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The CD200-CD200R Axis Promotes Squamous Cell Carcinoma Metastasis via Regulation of Cathepsin K
Cancer Research ( IF 12.5 ) Pub Date : 2021-10-01 , DOI: 10.1158/0008-5472.can-20-3251
Iasha Z Khan 1 , Christina A Del Guzzo 1 , Anqi Shao 1 , Jiyoon Cho 1 , Rong Du 1 , Adrienne O Cohen 1 , David M Owens 1, 2
Affiliation  

The CD200–CD200R immunoregulatory signaling axis plays an etiologic role in the survival and spread of numerous cancers, primarily through suppression of antitumor immune surveillance. Our previous work outlined a prometastatic role for the CD200–CD200R axis in cutaneous squamous cell carcinoma (cSCC) that is independent of direct T-cell suppression but modulates the function of infiltrating myeloid cells. To identify effectors of the CD200–CD200R axis important for cSCC metastasis, we conducted RNA sequencing profiling of infiltrating CD11B+Cd200R+ cells isolated from CD200+ versus CD200-null cSCCs and identified the cysteine protease cathepsin K (Ctsk) to be highly upregulated in CD200+ cSCCs. CD11B+Cd200R+ cells expressed phenotypic markers associated with myeloid-derived suppressor cell–like cells and tumor-associated macrophages and were the primary source of Ctsk expression in cSCC. A Cd200R+ myeloid cell–cSCC coculture system showed that induction of Ctsk was dependent on engagement of the CD200–CD200R axis, indicating that Ctsk is a target gene of this pathway in the cSCC tumor microenvironment. Inhibition of Ctsk, but not matrix metalloproteinases, significantly blocked cSCC cell migration in vitro . Finally, targeted CD200 disruption in tumor cells and Ctsk pharmacologic inhibition significantly reduced cSCC metastasis in vivo . Collectively, these findings support the conclusion that CD200 stimulates cSCC invasion and metastasis via induction of Ctsk in CD200R+ infiltrating myeloid cells. Significance: These findings highlight the relationship between CD200–CD200R and cathepsin K in cutaneous squamous cell carcinoma metastasis and suggest that either of these components may serve as a viable therapeutic target in this disease.

中文翻译:

CD200-CD200R 轴通过调节组织蛋白酶 K 促进鳞状细胞癌转移

CD200-CD200R 免疫调节信号轴在许多癌症的生存和扩散中发挥病因学作用,主要是通过抑制抗肿瘤免疫监视。我们之前的工作概述了 CD200-CD200R 轴在皮肤鳞状细胞癌 (cSCC) 中的前转移作用,该作用独立于直接 T 细胞抑制,但调节浸润性骨髓细胞的功能。为了确定对 cSCC 转移重要的 CD200–CD200R 轴的效应子,我们对从 CD200+ 与 CD200 无效 cSCC 分离的浸润性 CD11B+Cd200R+ 细胞进行了 RNA 测序分析,并确定半胱氨酸蛋白酶组织蛋白酶 K (Ctsk) 在 CD200+ cSCC 中高度上调. CD11B+Cd200R+ 细胞表达与髓源性抑制细胞样细胞和肿瘤相关巨噬细胞相关的表型标志物,并且是 cSCC 中 Ctsk 表达的主要来源。Cd200R+ 骨髓细胞-cSCC 共培养系统显示 Ctsk 的诱导依赖于 CD200-CD200R 轴的参与,表明 Ctsk 是 cSCC 肿瘤微环境中该途径的靶基因。在体外,抑制 Ctsk 而不是基质金属蛋白酶显着阻断了 cSCC 细胞迁移。最后,肿瘤细胞中的靶向 CD200 破坏和 Ctsk 药物抑制显着减少了体内 cSCC 转移。总的来说,这些发现支持 CD200 通过在 CD200R+ 浸润性骨髓细胞中诱导 Ctsk 刺激 cSCC 侵袭和转移的结论。意义:
更新日期:2021-10-01
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