Exosomes Facilitate Therapeutic Targeting of Oncogenic Kras in Pancreatic Cancer

By S. Kamerkar, Valerie S. LeBleu, H. Sugimoto, Sujuan Yang, C. Ruivo, Sonia A Melo, J. Lee, Raghu Kalluri. Nature, 2017

2,307 citations recorded by the source corpus.

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.

Subfields: Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/187896c9dc54bfbccc3013093e8e7ed79a225968

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In Immunology

1. G. Raposo
2. Guillaume van Niel
3. Yan Yu
4. Weitong Gao
5. Yang Zhou
6. Xuepeng Wang
7. C. Théry

In Molecular Biology

1. G. Raposo
2. Guillaume van Niel
3. P. Vader
4. Yan Luo
5. Ben Wang
6. Chuanjiang He
7. Shu Zheng
8. Aled Clayton

Citations in the corpus

• Challenges and directions in studying cell–cell communication by extracellular vesicles (2022, background): “It is important to acknowledge also that some of the EV surface components may play negative, regulatory functions during cell interactions such as CD47 which inhibits phagocytic uptake 71 72 .”
• Exosome-Based Cell-Cell Communication in the Tumor Microenvironment (2018, background): “Specifically, it was shown that engineered cells can produce exosomes capable to preferentially bind to tumor cells, target oncogenic KRAS and suppress cancer in multiple mouse models of pancreatic cancer (Kamerkar et al., 2017).”
• The biology, function, and biomedical applications of exosomes (2020, neutral): “Further, macropinocytosis associated with cancer cells enhanced the entry of exogenously administered iExosomes (28).”
• Autophagy, ferroptosis, pyroptosis, and necroptosis in tumor immunotherapy (2022, background): “Exosomal CD47 can inhibit pancreatic cancer cells from being cleared by phagocytes.(206) It’s worth noting that PD-L1 or CD47 can be released by exosomes, cellular secreted vesicles (30–150 nm) with double-layer membrane not degraded by lysosomes, which is key to regulate crosstalk between cells.”
• Exosome Theranostics: Biology and Translational Medicine (2018, background): “Such properties of exosomes with an enhanced potency for delivering miRNA to pancreatic tumors, along with the use of these types of exosomes as RNA interference (RNAi) mediators specifically targeting oncogenic KRAS in PDAC, have significantly improved overall survival in many mouse models (Figure ”