RRC ID 56893
Author Kamerkar S, LeBleu VS, Sugimoto H, Yang S, Ruivo CF, Melo SA, Lee JJ, Kalluri R.
Title Exosomes facilitate therapeutic targeting of oncogenic KRAS in pancreatic cancer.
Journal Nature
Abstract The mutant form of the GTPase KRAS is a key driver of pancreatic cancer but remains a challenging therapeutic target. Exosomes are extracellular vesicles generated by all cells, and are naturally present in the blood. Here we show that enhanced retention of exosomes, compared to liposomes, in the circulation of mice is likely due to CD47-mediated protection of exosomes from phagocytosis by monocytes and macrophages. Exosomes derived from normal fibroblast-like mesenchymal cells were engineered to carry short interfering RNA or short hairpin RNA specific to oncogenic KrasG12D, a common mutation in pancreatic cancer. Compared to liposomes, the engineered exosomes (known as iExosomes) target oncogenic KRAS with an enhanced efficacy that is dependent on CD47, and is facilitated by macropinocytosis. Treatment with iExosomes suppressed cancer in multiple mouse models of pancreatic cancer and significantly increased overall survival. Our results demonstrate an approach for direct and specific targeting of oncogenic KRAS in tumours using iExosomes.
Volume 546(7659)
Pages 498-503
Published 2017-6-22
DOI 10.1038/nature22341
PII nature22341
PMID 28607485
PMC PMC5538883
MeSH Animals CD47 Antigen / metabolism Disease Models, Animal Exosomes / immunology Exosomes / metabolism* Female Gene Silencing* Genetic Therapy Liposomes / immunology Mice Monocytes / cytology Monocytes / immunology Neoplasm Metastasis / prevention & control Pancreatic Neoplasms / blood Pancreatic Neoplasms / genetics* Pancreatic Neoplasms / pathology Pancreatic Neoplasms / therapy* Pinocytosis Proto-Oncogene Proteins p21(ras) / genetics* Proto-Oncogene Proteins p21(ras) / metabolism RNA, Small Interfering / administration & dosage* RNA, Small Interfering / genetics* Survival Rate
IF 43.07
Times Cited 442
Human and Animal Cells T3M-4(RCB1021)