KRas突變體是一種常見的胰腺癌驅動因素,利用siRNA減少其表達是一種預防胰腺腫瘤生長的可能方法。Raghu Kalluri及同事借助外泌體提升了siRNA向胰腺的遞送,并表明這些內源性囊泡可以比人工脂質體更好地避開免疫清除,原因可能是其膜內的CD47表達。胰腺腫瘤細胞傾向于攝取經過改造的外泌體(iExosome)。作者認為,這種攝取受到了巨胞飲作用增強的推動。在胰腺癌小鼠模型中,iExosome能夠降低KRas致瘤信號轉導,減少腫瘤生長。

Exosomes facilitate therapeutic targeting of oncogenic KRAS in pancreatic cancer

Sushrut Kamerkar,Valerie S. LeBleu,Hikaru Sugimoto,Sujuan Yang, Carolina F. Ruivo, Sonia A. Melo,J. Jack Lee & Raghu Kalluri

Nature 546, 498–503 (22 June 2017) doi:10.1038/nature22341

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.