Molecular dissection of CRC primary tumors and their matched liver metastases reveals critical role of immune microenvironment, EMT and angiogenesis in cancer metastasis
Molecular dissection of CRC primary tumors and their matched liver metastases reveals critical role of immune microenvironment, EMT and angiogenesis in cancer metastasis
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DOI：
10.1038/s41598-020-67842-5
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发表时间：
2020-07-01
影响因子：
4.6
通讯作者：
Peng, Sheng-Bin
中科院分区：
文献类型：
--
作者：
Liu, Jiangang;Cho, Yong Beom;Peng, Sheng-Bin
转移是癌症死亡的主要原因。结直肠癌(CRC)的原发肿瘤常转移至肝脏。在本研究中，我们收集了45例大肠癌患者的122份样本。其中32例患者有原发肿瘤、邻近正常组织和配对的肝转移瘤。13例为无远处转移的原发肿瘤，与正常组织相匹配。通过全外显子组和RNA测序以及SNP6.0分析对这些样品进行了鉴定。我们的结果显示，包括常见的致癌突变、全基因组突变和拷贝数变异在内的遗传改变在原发肿瘤和转移性肿瘤之间没有显著差异。然后我们组装了基因共表达网络，并确定免疫抑制、上皮-间充质转化(EMT)和血管生成等转移相关基因网络是与结直肠癌转移相关的关键事件和潜在的协同驱动因素。使用公布的数据集进行的进一步独立队列验证证实，这些特定的基因网络在肿瘤进展过程中上调。EMT、血管生成、免疫抑制和T细胞耗竭等基因网络与患者预后不良和固有的抗PD-1耐药密切相关。这些结果为转移性结直肠癌的联合治疗提供了新的思路。
Metastasis is the primary cause of cancer mortality. The primary tumors of colorectal cancer (CRC) often metastasize to the liver. In this study, we have collected 122 samples from 45 CRC patients. Among them, 32 patients have primary tumors, adjacent normal tissues, and matched liver metastases. Thirteen patients have primary tumors without distant metastasis and matched normal tissues. Characterization of these samples was conducted by whole-exome and RNA sequencing and SNP6.0 analysis. Our results revealed no significant difference in genetic alterations including common oncogenic mutations, whole genome mutations and copy number variations between primary and metastatic tumors. We then assembled gene co-expression networks and identified metastasis-correlated gene networks of immune-suppression, epithelial-mesenchymal transition (EMT) and angiogenesis as the key events and potentially synergistic drivers associated with CRC metastasis. Further independent cohort validation using published datasets has verified that these specific gene networks are up regulated throughout the tumor progression. The gene networks of EMT, angiogenesis, immune-suppression and T cell exhaustion are closely correlated with the poor patient outcome and intrinsic anti-PD-1 resistance. These results offer insights of combinational strategy for the treatment of metastatic CRC.