Genome-wide in vivo screen identifies host molecule in promoting cancer metastasis.
Genome-wide in vivo screen identifies host molecule in promoting cancer metastasis.
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全基因组体内筛选鉴定促进癌症转移的宿主分子
DOI：
10.1007/s13238-017-0391-9
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发表时间：
2017-06
期刊：
影响因子：
21.1
通讯作者：
Cao X
中科院分区：
文献类型：
--
作者：
Gu Y;Liu Y;Cao X
转移，即肿瘤细胞从原发部位向远处器官逐渐移行，是癌症死亡的主要原因。新的证据表明，肿瘤减少的宿主微环境在转移的多个阶段与肿瘤细胞合作，使肿瘤细胞逃避免疫攻击，抵抗凋亡，并在远处器官中增殖(Liu等，2016；Quail and Joyce，2013)。这种微环境由一系列复杂的炎症细胞、成纤维细胞、血管和细胞外基质组成(Joyce和Fearon，2015；Liu和曹，2016)。重新教育促进肿瘤的微环境，特别是激活残疾的免疫系统，被证明是治疗癌症的有效策略，例如免疫检查点阻断(Pardoll，2012；Tan等人，2016)。因此，揭示可能促进或抑制肿瘤细胞转移的宿主微环境分子，将有助于肿瘤治疗方法的设计，虽然具有挑战性，但迫切需要。在最近一期的《自然》杂志上，Adams及其同事对810个突变小鼠品系进行了全基因组体内筛选，以确定宿主微环境中重要的转移调节因子(van der Weyden等人，2017年)。这项研究是基于他们研究所的“桑格老鼠遗传学项目”，通过产生900多只基因敲除小鼠来研究一系列基因的新作用(White等人，2013年)。因此，研究人员通过静脉注射810个小鼠黑色素瘤细胞系来进行“实验性转移试验”，然后评估肺转移情况。与野生型小鼠相比，他们发现15个突变小鼠的肺转移灶显著减少，8个突变小鼠的肺转移灶增加。值得注意的是，这23个基因中的大多数与免疫相关，表明免疫系统在转移的微环境调节中发挥关键作用。他们进一步关注鞘氨醇-1-磷酸转运体同源2(Spns2)，因为Spns2突变小鼠显示出最显著的肺转移减少。Spns2是S1P的细胞表面转运体，它调节免疫细胞(T和B细胞)从淋巴器官进入淋巴管(MatLoubian等人，2004年)。Spns2tm1a/tm1a小鼠一直表现出血清中S1P水平的降低，循环中T和B细胞的显著减少，但其他细胞系没有。突变小鼠肺组织中T、B细胞减少，NK细胞增加。淋巴管内皮细胞(LEC)特异性Spns2基因缺失的小鼠(Spns2tm1c/tm1c；Lyve1cre/+小鼠)与Spns2tm1a/tm1a小鼠具有相似的表型，表明LEC Spns2缺陷是导致外周T和B细胞减少的原因。为了确定交替的淋巴细胞分布如何影响转移，对T细胞亚群进行了深入的分析。有趣的是，尽管Spns2tm1a/tm1a小鼠的T细胞数量减少，但它们显示出极高比例的抗肿瘤效应T细胞。Spns2tm1a/tm1a小鼠CD_8~+T细胞产生干扰素-γ和增强B16-F10靶细胞杀伤作用，提示CD_8~+T细胞在抑制肿瘤转移中起一定作用。然而，通过体内抗体清除CD8+T细胞，突变小鼠的转移灶数仍然少于野生型小鼠。考虑到肺中NK细胞的升高，研究人员消除了这些小鼠中尚不能恢复肺转移的NK细胞。只有当突变的小鼠接受了…
Metastasis, the movement of tumor cells from a primary site to progressively colonize distant organs, is the leading cause of cancer mortality. Emerging evidences show that tumoreducated host microenvironment cooperates with tumor cells during the multiple stage of metastasis, making tumor cells evade immune attack, resistant to apoptosis, and proliferate in distant organ (Liu et al., 2016; Quail and Joyce, 2013). This microenvironment consists of an elaborate array of inflammatory cells, fibroblastic cells, blood vessels, and the extracellular matrix (Joyce and Fearon, 2015; Liu and Cao, 2016). Re-educating the tumor-promoting microenvironment, especially activating the disabled immune system, is proved to be an effective strategy for treating cancer, such as immune checkpoint blockade (Pardoll, 2012; Tan et al., 2016). Therefore, uncovering the molecules of host microenvironment which may promote or inhibit tumor cell metastasis will be helpful to the design of cancer therapeutic approaches, although challenging but desperately needed. In recent issue of Nature, Adams and colleagues performed a genome-wide in vivo screen of 810 mutant mouse lines to identify important metastatic regulators in host microenvironment (van der Weyden et al., 2017). This study was based on the “Sanger Mouse Genetics Project” in their institute to study new roles for a broad range of genes by generating more than 900 knockout mice (White et al., 2013). Therefore, the researchers used an “experimental metastasis assay” by intravenous administration of mouse metastatic melanoma cells in 810 mouse lines therein and then assessed the pulmonary metastasis. Compared with the wild-type mouse, they found that 15 mutant mouse lines showed significantly decreased pulmonary metastatic foci and 8 mutant mouse lines increased. Notably, most of these 23 genes were immune-related, indicating a key role of the immune system in microenvironmental regulation of metastasis.They further focused on sphingosine-1-phosphate (S1P) transporter spinster homologue 2 (Spns2), as Spns2 mutant mice showed the most significant decrease in pulmonary metastasis. Spns2 is the cell-surface transporter of S1P, which regulates the egress of immune cells (T and B cells) from the lymphoid organs into the lymphatic vessels (Matloubian et al., 2004). Consistently, Spns2tm1a/tm1a mice showed decreased S1P level in the serum, and a significant reduction in circulating T and B cells, but not other cell lineages. In the lung of mutant mice, T and B cells were also reduced, while NK cells were increased. Mice with lymphatic endothelial cell (LEC)-specific deletion of Spns2 (Spns2tm1c/tm1c; Lyve1cre/+ mice) had the similar phenotype with Spns2tm1a/tm1a mice, indicating deficiency in LEC Spns2 was responsible for the reduction of peripheral T and B cells. To determine how the alternated lymphocyte distribution could affect metastasis, intensive analysis of T cell subgroup was conducted. Interestingly, despite of their reduction in T cell numbers, Spns2tm1a/tm1a mice showed an extremely higher percentage of anti-tumoral effector T cells. And increased production of interferon-γ (IFN-γ) and enhanced B16-F10 target cell killing was also found in CD8+ T cells from Spns2tm1a/tm1a mice, suggesting a role of CD8+ T cells in the suppression of metastasis. However, by in vivo antibody depletion of CD8+ T cells, the number of metastatic foci in mutant mice was still less than that in wild-type mice. In consideration of elevated NK cells in the lung, researchers eliminated NK cells in these mice, which could not restore the pulmonary metastasis yet. Only when the mutant mice received …