Pioneering models of pediatric brain tumors

Grigore, Florina; Yang, Serena Johanna; Chen, Clark C.; Koga, Tomoyuki

doi:10.1016/j.neo.2022.100859

Cited by 8 publications

(8 citation statements)

References 145 publications

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“…Finally, our animal model performed in mice intracranially engrafted with SHH-MB cell lines can be further improved by using patient-derived primary cells collected at recurrence. Once overcoming the low establishment rate of only around 35% [ 48 , 49 ], this type of model can more accurately recapitulate MB recurrence and metastasis in response to conventional therapies.…”

Section: Discussionmentioning

confidence: 99%

LOXL1-AS1 contributes to metastasis in sonic-hedgehog medulloblastoma by promoting cancer stem-like phenotypes

Do,

Wu,

Chu

et al. 2024

J Exp Clin Cancer Res

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Background Medulloblastomas (MBs) are one of the most common malignant brain tumor types in children. MB prognosis, despite improvement in recent years, still depends on clinical and biological risk factors. Metastasis is the leading cause of MB-related deaths, which highlights an unmet need for risk stratification and targeted therapy to improve clinical outcomes. Among the four molecular subgroups, sonic-hedgehog (SHH)-MB harbors clinical and genetic heterogeneity with a subset of high-risk cases. Recently, long non-coding (lnc)RNAs were implied to contribute to cancer malignant progression, but their role in MB remains unclear. This study aimed to identify pro-malignant lncRNAs that have prognostic and therapeutic significance in SHH-MB. Methods The Daoy SHH-MB cell line was engineered for ectopic expression of MYCN, a genetic signature of SHH-MB. MYCN-associated lncRNA genes were identified using RNA-sequencing data and were validated in SHH-MB cell lines, MB tissue samples, and patient cohort datasets. SHH-MB cells with genetic manipulation of the candidate lncRNA were evaluated for metastatic phenotypes in vitro, including cell migration, invasion, sphere formation, and expressions of stemness markers. An orthotopic xenograft mouse model was used to evaluate metastasis occurrence and survival. Finally, bioinformatic screening and in vitro assays were performed to explore downstream mechanisms. Results Elevated lncRNA LOXL1-AS1 expression was identified in MYCN-expressing Daoy cells and MYCN-amplified SHH-MB tumors, and was significantly associated with lower survival in SHH-MB patients. Functionally, LOXL1-AS1 promoted SHH-MB cell migration and cancer stemness in vitro. In mice, MYCN-expressing Daoy cells exhibited a high metastatic rate and adverse effects on survival, both of which were suppressed under LOLX1-AS1 perturbation. Integrative bioinformatic analyses revealed associations of LOXL1-AS1 with processes of cancer stemness, cell differentiation, and the epithelial-mesenchymal transition. LOXL1-AS1 positively regulated the expression of transforming growth factor (TGF)-β2. Knockdown of TGF-β2 in SHH-MB cells significantly abrogated their LOXL1-AS1-mediated prometastatic functions. Conclusions This study proved the functional significance of LOXL1-AS1 in SHH-MB metastasis by its promotion of TGF-β2-mediated cancer stem-like phenotypes, providing both prognostic and therapeutic potentials for targeting SHH-MB metastasis.

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Section: Discussionmentioning

confidence: 99%

LOXL1-AS1 contributes to metastasis in sonic-hedgehog medulloblastoma by promoting cancer stem-like phenotypes

Do,

Wu,

Chu

et al. 2024

J Exp Clin Cancer Res

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“…Here, we use a novel, iPSC-based model of H3.3K27M DMG to show that PDGFRA D842V and H3.3K27M cooperate to increase tumor cell proliferation, alter intracellular signaling and metabolism, and present vulnerabilities to combination therapy. A variety of mouse and human model systems of H3.3K27M DMG have been used to elucidate the impact of this histone mutation on the epigenetic and transcriptomic landscapes of normal and tumor cells (Cordero et al 2017; Grasso et al 2015; Grigore et al 2023; Haag et al 2021; Larson et al 2019; Misuraca et al 2016; Pathania et al 2017). iDMG augment these existing models in several important ways.…”

Section: Discussionmentioning

confidence: 99%

Cooperativity between H3.3K27M and PDGFRA poses multiple therapeutic vulnerabilities in human iPSC-derived diffuse midline glioma avatars

Skinner

Koga

Miki

et al. 2023

Preprint

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Diffuse midline glioma (DMG) is a leading cause of brain tumor death in children. In addition to hallmark H3.3K27M mutations, significant subsets also harbor alterations of other genes, such asTP53andPDGFRA. Despite the prevalence of H3.3K27M, the results of clinical trials in DMG have been mixed, possibly due to the lack of models recapitulating its genetic heterogeneity. To address this gap, we developed human iPSC-derived tumor models harboring TP53R248Qwith or without heterozygous H3.3K27M and/or PDGFRAD842Voverexpression. The combination of H3.3K27M and PDGFRAD842Vresulted in more proliferative tumors when gene-edited neural progenitor (NP) cells were implanted into mouse brains compared to NP with either mutation alone. Transcriptomic comparison of tumors and their NP cells of origin identified conserved JAK/STAT pathway activation across genotypes as characteristic of malignant transformation. Conversely, integrated genome-wide epigenomic and transcriptomic analyses, as well as rational pharmacologic inhibition, revealed targetable vulnerabilities unique to the TP53R248Q; H3.3K27M; PDGFRAD842Vtumors and related to their aggressive growth phenotype. These include AREG-mediated cell cycle control, altered metabolism, and vulnerability to combination ONC201/trametinib treatment. Taken together, these data suggest that cooperation between H3.3K27M and PDGFRA influences tumor biology, underscoring the need for better molecular stratification in DMG clinical trials.

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“…The utilization of cell lines derived from murine and rodent brain tumors has been extensively employed in scientific research. Notable examples encompass RG2, BT7C, CNS1, C6, and 9L [ 30 ]. A study by Hormuth et al used a chemically induced C6 glioma model to investigate the therapeutic effects of whole-brain radiation therapy in a cohort of 12 rats [ 31 ].…”

Section: In Vivo Models Of Brain Tumorsmentioning

confidence: 99%

Modeling of brain tumors using in vitro, in vivo, and microfluidic models: A review of the current developments

Raju R,

AlSawaftah,

Husseini

2024

Heliyon

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Pioneering models of pediatric brain tumors

Cited by 8 publications

References 145 publications

LOXL1-AS1 contributes to metastasis in sonic-hedgehog medulloblastoma by promoting cancer stem-like phenotypes

LOXL1-AS1 contributes to metastasis in sonic-hedgehog medulloblastoma by promoting cancer stem-like phenotypes

Cooperativity between H3.3K27M and PDGFRA poses multiple therapeutic vulnerabilities in human iPSC-derived diffuse midline glioma avatars

Modeling of brain tumors using in vitro, in vivo, and microfluidic models: A review of the current developments

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