An integrated model of N6-methyladenosine regulators to predict tumor aggressiveness and immune evasion in pancreatic cancer.
An integrated model of N6-methyladenosine regulators to predict tumor aggressiveness and immune evasion in pancreatic cancer.
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预测胰腺癌肿瘤侵袭性和免疫逃逸的N6-甲基腺苷调节剂集成模型。
DOI：
10.1016/j.ebiom.2021.103271
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发表时间：
2021-03
期刊：
影响因子：
11.1
通讯作者：
Li M
中科院分区：
文献类型：
--
作者：
Zhou Z;Zhang J;Xu C;Yang J;Zhang Y;Liu M;Shi X;Li X;Zhan H;Chen W;McNally LR;Fung KM;Luo W;Houchen CW;He Y;Zhang C;Li M
n6 -甲基腺苷（m6A）是最丰富的mRNA修饰。m6A调节因子是否可以决定胰腺导管腺癌（PDAC）的肿瘤侵袭性和免疫逃避风险尚不清楚。基于PDAC中m6A调控子的RNA-seq数据，构建了一个名为“m6Ascore”的集成模型。通过几个不同的数据集验证了m6Ascore与总生存期的关联。研究了m6Ascore与PDAC分子分类的重叠。比较了m6ascore -高和m6ascore -低肿瘤之间的免疫浸润、富集通路、体细胞拷贝数改变（SCNAs）、突变谱和对免疫检查点抑制剂的反应。m6Ascore与PDAC以及其他几种实体肿瘤（包括结直肠癌和乳腺癌）的总生存率低和肿瘤复发率增加相关。基底样（鳞状）PDAC的m6评分高于经典PDAC。机制研究表明，m6ascore高肿瘤以免疫浸润减少和T细胞耗竭为特征。同时，m6Ascore与PDAC中恶病质和化疗耐药的调控基因相关。此外，在m6ascore高肿瘤中存在不同的SCNAs模式和KRAS和TP53突变谱，表明免疫逃避。m6ascore低的肿瘤对免疫检查点抑制剂（ICIs）有更高的应答率。这些发现提示m6Ascore可以预测胰腺癌的侵袭性和免疫逃避。该模型对胰腺癌预后和ICIs治疗反应具有指导意义。这项工作部分由美国国立卫生研究院（NIH）资助M. Li （R01 CA186338, R01 CA203108， R01 CA247234和William and Ella Owens医学研究基金会）和美国国立卫生研究院/国家癌症研究所Q39奖P30CA225520资助斯蒂芬森癌症中心。
N6-methyladenosine (m6A) is the most abundant mRNA modification. Whether m6A regulators can determine tumor aggressiveness and risk of immune evasion in pancreatic ductal adenocarcinoma (PDAC) remains unknown. An integrated model named “m6Ascore” is constructed based on RNA-seq data of m6A regulators in PDAC. Association of m6Ascore and overall survival is validated across several different datasets. Overlaps of m6Ascore and established molecular classifications of PDAC is examined. Immune infiltration, enriched pathways, somatic copy number alterations (SCNAs), mutation profiles and response to immune checkpoint inhibitors are compared between m6Ascore-high and m6Ascore-low tumors. m6Ascore is associated with dismal overall survival and increased tumor recurrence in PDAC as well as several other solid tumors including colorectal cancer and breast cancer. Basal-like (Squamous) PDAC has higher m6Ascore than that in the classical PDAC. Mechanism study showed m6Ascore-high tumors are characterized with reduced immune infiltration and T cells exhaustion. Meanwhile, m6Ascore is associated with genes regulating cachexia and chemoresistance in PDAC. Furthermore, distinct SCNAs patterns and mutation profiles of KRAS and TP53 are present in m6Ascore-high tumors, indicating immune evasion. m6Ascore-low tumors have higher response rates to immune checkpoint inhibitors (ICIs). These findings indicate m6Ascore can predict aggressiveness and immune evasion in pancreatic cancer. This model has implications for pancreatic cancer prognosis and treatment response to ICIs. This work was supported in part by National Institutes of Health (NIH) grants to M. Li (R01 CA186338, R01 CA203108, R01 CA247234 and the William and Ella Owens Medical Research Foundation) and NIH/National Cancer Institute Q39 award P30CA225520 to Stephenson Cancer Center.
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