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
|
Resource |
Human and Animal Cells |
T3M-4(RCB1021) |