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Exosomes facilitate therapeutic targeting of oncogenic KRAS in pancreatic cancer

Author

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  • Sushrut Kamerkar

    (Metastasis Research Center, University of Texas MD Anderson Cancer Center)

  • Valerie S. LeBleu

    (Metastasis Research Center, University of Texas MD Anderson Cancer Center)

  • Hikaru Sugimoto

    (Metastasis Research Center, University of Texas MD Anderson Cancer Center)

  • Sujuan Yang

    (Metastasis Research Center, University of Texas MD Anderson Cancer Center)

  • Carolina F. Ruivo

    (Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Portugal (I3S)
    Institute of Pathology and Molecular Immunology of the University of Porto (IPATIMUP))

  • Sonia A. Melo

    (Metastasis Research Center, University of Texas MD Anderson Cancer Center
    Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Portugal (I3S)
    Institute of Pathology and Molecular Immunology of the University of Porto (IPATIMUP))

  • J. Jack Lee

    (University of Texas MD Anderson Cancer Center)

  • Raghu Kalluri

    (Metastasis Research Center, University of Texas MD Anderson Cancer Center)

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.

Suggested Citation

  • Sushrut Kamerkar & Valerie S. LeBleu & Hikaru Sugimoto & Sujuan Yang & Carolina F. Ruivo & Sonia A. Melo & J. Jack Lee & Raghu Kalluri, 2017. "Exosomes facilitate therapeutic targeting of oncogenic KRAS in pancreatic cancer," Nature, Nature, vol. 546(7659), pages 498-503, June.
    • Handle: RePEc:nat:nature:v:546:y:2017:i:7659:d:10.1038_nature22341
    DOI: 10.1038/nature22341
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    Cited by:

    1. Chi-Ling Chiang & Yifan Ma & Ya-Chin Hou & Junjie Pan & Sin-Yu Chen & Ming-Hsien Chien & Zhi-Xuan Zhang & Wei-Hsiang Hsu & Xinyu Wang & Jingjing Zhang & Hong Li & Lili Sun & Shannon Fallen & Inyoul Le, 2023. "Dual targeted extracellular vesicles regulate oncogenic genes in advanced pancreatic cancer," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    2. Ting Li & Shuhui Jiang & Ying Zhang & Jie Luo & Ming Li & Hengte Ke & Yibin Deng & Tao Yang & Xiaohui Sun & Huabing Chen, 2023. "Nanoparticle-mediated TRPV1 channel blockade amplifies cancer thermo-immunotherapy via heat shock factor 1 modulation," Nature Communications, Nature, vol. 14(1), pages 1-25, December.
    3. Ghulam Hassan Dar & Cláudia C. Mendes & Wei-Li Kuan & Alfina A. Speciale & Mariana Conceição & André Görgens & Inna Uliyakina & Miguel J. Lobo & Wooi F. Lim & Samir EL Andaloussi & Imre Mäger & Thomas, 2021. "GAPDH controls extracellular vesicle biogenesis and enhances the therapeutic potential of EV mediated siRNA delivery to the brain," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    4. Wanzun Lin & Li Chen & Haojiong Zhang & Xianxin Qiu & Qingting Huang & Fangzhu Wan & Ziyu Le & Shikai Geng & Anlan Zhang & Sufang Qiu & Long Chen & Lin Kong & Jiade J. Lu, 2023. "Tumor-intrinsic YTHDF1 drives immune evasion and resistance to immune checkpoint inhibitors via promoting MHC-I degradation," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    5. Lixue Wang & Guosheng Wang & Wenjun Mao & Yundi Chen & Md. Mofizur Rahman & Chuandong Zhu & Peter M. Prisinzano & Bo Kong & Jing Wang & Luke P. Lee & Yuan Wan, 2023. "Bioinspired engineering of fusogen and targeting moiety equipped nanovesicles," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    6. Shiyan Dong & Xuan Liu & Ye Bi & Yifan Wang & Abin Antony & DaeYong Lee & Kristin Huntoon & Seongdong Jeong & Yifan Ma & Xuefeng Li & Weiye Deng & Benjamin R. Schrank & Adam J. Grippin & JongHoon Ha &, 2023. "Adaptive design of mRNA-loaded extracellular vesicles for targeted immunotherapy of cancer," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

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