Mosaic Analysis with Double Markers Reveals Tumor Cell of Origin in Glioma

Abstract

SUMMARY Cancer cell-of-origin is difficult to identify by analyzing cells within terminal-stage tumors, whose identity could be concealed by the acquired plasticity. Thus an ideal approach to identify the cell-of-origin is to analyze proliferative abnormalities in distinct lineages prior to malignancy. Here we use Mosaic Analysis with Double Markers (MADM) in mice to model gliomagenesis by initiating concurrent p53/Nf1 mutations sporadically in neural stem cells (NSCs). Surprisingly, MADM-based lineage tracing revealed significant aberrant growth prior to malignancy only in oligodendrocyte precursor cells (OPCs), but not in any other NSC-derived lineages or NSCs themselves. Upon tumor formation, phenotypic and transcriptome analyses of tumor cells revealed salient OPC features. Finally, introducing the same p53/Nf1 mutations directly into OPCs consistently led to gliomagenesis. 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 pre-malignant stages to identify the cancer cell-of-origin.

Transposon mutagenesis identifies genes that transform neural stem cells into glioma-initiating cells

“…Recent data have suggested that the COO for the proneural subtype of GBM is an OPC, even though the originating mutations occurred in the NSC (38). Likewise, our results suggest that the COO for the mesenchymal subtype of GBM is an astroglial-like cell, even when the originating mutations occurred in the NSC.…”

“…The in vitro propagation stage, which allows mutagenesis to select for distinct properties, such as immortalization, has much potential, although this strategy also has its limitations, because not all cell types can be propagated in vitro. Liu et al (38) showed that OPCs are the COO for the proneural subtype of GBM. OPCs can be induced from NSCs by culturing the cells with defined media (52), raising the possibility that the proneural subtype of GBMs can be modeled by inducing OPCs from NSCs and then transplanting these cells into immunocompromised mice to generate tumors.…”

Understanding cancer stem cell heterogeneity and plasticity

“…The transformed cell may remain dormant for decades without generating a clinically detectable tumor. Recent studies using elegant MADM (mosaic www.cell-research.com | Cell Research Dean G Tang 463 npg analysis using double markers) mouse models provide strong support for this scenario by showing that the oligodendrocyte precursor cells represent the cell-of-origin for malignant gliomas, although the initial transformation occurs in all neural and glial progenitors [45]. Fourth, as CSCs are in most cases defined, operationally, as tumorinitiating cells and because the current CSC assays have inherent limitations (e.g., relying heavily on xenotransplantations), the reported CSCs may not necessarily be the same as the founding cells that gave rise to patient tumors in vivo.…”

Roles for Hedgehog signaling in adult organ homeostasis and repair

“…Augmentation of SHH signaling by in vivo ligand infusion was shown to increase oligodendrocyte production in the adult forebrain and spinal cord (Bambakidis et al, 2003;Loulier et al, 2006), although the identity of the SHH-responding cells in the latter case is unclear. The role for SHH signaling in oligodendrogenesis is particularly intriguing in light of a recent study indicating that oligodendrocyte progenitor cells can act as the cell of origin for glioblastomas (Liu et al, 2011). Such observations raise the possibility that atypical activation of SHH signaling could be sufficient to transform the ability of the brain to repair itself into a malignant process.…”