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首页> 外文会议>Conference on biochemical and molecular engineering >CELL COMMUNICATION NETWORK FACTOR 4 (CCN4/WISP1) SHIFTS MELANOMA CELLS FROM A FRAGILE PROLIFERATIVE TO A RESILIENT METASTATIC STATE AND SUPPRESSES IMMUNE SURVEILLANCE
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CELL COMMUNICATION NETWORK FACTOR 4 (CCN4/WISP1) SHIFTS MELANOMA CELLS FROM A FRAGILE PROLIFERATIVE TO A RESILIENT METASTATIC STATE AND SUPPRESSES IMMUNE SURVEILLANCE

机译：细胞通信网络因子4（CCN4 / WISP1）将黑色素瘤细胞从脆弱的增殖状态转变为弹性的转移状态，并抑制了免疫监视

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While deregulated intracellular signaling initiates melanoma, patient survival is limited by progression and metastasis - processes often coordinated by secreted signals. Secreted signals can reinforce cell fate decisions by acting on the same cell and sustain pathology by influencing the stromal and immune cells present within the tumor microenvironment. Understanding how these secreted signals contribute to pathology remains a challenge as the relevance of a secreted signal depends highly on context. Identified by an unbiased phenotypic screen for inhibitors of immune cell crosstalk, Cell Communication Network Factor 4 (CCN4/WISP1) is a secreted matricellular protein that is upregulated in melanoma and breast cancer and correlates with a worse overall outcome. Here, I will discuss our recent in vitro and in vivo results to clarify the functional role that CCN4 plays in melanoma. Interestingly, we found that CCN4 shifts melanoma cells from a fragile proliferative to a resilient metastatic state. CCN4 drives this phenotypic shift by activating AKT Ser/Thr kinase and MEK/ERK signaling pathways that induce snail family transcriptional repressor 1 (SNAI1) expression. SNAI1 then initiates a transcriptional response similar to the epithelial-mesenchymal transition (EMT), including E-cadherin repression and fibronectin and N-cadherin induction. In vivo, knocking out CCN4 represses tumor metastasis of B16F10 and YUMM1.7 melanoma cells in syngeneic C57BL/6Ncrl and immunocompromised NOD-scid IL2Rgamma~(null) (NSG) mice. While CCN4-KO variants of B16F10 and YUMM1.7 cells grow faster that WT cells both in vitro and in NSG mice, tumors initiated by CCN4-KO variants consistently grow slower in immunocompetent hosts. This reduction in tumor growth by CCN4-KO variants also corresponds to an increase in tumor-infiltrating lymphocytes. CCN4-KO variants of B16F0 and YUMM1.7 melanoma cells are also more responsive to immune checkpoint blockade. While some mechanistic details of this heterocellular crosstalk remain unclear, the results suggest an intriguing collateral target to both enhance the efficacy of immune checkpoint blockage and inhibit metastasis.
机译：虽然细胞内信号转导失调会引发黑色素瘤，但患者的生存受到进展和转移的限制-进程通常由分泌的信号协调。分泌的信号可以通过作用于同一细胞来增强细胞命运的决定，并通过影响肿瘤微环境中存在的基质细胞和免疫细胞来维持病理状态。由于这些分泌信号的相关性在很大程度上取决于环境，因此了解这些分泌信号如何导致病理仍然是一个挑战。细胞通讯网络因子4（CCN4 / WISP1）由无偏见的免疫细胞串扰抑制剂表型筛选所鉴定，是一种分泌的基质细胞蛋白，在黑色素瘤和乳腺癌中表达上调，并且与更差的总体预后相关。在这里，我将讨论我们最近的体内和体外研究结果，以阐明CCN4在黑色素瘤中的功能性作用。有趣的是，我们发现CCN4将黑色素瘤细胞从脆弱的增殖状态转变为弹性转移状态。 CCN4通过激活AKT Ser / Thr激酶和MEK / ERK信号转导通路来诱导蜗牛家族转录阻遏物1（SNAI1）表达，从而驱动这种表型转变。然后，SNAI1启动类似于上皮-间质转化（EMT）的转录反应，包括E-钙粘着蛋白阻抑和纤连蛋白和N-钙粘着蛋白诱导。在体内，敲除CCN4可抑制同源C57BL / 6Ncrl和免疫功能受损的NOD-scid IL2Rgamma（null）（NSG）小鼠中B16F10和YUMM1.7黑色素瘤细胞的肿瘤转移。虽然B16F10和YUMM1.7细胞的CCN4-KO变体在体外和NSG小鼠中的生长均比野生型细胞快，但由CCN4-KO变体引发的肿瘤在具有免疫能力的宿主中始终生长较慢。 CCN4-KO变体在肿瘤生长中的这种减少也对应于肿瘤浸润淋巴细胞的增加。 B16F0和YUMM1.7黑色素瘤细胞的CCN4-KO变体也对免疫检查点封锁有更高的反应性。虽然尚不清楚这种异源细胞串扰的一些机理细节，但结果表明，一个有趣的附带靶标既可以增强免疫检查点阻断的功效，又可以抑制转移。

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