Image-based detection and targeting of therapy resistance in pancreatic adenocarcinoma.
Image-based detection and targeting of therapy resistance in pancreatic adenocarcinoma.
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DOI：
10.1038/nature17988
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发表时间：
2016-06-16
期刊：
影响因子：
64.8
通讯作者：
Reya T
中科院分区：
文献类型：
--
作者：
Fox RG;Lytle NK;Jaquish DV;Park FD;Ito T;Bajaj J;Koechlein CS;Zimdahl B;Yano M;Kopp J;Kritzik M;Sicklick J;Sander M;Grandgenett PM;Hollingsworth MA;Shibata S;Pizzo D;Valasek M;Sasik R;Scadeng M;Okano H;Kim Y;MacLeod AR;Lowy AM;Reya T
胰腺上皮内瘤变（PanIN）是一种癌前病变，可进展为胰腺导管腺癌，这是一种高度致命的恶性肿瘤，其特点是临床表现晚期和严重的耐药性。胰腺癌中常见的基因组改变包括KRAS 2的激活和p53和SMAD 4的失活。然而，迄今为止，靶向这些途径的治疗一直具有挑战性;因此寻找胰腺癌生长的其他关键介质仍然是一项重要的奋进。在这里，我们表明，干细胞决定因子Musashi（Msi）是胰腺癌进展的遗传模型和患者来源的异种移植的关键因素。具体来说，我们开发了Msi报告小鼠，允许基于图像跟踪癌症内的干细胞信号，揭示了Msi表达随着PanIN进展为腺癌而升高，并且Msi表达细胞是胰腺癌的关键驱动因素：它们优先具有繁殖腺癌的能力，富含循环肿瘤细胞，并且具有显著的耐药性。通过缺失Msi 1或Msi 2可以有效靶向该人群，这导致PanIN进展为腺癌的显著缺陷和总生存率的改善。抑制Msi也能阻断原发性患者源性肿瘤的生长，这表明这种信号是人类疾病所必需的。为了确定这项工作的翻译潜力，我们开发了针对Msi的反义寡核苷酸;这些寡核苷酸显示出可靠的肿瘤渗透、摄取和靶向抑制，并有效地阻断了胰腺癌生长。总的来说，这些研究突出了Msi报告基因作为鉴定治疗抗性的独特工具，并将Msi信号传导定义为胰腺癌的中心调节因子。
Pancreatic intraepithelial neoplasia (PanIN) is a premalignant lesion that can progress to pancreatic ductal adenocarcinoma, a highly lethal malignancy marked by its late stage at clinical presentation and profound drug resistance. The genomic alterations that commonly occur in pancreatic cancer include activation of KRAS2 and inactivation of p53, and SMAD4. To date, however, it has been challenging to target these pathways therapeutically; thus the search for other key mediators of pancreatic cancer growth remains an important endeavor. Here we show that the stem cell determinant Musashi (Msi) is a critical element of pancreatic cancer progression in both genetic models and patient derived xenografts. Specifically, we developed Msi reporter mice that allowed image based tracking of stem cell signals within cancers, revealing that Msi expression rises as PanIN progresses to adenocarcinoma, and that Msi-expressing cells are key drivers of pancreatic cancer: they preferentially harbor the capacity to propagate adenocarcinoma, are enriched in circulating tumor cells, and are markedly drug resistant. This population could be effectively targeted by deletion of either Msi1 or Msi2, which led to a striking defect in PanIN progression to adenocarcinoma and an improvement in overall survival. Msi inhibition also blocked the growth of primary patient-derived tumors, suggesting that this signal is required for human disease. To define the translational potential of this work we developed antisense oligonucleotides against Msi; these showed reliable tumor penetration, uptake and target inhibition, and effectively blocked pancreatic cancer growth. Collectively, these studies highlight Msi reporters as a unique tool to identify therapy resistance, and define Msi signaling as a central regulator of pancreatic cancer.