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Many genes that drive normal cellular development also contribute to oncogenesis. Medulloblastoma (MB) tumors likely arise from neuronal progenitors in the cerebellum, and we hypothesized that the heterogeneity observed in MBs with sonic hedgehog (SHH) activation could be due to differences in developmental pathways. To investigate this question, here we perform single-nucleus RNA sequencing on highly differentiated SHH MBs with extensively nodular histology and observed malignant cells resembling each stage of canonical granule neuron development. Through innovative computational approaches, we connect these results to published datasets and find that some established molecular subtypes of SHH MB appear arrested at different developmental stages. Additionally, using multiplexed proteomic imaging and MALDI imaging mass spectrometry, we identify distinct histological and metabolic profiles for highly differentiated tumors. Our approaches are applicable to understanding the interplay between heterogeneity and differentiation in other cancers and can provide important insights for the design of targeted therapies. The role of developmental pathways in medulloblastoma tumours (MB) with sonic hedgehog (SHH) activation remains to be explored. Here, the authors perform multi-omic analysis and characterise the key transcriptomic and metabolic patterns of highly differentiated cells in SHH MBs. [ABSTRACT FROM AUTHOR]

Medulloblastoma is the most common malignant brain tumor in children. It is thought to result from the transformation of granule cell precursors (GCPs) in the developing cerebellum, but little is known about the early stages of the disease. Here, we identify a pre-neoplastic stage of medulloblastoma in patched heterozygous mice, a model of the human disease. We show that pre-neoplastic cells are present in the majority of patched mutants, although only 16% of these mice develop tumors. Pre-neoplastic cells, like tumor cells, exhibit activation of the Sonic hedgehog pathway and constitutive proliferation. Importantly, they also lack expression of the wild-type patched allele, suggesting that loss of patched is an early event in tumorigenesis. Although pre-neoplastic cells resemble GCPs and tumor cells in many respects, they have a distinct molecular signature. Genes that mark the pre-neoplastic stage include regulators of migration, apoptosis and differentiation, processes crucial for normal development but previously unrecognized for their role in medulloblastoma. The identification and molecular characterization of pre-neoplastic cells provides insight into the early steps in medulloblastoma formation, and may yield important markers for early detection and therapy of this disease. [ABSTRACT FROM AUTHOR]

Brain tumors are among the most aggressive and intractable types of cancer. Recent studies indicate that brain tumor cells resemble neural stem cells in terms of phenotype, signaling, and behavior in vitro. In light of these similarities, it has been suggested that brain tumors arise from stem cells, that they co-opt stem cell strategies for self-renewal, and even that they contain “cancer stem cells” that are critical for tumor maintenance. We will examine these possibilities and discuss their implications for the understanding and treatment of brain tumors. [Copyright &y& Elsevier]

The capacity for self-renewal is thought to be a critical property of tumor-initiating cells. This capacity is often associated with the ability to generate spheres in vitro. In this issue of Cancer Cell, Barrett et al. show that cells lacking sphere-forming ability can still be very efficient at propagating tumors. [Copyright &y& Elsevier]

Cancer stem cells (CSCs) are thought to be critical for initiation and propagation of many types of cancer. Because these cells are resistant to conventional therapies, they have been very difficult to eliminate. A study in this issue of Cancer Cell suggests that brain tumor CSCs live in a “vascular niche” that promotes their long-term growth and self-renewal. Disrupting this niche impairs CSC self-renewal and thereby significantly inhibits the growth of tumors. Targeting the unique microenvironment of CSCs may be the key to effective cancer therapy. [Copyright &y& Elsevier]

Recent studies have suggested that brain tumors arise from neural stem cells and are maintained by stem-like tumor-initiating cells (TICs). In this issue of Cancer Cell, Persson et al. report that oligodendrogliomas, unlike malignant astrocytomas, originate from—and are propagated by—cells that resemble oligodendrocyte progenitors. [ABSTRACT FROM AUTHOR]