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Targeting Subgroup-specific Cancer Epitopes for Effective Treatment of Pediatric Medulloblastoma
Published in Surinder K. Batra, Moorthy P. Ponnusamy, Gene Regulation and Therapeutics for Cancer, 2021
Sidharth Mahapatra, Naveenkumar Perumall
During embryonic growth, neural precursor cells generated in the rhombic lip of the dorsal hindbrain migrate along the surface of the cerebellum to form the external granule layer (EGL). The secretion of bone morphogenic proteins (BMPs), such as BMP6, BMP7, and GDF7, encourages further proliferation generating a rich pool of granule cell precursors (GCPs) in the developing EGL [20, 36]. As older cells exit the EGL and migrate through a layer of Purkinje cells, they encounter the Hedgehog pathway ligand, Sonic hedgehog (SHH), a highly conserved embryonic signaling system which binds to its receptor, Patched 1 (PTCH1), expressed on GCPs in the EGL [37, 38]. Downstream effectors include the GLI family of transcription factors (GLI1, GLI2, and GLI3), which activate transcription of genes, such as cyclinD1 (CCND1) and MYC, thereby facilitating GCP proliferation and migration [7, 20, 36, 39]. After post-natal cerebellar development, this pathway goes dormant with the 12-pass transmembrane receptor, PTCH1, keeping the 7-pass transmembrane protein, Smoothened (SMO), in an inactivated state [40]. This, in turn, leads to the sequestration of downstream effectors of the SHH pathway by Suppressor-of-Fused (SUFU), effectively silencing gene expression [7]. Deregulated binding of SHH to PTCH1 releases and constitutively activates SMO which, in turn, inhibits SUFU, leading to release and nuclear translocation of GLI1-3; as a result, aberrant gene transcription is activated, facilitating phenotypic transformation into medulloblastoma [7].
Principles of neuromotor development
Published in Mijna Hadders-Algra, Kirsten R. Heineman, The Infant Motor Profile, 2021
Mijna Hadders-Algra, Kirsten R. Heineman
The development of the cerebellum has its own timing. Cells in the cerebellum originate from two proliferative zones: (1) the ventricular zone which brings forth the deep cerebellar nuclei and the Purkinje cells, and (2) the external granular layer originating from the rhombic lip (Volpe 2009b). Cell proliferation in the cerebellum starts at 11 weeks PMA in the ventricular zone and at 15 weeks in the external granular layer. The external granular layer is a transient structure reaching its peak thickness between 28 and 34 weeks PMA. It produces the most numerous cells of the cerebellum, the granule cells. These cells migrate from the external granular layer inward to their final destination in the internal granular layer. The latter grows most prominently between mid-gestation and three months post-term. The external granular layer shrinks, in particular between two and three months post-term. However, it takes until the second half of the first postnatal year for the external granular layer to dissolve entirely (Hadders-Algra 2018a).
Anatomical and Biological Imaging of Pediatric Brain Tumor
Published in David A. Walker, Giorgio Perilongo, Roger E. Taylor, Ian F. Pollack, Brain and Spinal Tumors of Childhood, 2020
Rob A. Dineen, Shivaram Avula, Andrew C. Peet, Giovanni Morana, Monika Warmuth-Metz
Analysis of conventional imaging features—location and enhancement pattern—for different molecular subtypes of medulloblastoma has shown that group III and IV tumors are located exclusively in the fourth ventricle; hemispheric tumors are highly likely to be SHH tumors (Figure 5.10a–d), although SHH tumors may still occur in the midline fourth ventricle, and WNT show lateralization.131 Indeed, when WNT medulloblastomas appear to be midline fourth ventricular tumors on preoperative imaging, review of the postoperative imaging may show evidence of a lateralized origin, and this lateralization has been related to the pathway of progenitor cell populations that have migrated from the embryologic lower rhombic lip, which give rise to the WNT tumors.132 Although all tumors subtypes can show enhancement, there is a higher frequency of non- or minimally enhancing tumors in group IV.131
Clinical and pre-clinical utility of genomics in medulloblastoma
Published in Expert Review of Neurotherapeutics, 2018
In contrast to the SHH models, tumors from the Wnt subgroup arise from the lower rhombic lip and embryonic dorsal brain stem [31]. Activating mutations of the Wnt pathway effector CTNNB1 lead to an accumulation of proliferative precursor cells on the embryonic dorsal brainstem. Several models of WNT medulloblastoma have been established; however, mutant mice harboring lesions in Ctnnb1 alone fail to form tumors. Somatic mutations of exon 3 of CTNNB1, promoting nuclear localization and stabilization of the β-catenin, are often accompanied by heterozygous TP53 mutations in Wnt medulloblastoma patients. Therefore, the addition of Trp53 deletion to the conditional stabilized allele of Ctnnb1 under the Blbp-Cre driver (Blbp-Cre; Ctnnb1lox(ex3); Trp53flox/+) generates WNT medulloblastoma with a 15% penetrance and latency of 290 days. Increased penetrance and lower latency for this model was achieved by introducing the Pik3ca mutant allele, a mutation found to cooperate with Wnt medulloblastoma progression, generating Blbp-Cre; Ctnnb1lox(ex3); Trp53flox/+; Pik3caE545K mice [54].
Overview and recent advances in the targeting of medulloblastoma cancer stem cells
Published in Expert Review of Anticancer Therapy, 2021
Normal cerebellar development begins during embryonic development and is completed several months after birth [43,44]. As medulloblastoma is an embryonal neoplasm derived from developing cells in the cerebellum, normal cerebellar development informs both the initiation of tumors and the pathways required for cancer stem cell maintenance [3]. Tumors from the different subgroups of medulloblastoma arise from cells from different parts of the developing cerebellum [10]. The upper rhombic lip is the source of the granule neuron precursors (GNPs) of the internal granule layer and external granule layer, the cells of origin for tumors in the SHH subgroup [3,45,46]. The lower rhombic lip is thought to be the site of origin of WNT subgroup tumors. Wnt signaling is active in neural stem cell proliferation, defining the midbrain-hindbrain boundary [43], and WNT medulloblastoma tumors are typically found in the fourth ventricle adjacent to the brainstem [47]. In 2019, Vladiou et al [11]. and Hovestadt et al [10]. applied single-cell RNA sequencing (scRNA-seq) to further investigate the cells of origin for each subtype as well as intratumoral cellular heterogeneity. They also clarified the cell of origin for Group 3/4 tumors; they appear to develop from the lineage of cells derived from a Nestin+ progenitor neural cell which differentiates into unipolar brush cells (UBC) and glutamatergic cerebellar nuclei (GCN) [10,11]. The scRNA-seq profile of Group 3/4 tumors lie along a continuum. Group 3 tumors contain higher numbers of cells that more closely resemble an undifferentiated progenitor cell, most markedly in MYC-amplified tumors, while Group 4 tumors are enriched in cells more similar to the more differentiated UBC and GCN cells [10]. These patterns correlate with the composition of methylation based Group 3/4 subtypes I–VIII [13]. Tumors that are in the middle of this continuum contained cells of both the differentiated and undifferentiated programs [10].
Pediatric embryonal brain tumors in the molecular era
Published in Expert Review of Molecular Diagnostics, 2020
Bryan K. Li, Salma Al-Karmi, Annie Huang, Eric Bouffet
SHH-activated tumors account for approximately 30% of MB cases. They often present in the cerebellar hemisphere and are proposed to arise from cerebellar granule neuron precursors originating from the rhombic lip [5,42]. SHH tumors includes a majority of MB with desmoplastic/nodular or MBEN histology, as well as a smaller proportion with classic histology, and rarely LCA histology.