Targeting the MAPK7/MMP9 axis for metastasis in primary bone cancer
Targeting the MAPK7/MMP9 axis for metastasis in primary bone cancer
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DOI：
10.1038/s41388-020-1379-0
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发表时间：
2020-07-13
期刊：
影响因子：
8
通讯作者：
Finegan, Katherine G.
中科院分区：
文献类型：
--
作者：
Green, Darrell;Eyre, Heather;Finegan, Katherine G.
转移是癌症相关死亡的主要原因。这个多阶段的过程涉及肿瘤细胞和肿瘤间质的共同作用，将转移细胞释放到血液循环中。循环中的肿瘤细胞(CTCs)存活于循环中的细胞毒作用下，渗出并定植于影响转移结果的继发部位。重新编程转录格局是一个转移的标志，但检测驱动病理基因表达的潜在主调控因子是一个关键挑战，特别是在儿童癌症中。在这里，我们使用整个肿瘤加上原发骨癌和CTCs的单细胞RNA测序来进行加权基因共表达网络分析，以系统地检测转移性转录表达的协调变化。这一方法与从细胞系模型、临床样本和异种移植小鼠模型收集的数据进行了比较，显示丝裂原活化蛋白激酶7/基质金属肽酶9(MAPK7/MMP9)是原发骨癌转移的驱动因素。RNA干扰敲除MAPK7可减少增殖、集落形成、迁移、肿瘤生长、巨噬细胞滞留/极化和肺转移。与这些观察相平行的是，MAPK7丢失后，激活的IL-1B、IL-6、IL-8加上间充质标记物VIM和VEGFs的活性降低。我们的研究结果表明，新发现的多维MAPK7/MMP9信号中枢参与了原发骨癌转移，这在临床上是可行的。
Metastasis is the leading cause of cancer-related death. This multistage process involves contribution from both tumour cells and the tumour stroma to release metastatic cells into the circulation. Circulating tumour cells (CTCs) survive circulatory cytotoxicity, extravasate and colonise secondary sites effecting metastatic outcome. Reprogramming the transcriptomic landscape is a metastatic hallmark, but detecting underlying master regulators that drive pathological gene expression is a key challenge, especially in childhood cancer. Here we used whole tumour plus single-cell RNA-sequencing in primary bone cancer and CTCs to perform weighted gene co-expression network analysis to systematically detect coordinated changes in metastatic transcript expression. This approach with comparisons applied to data collected from cell line models, clinical samples and xenograft mouse models revealed mitogen-activated protein kinase 7/matrix metallopeptidase 9 (MAPK7/MMP9) signalling as a driver for primary bone cancer metastasis. RNA interference knockdown ofMAPK7reduces proliferation, colony formation, migration, tumour growth, macrophage residency/polarisation and lung metastasis. Parallel to these observations were reduction of activated interleukinsIL1B,IL6,IL8plus mesenchymal markersVIMandVEGFin response toMAPK7loss. Our results implicate a newly discovered, multidimensional MAPK7/MMP9 signalling hub in primary bone cancer metastasis that is clinically actionable.