小细胞肺癌的外源性与内在特征及其治疗脆弱性的研究

小细胞肺癌的外源性与内在特征及其治疗脆弱性的研究

Characterization of the extrinsic and intrinsic signatures and therapeutic vulnerability of small cell lung cancers

作者:Gui-Zhen Wang, Zheng Wang, Shi-Hao Bai, Yun Tan, Wen-Zhao Zhong, Guo-Gui Sun, Yu-Tao Liu, Bo Pan, Chen Huang, Di Wang, Bei-Bei Sun, Dong-Ni Chen, Bin Zhang, Yong-Chun Zhou, Sheng Li, Xiang-Wei Zhang, Si-Chong Han, Fu-Ying Yang, Xue-Yan Shi, Xiao-Liang Jie, Yu-Ke Shen, Li-Jun Liang, Zhe-Sheng Wen, Li Zhang, Ming-Kun Li, Na Wang, Jin-Song Liu, Ying Dong, Man-Li Wang, Yan Wang, Chang-Li Wang, Da-Wei Xie, Ze-Guang Han, Jian-Ming Ying, Chong Chen, Yun-Chao Huang, Hong-Bin Ji, Yuan-Yuan Zhang, Yan Yu, Guang-Biao Zhou

期刊:Signal Transduction and Targeted Therapy

摘要

小细胞肺癌（SCLC）是一种高度侵袭性的神经内分泌肿瘤，强烈相关于烟草致癌物暴露，表现为早期转移和预后极差，五年总体生存率不足7%。关于其癌基因高频激活突变尚少见报道，肿瘤内异质性（ITH）仍待明确。通过对314例SCLC的多组学分析，我们发现，ASCL1+/MKI67+和ASCL1+/CRIP2+两个亚群占据全部190,313个SCLC癌细胞的74.38%，其中ASCL1+SOX1+的干细胞样群在不同亚型中存在。主要组织相容性复合体（MHC）I类分子在六个细胞簇中表达水平低，在五个细胞簇中表达水平高，与KI67表达呈负相关。SCLC的一个特色是mRNA异常剪接，在154例患者中，有119例（77.3%）检测到焦粘着激酶（FAK）剪接变异。FAK变异表现为激酶活性增强，预后最差，在患者来源的类器官和异种移植模型中对FAK抑制剂敏感。检测到除TP53和RB1外的11个高频突变，吸烟状态和肿瘤分期未影响SCLC的微生物群差异。综上，我们的研究揭示了SCLC复杂的内在异质性，发现FAK剪接变异作为高频激活型突变，为这一难治性癌症提供了潜在的治疗靶点。

Abstract

Small-cell lung cancer (SCLC), an aggressive neuroendocrine tumor strongly associated with exposure to tobacco carcinogens, is characterized by early dissemination and dismal prognosis with a five-year overall survival of less than 7%. High-frequency gain-of-function mutations in oncogenes are rarely reported, and intratumor heterogeneity (ITH) remains to be determined in SCLC. Here, via multiomics analyses of 314 SCLCs, we found that the ASCL1+/MKI67+ and ASCL1+/CRIP2+ clusters accounted for 74.38% of the 190,313 SCLC cancer cells from 39 patients, with the ASCL1+SOX1+ stem-like cell cluster across SCLC subtypes. The major histocompatibility complex (MHC) class I molecules were expressed at low levels in six and high levels in five cancer cell clusters and were inversely associated with the KI67 expression level. Abnormal splicing of mRNAs was a feature of SCLC, with focal adhesion kinase (FAK) splicing variants identified in 119 (77.3%) of 154 patients. FAK variants exhibited elevated kinase activity, were associated with the worst prognosis, and were sensitive to FAK inhibitors in patient-derived organoids and xenograft models. Eleven high-frequency mutations were identified in addition to TP53 and RB1, and smoking status and tumor stage did not affect microbiota variance in SCLC. Taken together, our data further revealed the complicated ITH and discovered that FAK splicing variants represent high-frequency gain-of-function alterations in oncogene in SCLC and potential therapeutic targets for this recalcitrant cancer.

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