miR200-regulated CXCL12β promotes fibroblast heterogeneity and immunosuppression in ovarian cancers.
miR200-regulated CXCL12β promotes fibroblast heterogeneity and immunosuppression in ovarian cancers.
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DOI：
10.1038/s41467-018-03348-z
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发表时间：
2018-03-13
影响因子：
16.6
通讯作者：
Mechta-Grigoriou F
中科院分区：
文献类型：
--
作者：
Givel AM;Kieffer Y;Scholer-Dahirel A;Sirven P;Cardon M;Pelon F;Magagna I;Gentric G;Costa A;Bonneau C;Mieulet V;Vincent-Salomon A;Mechta-Grigoriou F
高级别浆液性卵巢癌（HGSOC）已细分为分子亚型。间充质HGSOC亚组，定义为基质相关的基因签名，总是与患者生存率差。我们证明，间质在间充质HGSOC中发挥关键作用。我们通过识别四种癌相关成纤维细胞（CAF-S1-4）来突出HGSOC中的基质异质性。间充质HGSOC在CAF-S1成纤维细胞中显示出高含量，其通过增加CD 25 + FOXP 3 + T淋巴细胞的吸引、存活和分化而表现出免疫抑制功能。CXCL 12趋化因子的β亚型（CXCL 12 β）通过miR-141/200 a依赖性机制在免疫抑制性CAF-S1亚群中特异性蓄积。此外，与CXCL 12 α相比，CAF-S1细胞中的CXCL 12 β表达在CAF-S1免疫抑制活性中起关键作用，并且是HGSOC中可靠的预后因子。因此，我们的数据突出了HGSOC中CXCL 12 α和CXCL 12 β亚型的差异调节，并揭示了间充质HGSOC中CXCL 12 β相关的基质异质性和免疫抑制环境。癌症相关成纤维细胞（CAF）是肿瘤微环境的重要组成部分。在这里，作者描述了卵巢癌亚型人类样本中CAF的四个子集，并在间充质亚型中显示了一个特定的CAF-S1群体，该群体通过CXCL 12 β吸引免疫抑制性TGFs。
High-grade serous ovarian cancers (HGSOC) have been subdivided into molecular subtypes. The mesenchymal HGSOC subgroup, defined by stromal-related gene signatures, is invariably associated with poor patient survival. We demonstrate that stroma exerts a key function in mesenchymal HGSOC. We highlight stromal heterogeneity in HGSOC by identifying four subsets of carcinoma-associated fibroblasts (CAF-S1-4). Mesenchymal HGSOC show high content in CAF-S1 fibroblasts, which exhibit immunosuppressive functions by increasing attraction, survival, and differentiation of CD25+FOXP3+ T lymphocytes. The beta isoform of the CXCL12 chemokine (CXCL12β) specifically accumulates in the immunosuppressive CAF-S1 subset through a miR-141/200a dependent-mechanism. Moreover, CXCL12β expression in CAF-S1 cells plays a crucial role in CAF-S1 immunosuppressive activity and is a reliable prognosis factor in HGSOC, in contrast to CXCL12α. Thus, our data highlight the differential regulation of the CXCL12α and CXCL12β isoforms in HGSOC, and reveal a CXCL12β-associated stromal heterogeneity and immunosuppressive environment in mesenchymal HGSOC. Cancer-associated fibroblasts (CAFs) are an important part of the tumor microenvironment. Here the authors characterize four subsets of CAFs across human samples of ovarian cancer subtypes and show in the mesenchymal subtype a specific CAF-S1 population that attracts immunosuppressive Tregs via CXCL12β.
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通过基因间DNA环和转录读取对miR-200c/141的调节。
影响因子：
16.6
作者：
Batista L;Bourachot B;Mateescu B;Reyal F;Mechta-Grigoriou F
通讯作者：
Mechta-Grigoriou F
DOI：
10.1007/s00262-015-1753-x
发表时间：
2015-12
期刊：
Cancer immunology, immunotherapy : CII
影响因子：
--
作者：
Knutson KL;Maurer MJ;Preston CC;Moysich KB;Goergen K;Hawthorne KM;Cunningham JM;Odunsi K;Hartmann LC;Kalli KR;Oberg AL;Goode EL
通讯作者：
Goode EL
影响因子：
45.3
作者：
Fong, Peter C.;Yap, Timothy A.;Kaye, Stan B.
通讯作者：
Kaye, Stan B.
影响因子：
10.3
作者：
Konecny, Gottfried E.;Wang, Chen;Goode, Ellen L.
通讯作者：
Goode, Ellen L.
DOI：
10.1073/pnas.1320318110
发表时间：
2013-12-10
影响因子：
11.1
作者：
Feig, Christine;Jones, James O.;Fearon, Douglas T.
通讯作者：
Fearon, Douglas T.