MiRNA profiles in Primary and Recurrent GBM
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ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Shih-Hwa Chiou
PROVIDER: E-GEOD-32466 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:Glioblastoma (GBM) bears a dismal prognosis with rapid relapse following complete resection and radiochemotherapy. The involvement of microRNAs in tumor progression has been demonstrated in hepatoma, breast cancer, and prostate cancers. However, the microRNAs involved in modulating the progression and relapse of GBM are still unclear. Initially, we compared the miRNA expression profiles between primary and recurrent GBM tissues from the same patient in twelve independent cases.
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Project description:Introduction: Glioblastoma (GBM) is a lethal brain tumor without effective treatment options. Here, we sought to characterize longitudinal tumor immune microenvironment (iTME) changes in order to find potential actionable targets to prevent GBM-induced immune evasion mechanisms. This study included 15 patient-matched treatment-naïve (primary, pGBM, WHO grade 4) and recurrent (rGBM) IDH1 wild type tumors. Methods:Extracted RNA and proteins from fresh frozen tumor samples from matched pGBM and rGBM were profiled via transcriptomics and proteomics, respectively. Paired formalin-fixed paraffin-embedded tumor samples were processed for spatial transcriptomics analysis.Results: Differentially expressed genes and proteins between pGBM and rGBM were involved in pathways responsible for synapse development and myelination which have been shown to play a role in GBM recurrence. By categorizing patients into short and long time-to-relapse (STTR vs LTTR), and by correlating TTR with gene expression, we detected genes positively or negatively associated with tumor relapse. Expression of FCG receptor and complement system genes such as FCGR1A (CD64), FCGR3A (CD16a) and the complement C3 were negatively correlated with STTR, whereas high expression of DNMT1/3A, and SMARCA4, involved in DNA methylation, were positively correlated with LTTR. Spatial transcriptomic analysis of the tumor cells compartment defined by GFAP expression showed enrichment in the proportion of oligodendrocytes in recurrent tumors in rGBM, whereas CD64-positive myeloid cell compartment showed a switch of quiescent to activated microglia, appearance of B cells and a reduction in macrophage proportion in recurrent tumors with STTR. Conclusion: Our results uncover a role of CD64-expressing myeloid cells, mostly activated microglia, in GBM recurrence and suggest that interfering with these cells may represent a new therapeutic option for preventing GBM relapse.
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Project description:Treating recurrent GBM is a clinical challenge due to its highly resistant and aggressive nature. In order to develop new therapeutic targets for recurrent GBM a better understanding of its molecular landscape is necessary. Here we used a cellular model, developed in our lab which generates paired primary and recurrent samples from GBM cell lines and primary patient samples hence allowing us to compare the molecular differences between the two populations. Total RNA seq analysis of parent and recurrent population of two cell lines and one patient sample revealed a significant upregulation of Extracellular matrix interaction in recurrent population. Since matrix stiffness plays a pivotal role in cell-ECM interaction and downstream signaling, we developed a system that mimicked the brain like substrate stiffness by using collagen coated polyacrylamide-based substrate whose stiffness can be modified from normal brain (0.5kPa) to tumorigenic (10kPa). Using these substrates, we were able to capture the morphological and physiological differences between parent and recurrent GBM which were not evident on plastic surfaces (~1 GPa). On 0.5kPa, unlike circular parent cells, recurrent GBM cells showed two morphologies (circular and elongated). The recurrent cells growing on 0.5kPa also showed higher proliferation, invasion, migration and in-vivo tumorigenicity in orthotropic GBM mouse model, compared to parent cells. Furthermore, recurrent cells exhibited elevated velocity irrespective of substrate stiffness, which indicated that recurrent cells may possess inherent differential mechanosignalling ability which was reflected by higher expression of ECM proteins like Collagen IVA, MMP2 and MMP9. Moreover, mice brain injected with recurrent cells grown on 0.5kPa substrate showed higher Young’s modulus values suggesting that recurrent cells conditioned on 0.5kPa make the surrounding ECM stiffer. Importantly, inhibition of EGFR signaling, that is amplified with tissue stiffening in GBM resulted in decreased invasion, migration and proliferation in 0.5kPa recurrent cells, but interestingly survival remained unaffected, highlighting the importance of mimicking the physiological stiffness of the brain mimicking clinical scenario. Total RNA seq analysis of parent and recurrent cells grown on plastic and 0.5kPa substrate identified PLEKHA7 as significantly upregulated gene specifically in 0.5kPa recurrent sample. Higher protein expression of PLEKHA7 in recurrent GBM as compared to primary GBM was validated in patient biopsies. Accordingly, PLEKHA7 knockdown reduced invasion and survival of recurrent GBM cells. Together, these data provides a model system that captures the differential mechanosensing signals of primary and recurrent GBM cells and identifies a novel potential target specific for recurrent GBM.
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Project description:Introduction: Glioblastoma (GBM) is a lethal brain tumor without effective treatment options. Here, we sought to characterize longitudinal tumor immune microenvironment (iTME) changes in order to find potential actionable targets to prevent GBM-induced immune evasion mechanisms. This study included 15 patient-matched treatment-naïve (primary, pGBM, WHO grade 4) and recurrent (rGBM) IDH1 wild type tumors. Methods: Extracted RNA and proteins from fresh frozen tumor samples from matched pGBM and rGBM were profiled via transcriptomics and proteomics, respectively. Paired formalin-fixed paraffin-embedded tumor samples were processed for spatial transcriptomics analysis. Results: Differentially expressed genes and proteins between pGBM and rGBM were involved in pathways responsible for synapse development and myelination which have been shown to play a role in GBM recurrence. By categorizing patients into short and long time-to-relapse (STTR vs LTTR), and by correlating TTR with gene expression, we detected genes positively or negatively associated with tumor relapse. Expression of FCG receptor and complement system genes such as FCGR1A (CD64), FCGR3A (CD16a) and the complement C3 were negatively correlated with STTR, whereas high expression of DNMT1/3A, and SMARCA4, involved in DNA methylation, were positively correlated with LTTR. Spatial transcriptomic analysis of the tumor cells compartment defined by GFAP expression showed enrichment in the proportion of oligodendrocytes in recurrent tumors in rGBM, whereas CD64-positive myeloid cell compartment showed a switch of quiescent to activated microglia, appearance of B cells and a reduction in macrophage proportion in recurrent tumors with STTR. Conclusion: Our results uncover a role of CD64-expressing myeloid cells, mostly activated microglia, in GBM recurrence and suggest that interfering with these cells may represent a new therapeutic option for preventing GBM relapse.
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