Developmental origins and oncogenic pathways in malignant brain tumors

Abstract

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.

Organoid Models of Glioblastoma to Study Brain Tumor Stem Cells

“…At present, it is not clear how this might influence tumor properties. In the future, it would be interesting to develop a similar approach to model and study prenatal and childhood tumors, such as pediatric gliomas and medulloblastomas, which should maintain a closer link to their developmental origin (Liu and Zong, 2012;Azzarelli et al, 2018;Lu et al, 2019). As medulloblastoma did not develop in organoids, even when genetic alterations typical of this tumors were introduced, it might be necessary to generate regionalized organoids (Muguruma et al, 2015;Dias and Guillemot, 2017;Renner et al, 2017;Ballabio et al, 2020) tailored to the area of origin of that specific tumor, prior to transformation.…”

“…The idea that tumor initiation, progression and regrowth after treatment are sustained by a subpopulation of cancer cells, the glioblastoma stem cells (GSCs), has been crucial to our current understating of glioblastoma (GBM) biology (Swartling et al, 2015;Alcantara Llaguno et al, 2016;Azzarelli et al, 2018;Hakes and Brand, 2019;Lu et al, 2019). Glioblastoma is a highly aggressive brain tumor characterized by elevated intratumor heterogeneity, which could be potentially attributed to variations in GSC behavior and stochastic consequences of their hierarchical growth pattern.…”

Accumulation of DNA methylation alterations in paediatric glioma stem cells following fractionated dose irradiation

“…Paediatric high-grade gliomas originate from cells along the neural stem cell lineages [31]. These cells have the capacity to generate a variety of different cell types: activated stem cells, progenitor cells and mature cells such as astrocytes, oligodendrocytes and neurons [32]. The DNA methylation pattern is strictly regulated during differentiation and development allowing each cell type to acquire its required phenotype to meet its specific functions and needs.…”

The Non-coding Side of Medulloblastoma

“…Medulloblastoma tumors are thought to originate in the cerebellum, except for the WNT subgroups that arise outside the cerebellum and are distributed within the fourth ventricle and infiltrated the dorsal surface of the brainstem (Gibson et al, 2010). Dorsal brainstem progenitor cells of cochlear, mossy fiber, and climbing fiber neurons are regarded as the potential source of these tumors (Gibson et al, 2010), following the activation of Ctnnb1 and the concurrent Trp53 deletion (Lu et al, 2019).…”

“…Differently, all available SHH-subtype tumors were localized away from the brainstem, within the cerebellar hemispheres. They are thought to originate from cerebellar neural stem cells (NSCs) or committed granule neuron precursor cells (GNPCs) following aberrant activation of SHH (Gibson et al, 2010;Lu et al, 2019). The group 3 MB tumors are often positioned near the fourth ventricle, pointing to cerebellar stem/progenitor cells or GNPCs as potential sources (Kawauchi et al, 2012;Pei et al, 2012;Lu et al, 2019).…”