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Effect of the different isoforms of RPL22L1 protein on the transcriptome of human glioblastoma cells.

ABSTRACT: Glioblastoma multiforme (GBM) is characterized by an exceptionally high intratumoral heterogeneity. However, the molecular mechanisms underlying the origin of different GBM cell populations remain unclear. Here we found that the composition of ribosomes of GBM cells in the tumor core and edge differ due to alternative RNA splicing. The acidic pH in the core switches pre-mRNA splicing of the ribosomal gene RPL22L1 toward the RPL22L1b isoform. This allows cells to survive acidosis, increases stemness and correlates with worse patient outcome. Mechanistically, RPL22L1b promotes RNA splicing by binding to lncMALAT1 in the nucleus, resulting in its degradation. Contrarily, in the tumor edge region, RPL22L1a interacts with ribosomes in cytoplasm and upregulates translation of multiple mRNAs including TP53. We found that RPL22L1 isoform switch is regulated by SRSF4 and identified the compound, that inhibits this process and decreases tumor growth. These findings demonstrate how distinct GBM cell populations arise during tumor growth. Targeting this mechanism may decrease GBM heterogeneity and facilitate therapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE180465 | GEO | 2021/12/01

REPOSITORIES: GEO

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Interactome of different isoforms of RPL22L1 protein in human glioblastoma cells

Project description:Glioblastoma multiforme (GBM) is characterized by an exceptionally high intratumoral heterogeneity. However, the molecular mechanisms underlying the origin of different GBM cell populations remain unclear. Here we found that the composition of ribosomes of GBM cells in the tumor core and edge differ due to alternative RNA splicing. The acidic pH in the core switches pre-mRNA splicing of the ribosomal gene RPL22L1 toward the RPL22L1b isoform. This allows cells to survive acidosis, increases stemness and correlates with worse patient outcome. Mechanistically, RPL22L1b promotes RNA splicing by binding to lncMALAT1 in the nucleus, resulting in its degradation. Contrarily, in the tumor edge region, RPL22L1a interacts with ribosomes in cytoplasm and upregulates translation of multiple mRNAs including TP53. We found that RPL22L1 isoform switch is regulated by SRSF4 and identified the compound, that inhibits this process and decreases tumor growth. These findings demonstrate how distinct GBM cell populations arise during tumor growth. Targeting this mechanism may decrease GBM heterogeneity and facilitate therapy.

2021-12-01 | GSE180464 | GEO

LC-MS/MS identification of proteins that were bound to recombinant His-tagged isoforms of RPL22L1

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LC-MS/MS identification of proteins that were co-purified with Fc-tagged isoforms of RPL22L1

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Phosphoproteome of glioblastoma cells after FG1059 treatment

Project description:We found that RPL22L1 isoform switch is regulated by SRSF4 protein and identified a small molecule compound FG1059, that inhibits this process and decreases tumor growth. To confirm that FG1059 affects RPL22L1 due to the inhibition of SRSF protein phosphorylation we studied the phosphoproteome of patient-derived GBM neurospheres treated with FG1059 for 0, 3, 6 and 12 hours.

2023-10-24 | PXD035855 | Pride

Glioma-initiating cells at tumor edge gain signals from tumor core cells to promote their malignancy

Project description:Intratumor spatial heterogeneity facilitates therapeutic resistance in glioblastoma (GBM). Nonetheless, understanding of GBM is limited to the resectable tumor core lesion while the seeds for recurrence reside in the unresectable tumor edge. In this study, stratification of GBM to core and edge demonstrated clinically relevant surgical sequelae. We establish regionally derived models of GBM edge and core that retain their spatial identity in a cell autonomous manner. Edge cells show a higher capacity for infiltrative growth, while core cells demonstrate greater therapy resistance. Investigation of intercellular signaling between these two cell populations uncovered the paracrine crosstalk from tumor core that provokes malignancy and therapy resistance of edge cells. These phenotypic alterations were initiated by HDAC1 in GBM core cells which subsequently affect edge cells by secreting the soluble form of CD109 protein. Our data reveal the role of intracellular communication between regionally different populations of GBM cells in tumor recurrence.

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Crosstalk with astrocytes establishes tumor edge in glioblastoma

Project description:Clinical outcomes for patients with glioblastoma (GBM) are extremely poor due to inevitable tumor recurrence even after extensive treatments. These recurrences are thought to manifest from cells located within the tumor edge. Despite this, the precise molecular mechanism governing GBM spatial phenotypic heterogeneity (e.g. edge vs. core) and subsequent tumor recurrence remains poorly elucidated. Here, using patient-derived GBM core and edge tissues, we analyzed transcriptional and metabolic signatures in an effort to determine how GBM facilitates the edge phenotype and its associated recurrence-initiating cells (RICs). In so doing, we unexpectedly identified CD38 as an essential protein in the formation of the edge phenotype and found a CD38-driven interaction between edge GBM cells and neighboring astrocytes that communally develops a GBM edge that is unresectable by surgery and retains RICs.

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2023-12-01 | GSE246697 | GEO

Splicing in gliomas

Project description:The objective of our study was to determine whether aberrant alternative splicing could play a role in the malignant phenotype of GBM. Patients with GBM were operated with 5-aminolevulinic fluorescence guided surgery. The fluorescent was used to take biopsies from the tumor center, and from adjacent normal-looking tissue. Three paired normal/GBM samples were analyzed in a HJAY J array. We validated our results with conventional PCR and qRT-PCR in those tumor samples and in ten additional GBMs. We performed functional studies using MTT assays (proliferation) and IF qRT-PCR (differentiation). We generated a list of seven genes with differential alternative splicing between central tumor samples and the adjacent normal-looking tissue. DPF-2(BAF45d) was one of our top candidates. Interestingly, DPF-2 is known as a tumor suppressor gene in the context of the SWI/SNF complex and plays a key role in the development of the central nervous system. The inhibition of our DPF-2 isoform resulted in a significative reduction in proliferation and in a morphology changes towards a more differentiated phenotype in GBM cell lines. Interestingly, our DPF2 tumoral isoform was the predominant transcript in early postnatal murine neural precursors and its expression disappeared as these cells were instructed towards neurons. Our results suggest that the alternative splicing of DPF-2 in GBM could participate in the maintenance of an undifferentiated cellular state. In addition, our data suggest that alternative splicing is a mechanism that could be central to GBM development We compared three paired samples of tumor (glioma)/normal like and 1 sample of pooled brain RNA from healthy donors

2016-09-01 | E-GEOD-76070 | biostudies-arrayexpress

Splicing in gliomas

2016-09-01 | GSE76070 | GEO

Multi-omics analysis of spatially distinct stromal cells reveals tumor-induced O-glycosylation of the CDK4-pRB axis in fibroblasts at the invasive tumor edge

Project description:The invasive leading edge represents a potential gateway for tumor metastasis. The role of fibroblasts from the tumor edge in promoting cancer invasion and metastasis has not been comprehensively elucidated. We hypothesize that crosstalk between tumor and stromal cells within the tumor microenvironment (TME) results in activation of key biological pathways depending on their position in the tumor (edge vs core). Here we highlight phenotypic differences between tumor-adjacent-fibroblasts (TAF) from the invasive edge and tumor core fibroblasts (TCF) from the tumor core, established from human lung adenocarcinomas. A multi-omics approach that includes genomics, proteomics, and O-glycoproteomics was used to characterize crosstalk between TAFs and cancer cells. These analyses showed that O-glycosylation, an essential post-translational modification resulting from sugar metabolism, alters key biological pathways including the cyclin-dependent kinase 4 and phosphorylated retinoblastoma protein (CDK4-pRB) axis in the stroma and indirectly modulates pro-invasive features of cancer cells. In summary, the O-glycoproteome represents a new consideration for important biological processes involved in tumor-stroma crosstalk and a potential avenue to improve the anti-cancer efficacy of CDK4 inhibitors.

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