Proteomics reveals NNMT as a master metabolic regulator of cancer-associated fibroblasts
Proteomics reveals NNMT as a master metabolic regulator of cancer-associated fibroblasts
复制标题
蛋白质组学揭示NNMT是癌症相关成纤维细胞的主要代谢调节因子
DOI：
10.1038/s41586-019-1173-8
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发表时间：
2019-05-30
期刊：
影响因子：
64.8
通讯作者：
Lengyel, Ernst
中科院分区：
文献类型：
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作者：
Eckert, Mark A.;Coscia, Fabian;Lengyel, Ernst
高级别浆液性癌预后差，主要是由于其早期扩散到整个腹腔。基因组学和蛋白质组学方法已经提供了卵巢癌蛋白质基因组学的快照（1,2），但是对肿瘤和间质室的系统检查对于了解卵巢癌转移至关重要。在这里，我们开发了一种无标记的蛋白质组学工作流程，以分析从每个隔室显微解剖的5000个福尔马林固定石蜡包埋细胞。肿瘤蛋白质组在原位病变到转移性疾病的过程中是稳定的；然而，转移相关基质具有高度保守的蛋白质组学特征，主要包括甲基转移酶烟酰胺n -甲基转移酶（NNMT）及其调节的几种蛋白质。基质NNMT的表达对于癌症相关成纤维细胞（CAF）表型的功能方面是必要和充分的，包括CAF标志物的表达和细胞因子和致癌细胞外基质的分泌。间质NNMT的表达支持卵巢癌的迁移、增殖和体内生长转移。NNMT在CAFs中的表达导致s -腺苷蛋氨酸的消耗和组蛋白甲基化的减少，这与肿瘤基质中广泛的基因表达变化有关。这项工作支持使用超低输入蛋白质组学来确定疾病表型的候选驱动因素。NNMT是基质中CAF分化和癌症进展的中心代谢调节剂，可能是治疗靶点。
High-grade serous carcinoma has a poor prognosis, owing primarily to its early dissemination throughout the abdominal cavity. Genomic and proteomic approaches have provided snapshots of the proteogenomics of ovarian cancer(1,2), but a systematic examination of both the tumour and stromal compartments is critical in understanding ovarian cancer metastasis. Here we develop a label-free proteomic workflow to analyse as few as 5,000 formalin-fixed, paraffin-embedded cells microdissected from each compartment. The tumour proteome was stable during progression from in situ lesions to metastatic disease; however, the metastasis-associated stroma was characterized by a highly conserved proteomic signature, prominently including the methyltransferase nicotinamide N-methyltransferase (NNMT) and several of the proteins that it regulates. Stromal NNMT expression was necessary and sufficient for functional aspects of the cancer-associated fibroblast (CAF) phenotype, including the expression of CAF markers and the secretion of cytokines and oncogenic extracellular matrix. Stromal NNMT expression supported ovarian cancer migration, proliferation and in vivo growth and metastasis. Expression of NNMT in CAFs led to depletion of S-adenosyl methionine and reduction in histone methylation associated with widespread gene expression changes in the tumour stroma. This work supports the use of ultra-low-input proteomics to identify candidate drivers of disease phenotypes. NNMT is a central, metabolic regulator of CAF differentiation and cancer progression in the stroma that may be therapeutically targeted.