BIRC3 is a biomarker of mesenchymal habitat of glioblastoma, and a mediator of survival adaptation in hypoxia-driven glioblastoma habitats.
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ABSTRACT:
SUBMITTER: Wang D
PROVIDER: S-EPMC5570925 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Genome-wide analysis of glioblastoma (GBM) reveals pervasive aberrations in apoptotic signaling pathways that collectively contribute to therapeutic resistance. Inhibitors of apoptosis proteins (IAP) exert critical control on the terminal segment of apoptosis leading to apoptosis evasion. In this study, we uncover a unique role for BIRC3, as an IAP that is critical in GBM in response to therapy. Using the TCGA dataset of 524 unique samples, we identify BIRC3 is the only IAP whose differential expression is associated with long-term survival in GBM patients. Using patient tissue samples we further show that BIRC3 expression increases with recurrence. When extrapolated to a preclinical model of a human GBM cell line, we find an increase in BIRC3 expression in response to irradiation (RT) and temozolomide (TMZ) treatment. More importantly, we mechanistically implicate STAT3 and PI3K signaling pathways as drivers of RT-induced up-regulation of BIRC3 expression. Lastly, we demonstrate that both in-vivo and in-vitro BIRC3 up-regulation results in apoptosis evasion and therapeutic resistance in GBM. Collectively, our study identifies a novel translational and targetable role for BIRC3 expression as a predictor of aggressiveness and therapeutic resistance to TMZ and RT mediated by STAT3 and PI3K signaling in GBM.
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Project description:Stemness reprogramming remains a largely unaddressed principal cause of lethality in glioblastoma (GBM). It is therefore of utmost importance to identify and target mechanisms that are essential for GBM stemness and self-renewal. Previously, we implicated BIRC3 as an essential mediator of therapeutic resistance and survival adaptation in GBM. In this study, we present novel evidence that BIRC3 has an essential noncanonical role in GBM self-renewal and stemness reprogramming. We demonstrate that BIRC3 drives stemness reprogramming of human GBM cell lines, mouse GBM cell lines and patient-derived GBM stem cells (GSCs) through regulation of BMP4 signaling axis. Specifically, BIRC3 induces stemness reprogramming in GBM through downstream inactivation of BMP4 signaling. RNA-Seq interrogation of the stemness reprogramming hypoxic (pseudopalisading necrosis and perinecrosis) niche in GBM patient tissues further validated the high BIRC3/low BMP4 expression correlation. BIRC3 knockout upregulated BMP4 expression and prevented stemness reprogramming of GBM models. Furthermore, siRNA silencing of BMP4 restored stemness reprogramming of BIRC3 knockout in GBM models. In vivo silencing of BIRC3 suppressed tumor initiation and progression in GBM orthotopic intracranial xenografts. The stemness reprograming of both GSCs and non-GSCs populations highlights the impact of BIRC3 on intra-tumoral cellular heterogeneity GBM. Our study has identified a novel function of BIRC3 that can be targeted to reverse stemness programming of GBM.
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Project description:Hypoxia inducible factor (HIFs) signaling contributes to malignant cell behavior in glioblastoma (GBM). We investigated a novel HIF2α inhibitor, PT2385, both in vitro, with low-passage patient-derived cell lines, and in vivo, using orthotopic models of glioblastoma. We focused on analysis of HIF2α expression in situ, cell survival/proliferation, and survival in brain tumor-bearing mice treated with PT2385 alone and in combination with standard of care chemoradiotherapy. HIF2α expression increased with glioma grade, with over half of GBM specimens HIF2α positive. Staining clustered in perivascular and perinecrotic tumor regions. Cellular phenotype including proliferation, viability, migration/invasion, and also gene expression were not altered after PT2385 treatment. In the animal model, PT2385 single-agent treatment did improve median overall survival compared to placebo (p = 0.04, n = 21) without a bioluminescence correlate (t = 0.67, p = 0.52). No difference in animal survival was seen in combination treatment with radiation (RT)/temozolomide (TMZ)/PT2385 (p = 0.44, n = 10) or mean tumor bioluminescence (t 1.13, p = 0.32). We conclude that HIF2α is a reasonable novel therapeutic target as expressed in the majority of glioblastomas in our cohort. PT2385 as a single-agent was efficacious in vivo, however, an increase in animal survival was not seen with PT2385 in combination with RT/TMZ. Further study for targeting HIF2α as a therapeutic approach in GBM is warranted.
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Project description:Microenvironmental conditions such as hypoxia potentiate the local invasion of malignant tumors including glioblastomas by modulating signal transduction and protein modification, yet the mechanism by which hypoxia controls cytoskeletal dynamics to promote the local invasion is not well defined. Here, we show that cyclin G2 plays pivotal roles in the cytoskeletal dynamics in hypoxia-driven invasion by glioblastoma cells. Cyclin G2 is a hypoxia-induced and cytoskeleton-associated protein and is required for glioblastoma expansion. Mechanistically, cyclin G2 recruits cortactin to the juxtamembrane through its SH3 domain-binding motif and consequently promotes the restricted tyrosine phosphorylation of cortactin in concert with src. Moreover, cyclin G2 interacts with filamentous actin to facilitate the formation of membrane ruffles. In primary glioblastoma, cyclin G2 is abundantly expressed in severely hypoxic regions such as pseudopalisades, which consist of actively migrating glioma cells. Furthermore, we show the effectiveness of dasatinib against hypoxia-driven, cyclin G2-involved invasion in vitro and in vivo. Our findings elucidate the mechanism of cytoskeletal regulation by which severe hypoxia promotes the local invasion and may provide a therapeutic target in glioblastoma.
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Project description:Understanding the key aspects of plant regeneration from seeds is crucial in assessing species assembly to their habitats. However, the regenerative traits of seed dormancy and germination are underrepresented in this context. In the alpine zone, the large species and microhabitat diversity provide an ideal context to assess habitat-related regenerative strategies. To this end, seeds of 53 species growing in alpine siliceous and calcareous habitats (6230 and 6170 of EU Directive 92/43, respectively) were exposed to different temperature treatments under controlled laboratory conditions. Germination strategies in each habitat were identified by clustering with k-means. Then, phylogenetic least squares correlations (PGLS) were fitted to assess germination and dormancy differences between species' main habitat (calcareous and siliceous), microhabitat (grasslands, heaths, rocky, and species with no specific microhabitats), and chorology (arctic-alpine and continental). Calcareous and siliceous grasslands significantly differ in their germination behaviour with a slow, mostly overwinter germination and high germination under all conditions, respectively. Species with high overwinter germination occurs mostly in heaths and have an arctic-alpine distribution. Meanwhile, species with low or high germinability in general inhabit in grasslands or have no specific microhabitat (they belong to generalist), respectively. Alpine species use different germination strategies depending on habitat provenance, species' main microhabitat, and chorotype. Such differences may reflect adaptations to local environmental conditions and highlight the functional role of germination and dormancy in community ecology.
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