Acquisition of granule neuron precursor identity is a critical determinant of progenitor cell competence to form Hedgehog-induced medulloblastoma

By U. Schüller, V. Heine, J. Mao, A. Kho, Allison K. Dillon, Young-Goo Han, E. Huillard, T. Sun, A. Ligon, Y. Qian and 5 more. Cancer Cell, 2008

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Origins of the brain tumor, medulloblastoma, from stem cells or restricted progenitor cells are unclear. To investigate this, we activated oncogenic Hedgehog (Hh) signaling in multipotent and lineage-restricted CNS progenitors. We observed that normal unipotent cerebellar granule neuron precursors (CGNP) derive from hGFAP+ and Olig2+ RL progenitors. Hh activation in a spectrum of early and late stage CNS progenitors generated similar medulloblastomas, but not other brain cancers, indicating that acquisition of CGNP identity is essential for tumorigenesis. We show in human and mouse medulloblastoma that cells expressing the glia-associated markers Gfap and Olig2 are neoplastic and that they retain features of embryonic-type granule lineage progenitors. Thus, oncogenic Hh signaling promotes medulloblastoma from lineage-restricted granule cell progenitors.

Subfields: Developmental Neuroscience, Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/28b293b750f72b5411d061aa2b9e411b4bd79759

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Citations in the corpus

Molecular subgroups of medulloblastoma: an international meta-analysis of transcriptome, genetic aberrations, and clinical data of WNT, SHH, Group 3, and Group 4 medulloblastomas (2012, background): “Most likely, they will also have different cellular origins, as has already been shown for the WNT and SHH subgroups [7, 8, 23, 26].”
Mosaic Analysis with Double Markers (MADM) Reveals Tumor Cell-of-Origin in Glioma (2011, neutral): “Our findings suggest OPCs as the cell of origin in this model, even when initial mutations occur in NSCs, and highlight the importance of analyzing premalignant stages to identify the cancer cell of origin.”
Hedgehog Signaling in Development and Cancer (2008, positive): “Consistent with this, two recent studies have demonstrated that Hh pathway activation in mouse neural stem cells or restricted neural progenitors induces only medullo-blastoma, not glioma (Schuller et al., 2008; Yang et al., 2008).”
Dysregulation of the Wnt pathway inhibits timely myelination and remyelination in the mammalian CNS. (2009, methodology): “A multifunctional mouse line was constructed previously (Schüller et al. 2008) by inserting tva, an avianspecific retroviral receptor, and an IRES-cre recombinase cassette into the endogenous Olig2 locus by homologous recombination.”
Cancer Stem Cells (CSCs) in Drug Resistance and their Therapeutic Implications in Cancer Treatment (2018, background): “In addition, it has been shown that oncogenic Hh signaling can promote medulloblastoma from either lineage-restricted granule cell progenitors or stem cells [48, 49].”
Cancer stem cells: impact, heterogeneity, and uncertainty. (2012, background): “Medulloblastomas can arise either from Sonic Hedgehog pathway activation in granule neuron precursors of the cerebellum or from Wnt pathway activation in dorsal brainstem progenitors (Gibson et al., 2010; Schüller et al., 2008; Yang et al., 2008) (Figure 2B).”