Diversity of Clinically Relevant Outcomes Resulting from Hypofractionated Radiation in Human Glioma Stem Cells Mirrors Distinct Patterns of Transcriptomic Changes

Abstract

Hypofractionated radiotherapy is the mainstay of the current treatment for glioblastoma. However, the efficacy of radiotherapy is hindered by the high degree of radioresistance associated with glioma stem cells comprising a heterogeneous compartment of cell lineages differing in their phenotypic characteristics, molecular signatures, and biological responses to external signals. Reconstruction of radiation responses in glioma stem cells is necessary for understanding the biological and molecular determinants of glioblastoma radioresistance. To date, there is a paucity of information on the longitudinal outcomes of hypofractionated radiation in glioma stem cells. This study addresses long-term outcomes of hypofractionated radiation in human glioma stem cells by using a combinatorial approach integrating parallel assessments of the tumor-propagating capacity, stemness-associated properties, and array-based profiling of gene expression. The study reveals a broad spectrum of changes in the tumor-propagating capacity of glioma stem cells after radiation and finds association with proliferative changes at the onset of differentiation. Evidence is provided that parallel transcriptomic patterns and a cumulative impact of pathways involved in the regulation of apoptosis, neural differentiation, and cell proliferation underly similarities in tumorigenicity changes after radiation.

Localization matters: nuclear-trapped Survivin sensitizes glioblastoma cells to temozolomide by elevating cellular senescence and impairing homologous recombination

“…An orthotopic intracranial murine model [21] was used to evaluate the tumorigenic potential of glioblastoma cells and the derived clones with differential subcellular localization of Survivin. Experiments were conducted at the Translational Animal Research Center (TARC) of the University Medical Center Mainz with the approval by the State Office of chemical investigations of Rhineland-Palatinate, Mainz, Germany (permission #23 177-07/G19-1-014).…”

DNA repair pathway activation features in follicular and papillary thyroid tumors, interrogated using 95 experimental RNA sequencing profiles

“…DNA damage is one of the major causes that trigger the development of tumors [ 14 , 15 ]. However, it also is an important focus in chemo and radiation therapy [ 16 , 17 , 18 ]. DNA repair mechanisms restore damaged DNA and may have a dual effect on the tumor: they prevent new somatic mutations and may restrict tumor development, but they also restore tumor cells with damaged DNA after chemo and radiation therapy [ 19 ].…”

Next-Generation Grade and Survival Expression Biomarkers of Human Gliomas Based on Algorithmically Reconstructed Molecular Pathways

“…The absence of clear genes and pathway biomarkers observed here may point to compromised biomarker capacity for previous expression biomarkers (such as EGFR and PD-L1), which may explain the controversial results for them in previous studies [38]. This may reflect outstandingly high heterogeneity in this group of tumors-at both the intra-and intertumoral levels [39,40]. Different sites within one GBM tumor may have different active driver fusion oncogenes [41], which complicates the molecular diagnosis and finding of effective long-standing treatment.…”