Distinct Cancer-Promoting Stromal Gene Expression Depending on Lung Function.
Distinct Cancer-Promoting Stromal Gene Expression Depending on Lung Function.
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DOI：
10.1164/rccm.201801-0080oc
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发表时间：
2019-08
影响因子：
24.7
通讯作者：
Brian J. Sandri;Laìa Masvidal;C. Murie;Margarita Bartish;Svetlana V. Avdulov;LeeAnn Higgins;Todd W Markowski;M. Peterson;J. Bergh;Ping Yang;Charlotte Rolny;A. Limper;T. Griffin;P. Bitterman;C. Wendt;O. Larsson
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作者：
Brian J. Sandri;Laìa Masvidal;C. Murie;Margarita Bartish;Svetlana V. Avdulov;LeeAnn Higgins;Todd W Markowski;M. Peterson;J. Bergh;Ping Yang;Charlotte Rolny;A. Limper;T. Griffin;P. Bitterman;C. Wendt;O. Larsson
慢性阻塞性肺疾病（COPD）是肺癌的独立危险因素，但其潜在的分子机制尚不清楚。我们假设肺间质细胞激活支持肿瘤发生的病理基因表达程序。目的：研究支持肺癌发生的肺间质分子机制。研究对象包括患有或不患有肺癌的患者，这些患者的肺功能各不相同。我们对非恶性肺组织进行了多组学分析，以定量转录组、翻译组和蛋白质组。测量和主要结果癌症相关基因表达的变化主要表现为在mRNA水平没有相应变化的情况下mRNA翻译调节蛋白水平的效率的改变。驱动这些癌症相关翻译程序的分子机制基于肺功能而不同。在肺功能正常至轻度受损的受试者中，哺乳动物雷帕霉素靶蛋白（mTOR）通路充当上游驱动器;而在严重气流阻塞中，病理性细胞外基质（ECM）下游通路出现。与癌症起始过程中的作用一致，mTOR和ECM基因表达程序均抑制先前鉴定的促癌分泌体的激活。此外，肺组织的原位检查记录了基质成纤维细胞表达来自两种促癌分泌物的癌症相关蛋白，包括轻度或无气流阻塞的IL 6和严重气流阻塞的BMP 1。结论肺癌患者存在两种不同的促进肿瘤发生的基质基因表达程序，这取决于肺功能。我们的工作对筛查策略和癌症治疗的个性化方法都有影响。
RATIONALE Chronic obstructive pulmonary disease (COPD) is an independent risk factor for lung cancer, but the underlying molecular mechanisms are unknown. We hypothesized that lung stromal cells activate pathological gene expression programs supporting oncogenesis. OBJECTIVE To identify molecular mechanisms operating in the lung stroma that support development of lung cancer. METHODS Study subjects included patients with- or without- lung cancer across a spectrum of lung function. We conducted multi-omics analysis of non-malignant lung tissue to quantify the transcriptome, translatome and proteome. MEASUREMENTS AND MAIN RESULTS Cancer-associated gene expression changes predominantly manifested as alterations in the efficiency of mRNA translation modulating protein levels in the absence of corresponding changes in mRNA levels. The molecular mechanisms driving these cancer-associated translation programs differed based on lung function. In subjects with normal to mildly impaired lung-function, the mammalian target of rapamycin (mTOR) pathway served as an upstream driver; whereas in severe airflow obstruction, pathways downstream of pathological extracellular matrix (ECM) emerged. Consistent with a role during cancer initiation, both the mTOR and ECM gene expression programs paralleled activation of previously identified pro-cancer secretomes. Furthermore, in situ examination of lung tissue documented that stromal fibroblasts express cancer-associated proteins from the two pro-cancer secretomes including IL6 in mild or no airflow obstruction and BMP1 in severe airflow obstruction. CONCLUSION Two distinct stromal gene expression programs promoting cancer initiation are activated in lung cancer patients depending on lung function. Our work has implications both for screening strategies and personalized approaches to cancer treatment.