Extracellular Vesicles Induce Mesenchymal Transition and Therapeutic Resistance in Glioblastomas through NF‐κB/STAT3 Signaling

Abstract

Gliomas account for about 80% of all malignant CNS tumors, of which glioblastoma (GBM) is the most common and malignant form. [1] Despite a multimodal treatment approach including surgery, radiation, and temozolomide (TMZ) chemotherapy, the prognosis remains dismal. The Central Brain Tumor Registry reports that the five-year survival rate of adult patients with GBM is 4.3%. Although tumors may initially respond to this treatment armamentarium, recurrence remains inevitable. [2-5] Large-scale genomic, epigenomic, and transcriptomic characterization of different subtypes has provided valuable insights into the heterogeneous landscape of GBM. [6-9] Notably, comprehensive longitudinal Glioblastoma (GBM) is the most common primary malignant brain tumor and despite optimal treatment, long-term survival remains uncommon. GBM can be roughly divided into three different molecular subtypes, each varying in aggressiveness and treatment resistance. Recent evidence shows plasticity between these subtypes in which the proneural (PN) glioma stemlike cells (GSCs) undergo transition into the more aggressive mesenchymal (MES) subtype, leading to therapeutic resistance. Extracellular vesicles (EVs) are membranous structures secreted by nearly every cell and are shown to play a key role in GBM progression by acting as multifunctional signaling complexes. Here, it is shown that EVs derived from MES cells educate PN cells to increase stemness, invasiveness, cell proliferation, migration potential, aggressiveness, and therapeutic resistance by inducing mesenchymal transition through nuclear factor-κB/signal transducer and activator of transcription 3 signaling. The findings could potentially help explore new treatment strategies for GBM and indicate that EVs may also play a role in mesenchymal transition of different tumor types.

Small but Fierce: Tracking the Role of Extracellular Vesicles in Glioblastoma Progression and Therapeutic Resistance

“…[65] Recently, we showed that MES GSCs release EVs which can be taken up by PN cells, leading to an increase in their invasiveness, stemness, migration, proliferation, aggressiveness, and therapeutic resistance through nuclear factor kappa B (NF-κB) and signal transducer and activator of transcription (STAT3) signaling. [66] Our study endorses the role of extracellular vesicles in intratumoral heterogeneity and therapeutic resistance in GBM. Gyuris et al showed that mRNA from medium-sized glioma EVs (0.22-0.79 µm) most closely reflects the cellular transcriptome, whereas RNA from the small EV fraction (0.21-0.02 µm) is enriched with small noncoding RNAs, highlighting the highly heterogeneous composition of GBM-derived EVs.…”

“…In addition to GBMs inter/ intratumoral heterogeneity, the bidirectional crosstalk of GSCs with the TME facilitates GBM to decrease/inactivate drug uptake or activate a multitude of repair mechanisms to render drug-induced damage inefficient. [22,66] Compelling evidence suggests that EVs add yet another facet to the GBM treatment evasion mechanism repertoire. GBM EVs appear to counteract therapeutic approaches in a more direct manner.…”

Mesenchymal Transformation: The Rosetta Stone of Glioblastoma Pathogenesis and Therapy Resistance

“…[122] We showed that PN GSCs can uptake MES-derived EVs contributing greatly to GBM intratumoral heterogeneity and therapeutic resistance through NF-B/STAT3-dependent manner. [121] In another study, macrophage-derived small EVs were shown to induce PMT by targeting CHD7 in PN GSCs. [123] As GBMs are highly angiogenic, it is believed that antiangiogenic therapy (bevacizumab) may reduce the disease burden, but practically, this therapy induces mesenchymal transformation ultimately leading to therapy failure.…”

“…[ 118,119 ] GSCs can induce an immunosuppressive nature in TAM through mTOR‐dependent regulation of STAT3 and NF‐ κ B activity. [ 120 ] Our group recently reported that GSCs with MES subtype can force PN cells to switch into a MES phenotype by means of extracellular vesicles (EVs), [ 121 ] a small vesicle released by practically every cell. [ 122 ] We showed that PN GSCs can uptake MES‐derived EVs contributing greatly to GBM intratumoral heterogeneity and therapeutic resistance through NF‐ κ B/STAT3‐dependent manner.…”

“…[ 122 ] We showed that PN GSCs can uptake MES‐derived EVs contributing greatly to GBM intratumoral heterogeneity and therapeutic resistance through NF‐ κ B/STAT3‐dependent manner. [ 121 ] In another study, macrophage‐derived small EVs were shown to induce PMT by targeting CHD7 in PN GSCs. [ 123 ]…”