Engineered Exosomes Targeting Myc Reverse the Proneural-Mesenchymal Transition and Extend Survival of Glioblastoma

Authors

Amanda R Haltom
Wafa E Hassen
Janine Hensel
Jiha Kim
Hikaru Sugimoto
Bingrui Li
Kathleen M McAndrews
Meagan R Conner
Michelle L Kirtley
Xin Luo
Bingqing Xie
Olga V Volpert
Susan Olalekan
Natalia Maltsev
Anindita Basu
Valerie S LeBleu
Raghu Kalluri

Publication Date

12-1-2022

Journal

Extracellular Vesicle

Abstract

Dysregulated Myc signaling is a key oncogenic pathway in glioblastoma multiforme (GBM). Yet, effective therapeutic targeting of Myc continues to be challenging. Here, we demonstrate that exosomes generated from human bone marrow mesenchymal stem cells (MSCs) engineered to encapsulate siRNAs targeting Myc (iExo-Myc) localize to orthotopic GBM tumors in mice. Treatment of late stage GBM tumors with iExo-Myc inhibits proliferation and angiogenesis, suppresses tumor growth, and extends survival. Transcriptional profiling of tumors reveals that the mesenchymal transition and estrogen receptor signaling pathways are impacted by Myc inhibition. Single nuclei RNA sequencing (snRNA-seq) shows that iExo-Myc treatment induces transcriptional repression of multiple growth factor and interleukin signaling pathways, triggering a mesenchymal to proneural transition and shifting the cellular landscape of the tumor. These data confirm that Myc is an effective anti-glioma target and that iExo-Myc offers a feasible, readily translational strategy to inhibit challenging oncogene targets for the treatment of brain tumors.

Keywords

iExosomes, Myc siRNA, drug delivery, glioblastoma, mesenchymal proneural transition

Comments

Supplementary Materials

PMID: 37503329