Engineered Mesenchymal Stem Cells Expressing CD::UPRT and TRAIL Exhibit Potent Anti-Tumor Effects in Glioblastoma Patient-Derived Organoids
TL;DR
These findings validate the multifaceted anti-tumor activity of BM03 in GBOs that retain clinically relevant tumor heterogeneity and provide organoid-based preclinical evidence supporting further in vivo evaluation of BM03 as an MSC-based targeted therapeutic strategy for GBM.
Abstract
Highlights What are the main findings? BM03 markedly reduced viability and invasive behavior in patient-derived GBM organoids (GBOs) while suppressing EMT- and stemness-associated markers. BM03 showed enhanced migration and infiltration into GBOs, accompanied by increased apoptosis. What are the implications of the main findings? These findings validate the multifaceted anti-tumor activity of BM03 in GBOs that retain clinically relevant tumor heterogeneity. The results provide organoid-based preclinical evidence supporting further in vivo evaluation of BM03 as an MSC-based targeted therapeutic strategy for GBM. Abstract Glioblastoma (GBM) is a highly aggressive brain tumor with limited therapeutic options due to its invasive nature, therapeutic resistance, and the challenge of drug delivery across the blood–brain barrier (BBB). Mesenchymal stem cells (MSCs), owing to their tumor tropic properties and ability to cross the BBB, offer a promising platform for targeted anti-cancer delivery. We previously engineered MSCs to express CD::UPRT and TRAIL, along with chemokine receptors to enhance tumor homing (MSC-CD-TRAIL; BM03). This study evaluated the anti-tumor efficacy of BM03 using GBM patient-derived organoids (GBOs), clinically relevant in vitro models. Using a GBO–MSC co-culture system, BM03 significantly increased cell death and reduced viability in GBOs from four GBM patients compared with controls and MSC-WT groups. In 3D invasion assays, BM03-treated GBOs showed markedly reduced invasive outgrowth, accompanied by downregulation of EMT markers (Zeb1 and Snail) and stem-like markers (Olig2 and Sox2), particularly in invasive regions. GFAP expression remained unchanged, suggesting selective targeting of tumor stem-like cells. Live-cell imaging further demonstrated BM03 infiltration into GBOs, which was associated with increased apoptosis, as evidenced by elevated cleaved caspase-3 levels. These findings provide organoid-based preclinical evidence supporting further evaluation of BM03 as an MSC-based therapeutic strategy for GBM.