Exosome-transmitted circCABIN1 promotes temozolomide resistance in glioblastoma via sustaining ErbB downstream signaling

Abstract

Although temozolomide (TMZ) provides significant clinical benefit for glioblastoma (GBM), responses are limited by the emergence of acquired resistance. Here, we demonstrate that exosomal circCABIN1 secreted from TMZ-resistant cells was packaged into exosomes and then disseminated TMZ resistance of receipt cells. CircCABIN1 could be cyclized by eukaryotic translation initiation factor 4A3 (EIF4A3) and is highly expressed in GBM tissues and glioma stem cells (GSCs). CircCABIN1 is required for the self-renewal maintenance of GSCs to initiate acquired resistance. Mechanistically, circCABIN1 regulated the expression of olfactomedin-like 3 (OLFML3) by sponging miR-637. Moreover, upregulation of OLFML3 activating the ErbB signaling pathway and ultimately contributing to stemness reprogramming and TMZ resistance. Treatment of GBM orthotopic mice xenografts with engineered exosomes targeting circCABIN1 and OLFML3 provided prominent targetability and had significantly improved antitumor activity of TMZ. In summary, our work proposed a novel mechanism for drug resistance transmission in GBM and provided evidence that engineered exosomes are a promising clinical tool for cancer prevention and therapy. Graphical Abstract

Biomimetic Macrophage Membrane-Camouflaged Nanoparticles Induce Ferroptosis by Promoting Mitochondrial Damage in Glioblastoma

“…PDOs were established and cultivated as described previously. 34 In Vitro BBB Model. bEnd.3 cells were cultured in the upper chamber of Transwell inserts, while LN229 cells were cultured in the lower chamber for 7 days in DMEM supplemented with 10% FBS.…”

Encapsulation and assessment of therapeutic cargo in engineered exosomes: a systematic review

“…The transgenic membrane permeable (Tango) peptide is one such example, it consists of a membrane translocation sequence derived from the zebrafish voltage-dependent anion channel. When this Tango peptide was fused to the mCherry fluorescent protein and anchored into exosome membranes using a laminin domain, the resulting Tango exosome demonstrated increased cellular internalization compared to unmodified exosomes, indicating that protein transfection domains could potentially enhance exosomal uptake and facilitate the delivery of encapsulated cargo across plasma membranes [ 70 ]. However, it's important to note that the tissue targeting ability of these domains may still require further optimization.…”

MicroRNAs as the pivotal regulators of Temozolomide resistance in glioblastoma

“…MiR-221 increased TMZ and radio therapeutic resistances in GBM cells by EGFR targeting [ 72 ]. CircCABIN1 induced TMZ resistance and stemness in GBM cells by miR-637 sponging and subsequent OLFML3 up regulation that activated ErbB pathway [ 73 ]. LRIG1 as an inhibitor of EGFR promoted the TMZ sensitivity in GBM cells [ 74 ].…”