finding that approximately 30% of medulloblastomas display deregulated sonic hedgehog (SHH) pathway signaling has led to the clinical development of Hedgehog pathway inhibitors in SHH medulloblastomas, but reports of resistance suggest that a certain cell population may be inherently refractive to SHH pathway inhibition. A subset of medulloblastoma cells expressing neuronal stem markers have been shown to circumvent irradiation by entering into quiescence, prompting Vanner and colleagues to examine whether specific subpopulations of cells can drive tumor cell expansion in SHH medulloblastoma. Characterization of tumors formed in the Ptch1+/− mouse model of SHH medulloblastoma revealed phenotypic heterogeneity, with the bulk of the tumor expressing markers of neural progenitor cells or nascent neurons and fewer than 5% of cells expressing the neural stem cell marker SOX2. Assessment of proliferative capacity revealed slow, continuous cycling of SOX2+ cells that was indicative of quiescence, and SOX2+ cells were shown to possess self-renewal and differentiation capacity in vitro and in vivo. Lineage tracing experiments further confirmed that the rare SOX2+ cell population is self-renewing and capable of differentiating into the rapidly cycling cells that make up the bulk of tumors, implicating SOX2+ cells as tumor-propagating cells in SHH medulloblastoma. Importantly, treatment of tumors with an antimitotic agent or the Smoothened inhibitor vismodegib led to an enrichment of SOX2+ cells, suggesting that these tumor-propagating cells are spared by traditional or targeted therapies and may comprise a reservoir for tumor relapse. Consistent with this concept, high SOX2 expression and a SOX2+ cell signature correlated with poor patient prognosis. A screen for compounds that target primary SOX2-expressing SHH medulloblastoma cells identified mithramycin, which limited self-renewal and tumor growth in the Ptch1+/− model. These findings implicate the SOX2+ quiescent cell population in SHH medulloblastoma propagation and provide a rationale for therapeutic strategies that target this population as well as the tumor bulk.

Vanner RJ, Remke M, Gallo M, Selvadurai HJ, Coutinho F, Lee L, et al. Quiescent Sox2+ cells drive hierarchical growth and relapse in Sonic Hedgehog subgroup medulloblastoma. Cancer Cell 2014;26:33–47.

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