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Gene Expression Profile of Radiation Therapy Resistant BRAFV600E Pediatric Gliomas

ABSTRACT: Inhibitors of the MAPK pathway (MAPKi) have shown significant activity in treatment of childhood BRAF-activated brain tumors. However, for tumors harboring BRAFV600E mutations, the drugs are rarely curative, and patients can become refractory to treatment. Combining MAPKi with low dose X-ray therapy (XRT) has the potential to improve the cure rate, but development of XRT resistance poses a major challenge. To understand the mechanisms of radiation resistance in BRAFV600E type pediatric low-grade gliomas, radiation resistance models were developed by using BT-40 pediatric low-grade glioma (PLGG) PDX model harboring BRAFV600E mutation. RNA sequencing was performed to determine the gene expression profile of primary tumors and resistant tumors. Each tumor tissue was transplanted to 3 scid mice respectively. When tumor volume reach ~0.3~0.6 cm3, tumor tissue (from three mice, triplicates) were collected and were snap-frozen in liquid nitrogen. RNA was isolated and applied to subsequent 100bp paired read sequencing run with Illumina NovaSeq 6000 platform at 100 bp paired-end module.

ORGANISM(S): Homo sapiens

PROVIDER: GSE271064 | GEO | 2025/09/17

REPOSITORIES: GEO

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Project description:Background Primitive brain tumors are the first cause of cancer-related death in children. Tumor cells with stem-like properties (TSCs), thought to account for tumorigenesis and therapeutic resistance, have been isolated from high-grade gliomas in adults. Whether TSCs are a common component of pediatric brain tumors and are of clinical relevance remains to be determined. Methodology/Principal findings Tumor cells with self-renewal properties were isolated with cell biology techniques from a majority of 55 pediatric brain tumors samples, regardless of their histopathologies and grades of malignancy (57% of embryonal tumors, 57% of low-grade gliomas and neuro-glial tumors, 70% of ependymomas, 91% of high-grade gliomas). The vast majority (10/12) of high-grade glioma-derived oncospheres sustained long-term self-renewal numbers akin to neural stem cells (>7 self-renewals), whereas cells with limited renewing abilities akin to neural progenitors dominated in all other tumor types. Regardless of tumor entities, the young age group was associated with self-renewal properties akin to neural stem cells (P=0.05, chi-square test). TSCs shared a complex molecular profile combining embryonic stem cell markers with elements controlling neural stem cell properties and epithelio-mesenchymal transitions. They were radio- and chemoresistant and formed aggressive tumors after intracerebral grafting. Survival analysis of the cohort showed an association between isolation of TSCs with long-term self-renewal abilities and a patients higher mortality rate (P = 0.022, log-rank test). Patients bearing cells with limited self-renewal properties constituted an intermediate group of survival but which did not reach statistical significance. Conclusions/Significance In brain tumors affecting adult patients, TSC have been isolated only from high-grade gliomas. In contrast, our data show that tumor cells with stem cell-like or progenitor-like properties can be isolated from a wide range of histological sub-types and grades of pediatric brain tumors. They suggest that cellular mechanisms fueling tumor development differ between adult and pediatric brain tumors.

Project description:Background Primitive brain tumors are the first cause of cancer-related death in children. Tumor cells with stem-like properties (TSCs), thought to account for tumorigenesis and therapeutic resistance, have been isolated from high-grade gliomas in adults. Whether TSCs are a common component of pediatric brain tumors and are of clinical relevance remains to be determined. Methodology/Principal findings Tumor cells with self-renewal properties were isolated with cell biology techniques from a majority of 55 pediatric brain tumors samples, regardless of their histopathologies and grades of malignancy (57% of embryonal tumors, 57% of low-grade gliomas and neuro-glial tumors, 70% of ependymomas, 91% of high-grade gliomas). The vast majority (10/12) of high-grade glioma-derived oncospheres sustained long-term self-renewal numbers akin to neural stem cells (>7 self-renewals), whereas cells with limited renewing abilities akin to neural progenitors dominated in all other tumor types. Regardless of tumor entities, the young age group was associated with self-renewal properties akin to neural stem cells (P=0.05, chi-square test). TSCs shared a complex molecular profile combining embryonic stem cell markers with elements controlling neural stem cell properties and epithelio-mesenchymal transitions. They were radio- and chemoresistant and formed aggressive tumors after intracerebral grafting. Survival analysis of the cohort showed an association between isolation of TSCs with long-term self-renewal abilities and a patientM-^Rs higher mortality rate (P = 0.022, log-rank test). Patients bearing cells with limited self-renewal properties constituted an intermediate group of survival but which did not reach statistical significance. Conclusions/Significance In brain tumors affecting adult patients, TSC have been isolated only from high-grade gliomas. In contrast, our data show that tumor cells with stem cell-like or progenitor-like properties can be isolated from a wide range of histological sub-types and grades of pediatric brain tumors. They suggest that cellular mechanisms fueling tumor development differ between adult and pediatric brain tumors.

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Gene Expression Profile of Radiation Therapy Resistant BRAFV600E Pediatric Gliomas

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