Dataset Information

Invadopodia small extracellular vesicles glioblastoma

ABSTRACT: The therapeutic efficacy of radiotherapy and chemotherapy with temozolomide (TMZ) for glioblastoma (GBM) is currently limited by the augmented invasive abilities of GBM cells that survive treatment, however the underlying mechanisms remain poorly understood. Due to their ability of transporting oncogenic material between cells, small extracellular vesicles (sEVs) have emerged as key mediators of tumour progression and resistance to treatment. Here, we report that sEVs secreted by GBM cells may facilitate tumour invasion through their ability to promote the formation and activity of actin-rich protrusions known as invadopodia, and that this may be further enhanced following exposure to radio-chemotherapeutic treatment. Furthermore, proteomic analysis of GBM cells exposed to this treatment revealed an increased abundance of invasion-related proteins (including adhesion, cytoskeletal, and membrane trafficking proteins), whilst sEVs were instead enriched in invadopodia-related signalling cargo proteins. Collectively, this work highlights the contributing role of invadopodia and sEVs to the pro-invasive abilities of GBM cells that survive radio-chemotherapeutic treatment.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Brain, Permanent Cell Line Cell

DISEASE(S): Brain Glioblastoma Multiforme

SUBMITTER: david greening

LAB HEAD: David Greening

PROVIDER: PXD031077 | Pride | 2023-07-24

REPOSITORIES: Pride

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Publications

Small extracellular vesicles promote invadopodia activity in glioblastoma cells in a therapy-dependent manner.

Whitehead Clarissa A CA Fang Haoyun H Su Huaqi H Morokoff Andrew P AP Kaye Andrew H AH Hanssen Eric E Nowell Cameron J CJ Drummond Katharine J KJ Greening David W DW Vella Laura J LJ Mantamadiotis Theo T Stylli Stanley S SS

Cellular oncology (Dordrecht) 20230404 4

<h4>Purpose</h4>The therapeutic efficacy of radiotherapy/temozolomide treatment for glioblastoma (GBM) is limited by the augmented invasiveness mediated by invadopodia activity of surviving GBM cells. As yet, however the underlying mechanisms remain poorly understood. Due to their ability to transport oncogenic material between cells, small extracellular vesicles (sEVs) have emerged as key mediators of tumour progression. We hypothesize that the sustained growth and invasion of cancer cells depe ...[more]

PMID: 37014551

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Project description:PD-L1 Inhibitor Regulates the miR-33a-5p/PTEN Signaling Pathway and Can Be Targeted to Sensitize Glioblastomas to Radiation. Glioblastoma (GBM) is the most common and lethal brain tumor in adults. Ionizing radiation (IR) is a standard treatment for GBM patients and results in DNA damage. However, the clinical efficacy of IR is limited due to therapeutic resistance. The programmed death ligand 1 (PD-L1) blockade has a shown the potential to increase the efficacy of radiotherapy by inhibiting DNA damage and repair responses. The miR-33a-5p is an essential microRNA that promotes GBM growth and self-renewal. In this study, we investigated whether a PD-L1 inhibitor (a small molecule inhibitor) exerted radio-sensitive effects to impart an anti-tumor function in GBM cells by modulating miR-33a-5p. U87 MG cells and U251 cells were pretreated with PD-L1 inhibitor. The PD-L1 inhibitor-induced radio-sensitivity in these cells was assessed by assaying cellular apoptosis, clonogenic survival assays, and migration. TargetScan and luciferase assay showed that miR-33a-5p targeted the phosphatase and tensin homolog (PTEN) 3' untranslated region. The expression level of PTEN was measured by western blotting, and was also silenced using small interfering RNAs. The levels of DNA damage following radiation was measured by the presence of γ-H2AX foci, cell cycle, and the mRNA of the DNA damage-related genes, BRCA1, NBS1, RAD50, and MRE11. Our results demonstrated that the PD-L1 inhibitor significantly decreased the expression of the target gene, miR-33a-5p. In addition, pretreatment of U87 MG and U251 cells with the PD-L1 inhibitor increased radio-sensitivity, as indicated by increased apoptosis, while decreased survival and migration of GBM cells. Mir-33a-5p overexpression or silencing PTEN in U87 MG and U251 cells significantly attenuated PD-L1 radiosensitive effect. Additionally, PD-L1 inhibitor treatment suppressed the expression of the DNA damage response-related genes, BRCA1, NBS1, RAD50, and MRE11. Our results demonstrated a novel role for the PD-L1 inhibitor in inducing radio- sensitivity in GBM cells, where inhibiting miR-33a-5p, leading to PTEN activated, and inducing DNA damage was crucial for antitumor immunotherapies to treat GBM.

Dataset Information

Invadopodia small extracellular vesicles glioblastoma

Publications

Small extracellular vesicles promote invadopodia activity in glioblastoma cells in a therapy-dependent manner.

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