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Developmental origins and oncogenic pathways in malignant brain tumors

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Brain tumors such as adult glioblastomas and pediatric high‐grade gliomas or medulloblastomas are among the leading causes of cancer‐related deaths, exhibiting poor prognoses with little improvement in outcomes in the past several decades. These tumors are heterogeneous and can be initiated from various neural cell types, contributing to therapy resistance. How such heterogeneity arises is linked to the tumor cell of origin and their genetic alterations. Brain tumorigenesis and progression recapitulate key features associated with normal neurogenesis; however, the underlying mechanisms are quite dysregulated as tumor cells grow and divide in an uncontrolled manner. Recent comprehensive genomic, transcriptomic, and epigenomic studies at single‐cell resolution have shed new light onto diverse tumor‐driving events, cellular heterogeneity, and cells of origin in different brain tumors. Primary and secondary glioblastomas develop through different genetic alterations and pathways, such as EGFR amplification and IDH1/2 or TP53 mutation, respectively. Mutations such as histone H3K27M impacting epigenetic modifications define a distinct group of pediatric high‐grade gliomas such as diffuse intrinsic pontine glioma. The identification of distinct genetic, epigenomic profiles and cellular heterogeneity has led to new classifications of adult and pediatric brain tumor subtypes, affording insights into molecular and lineage‐specific vulnerabilities for treatment stratification. This review discusses our current understanding of tumor cells of origin, heterogeneity, recurring genetic and epigenetic alterations, oncogenic drivers and signaling pathways for adult glioblastomas, pediatric high‐grade gliomas, and medulloblastomas, the genetically heterogeneous groups of malignant brain tumors. This article is categorized under: Gene Expression and Transcriptional Hierarchies > Gene Networks and Genomics Adult Stem Cells, Tissue Renewal, and Regeneration > Stem Cell Differentiation and Reversion Signaling Pathways > Cell Fate Signaling
Cells of origin and tumor‐driving pathways in brain tumors. (a) Multipotent NSCs have capability to self‐renew and differentiate into different fate‐restricted progenitors. Under genetic and epigenetic alterations, these progenitor cells could be transformed into malignant tumors including gliomas from NSC, OPC or APC as well as medulloblastomas from NPCs. (b) A hierarchical model for tumor cell evolution and plasticity to generate distinct tumor‐forming cells and tumor heterogeneity gained after tumor initiation. (c) Malignant transformation of GBM is the result of different driver pathway alterations. RTK signaling pathway activation mediated by extracellular signal (growth factors, cytokines, and hormones) promotes cell cycling for tumorigenesis. Besides, point mutation of histone 3 (H3K27M, H3G34R/V) and upregulation of oncogenic factors, like MYC(N) and AURK, which lead to tumor cell proliferation. Moreover, IDH mutations later Krebs cycle in mitochondria, which further alter activity of downstream epigenetic regulators, including TET1/2 and KDM, leading to methylation alterations for DNA and nucleosome states susceptible to for tumorigenesis. APC, astrocyte progenitor cell; AURK, aurora kinase; GBM, glioblastoma; IDH, isocitrate dehydrogenase; KDM, lysine(K)‐specific demethylase; MYC, myelocytomatosis viral oncogene; NPC, neuron progenitor cell; NSCs, neural stem cells; OPC, oligodendrocyte progenitor cell; RTK, receptor tyrosine kinase; TET, Tet oncogene
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Developmental origins and key signaling pathways in MB tumorigenesis. (a) Potential progenitor sources for distinct MB in the posterior fossa. Progenitor cells in the ventricular zone (SHH, Group 3 and Group 4), EGL (SHH), anterior brainstem progenitors (SHH or other groups), and dorsal brainstem (WNT) contribute to distinct MB subtype tumorigenesis. (b) Distinct MB subtypes (WNT, SHH, Group 3 and Group 4) show different signaling driving pathways for promoting cell cycling and growth. In WNT MB, activated β‐catenin cooperates with transcription factor LEF/TCF to promote cell proliferation. In SHH MB, transmembrane proteins PTCH, SMO‐ and GPCR‐mediated transcriptional factor Gli activation for tumorigenesis. In Group 3 MB, oncogene MYC activates transcriptional factor GFI1 and promote tumorigenesis. Group 4 MB shows activation of ERBB4 and EGFR signaling. GFI1, growth factor independent 1 transcriptional repressor; Gli, glioma‐associated oncogene; GPCR, G protein coupled receptor; LEF/TCF, lymphoid enhancer binding factor/T‐cell specific transcription factor; MB, medulloblastoma; MYC, myelocytomatosis viral oncogene; PTCH, patched; SMO, smoothed
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Adult Stem Cells, Tissue Renewal, and Regeneration > Stem Cell Differentiation and Reversion
Signaling Pathways > Cell Fate Signaling
Gene Expression and Transcriptional Hierarchies > Gene Networks and Genomics