IDEAS home Printed from https://ideas.repec.org/a/nat/nature/v546y2017i7659d10.1038_nature22341.html
   My bibliography  Save this article

Exosomes facilitate therapeutic targeting of oncogenic KRAS in pancreatic cancer

Author

Listed:
  • 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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/nature22341
    File Function: Abstract
    Download Restriction: Access to the full text of the articles in this series is restricted.
    File URL: https://libkey.io/10.1038/nature22341?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    As the access to this document is restricted, you may want to search for a different version of it.

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. 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.
    2. 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.
    3. 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.
    4. 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.
    5. 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.
    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.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:nature:v:546:y:2017:i:7659:d:10.1038_nature22341. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.