法国发现促进原发性乳腺癌转移新机制

　　癌症相关成纤维细胞是被癌细胞激活的肿瘤组织纤维母细胞，也是肿瘤微环境的主要成分，对原发肿瘤的影响已被证实。不过，癌症相关成纤维细胞不同亚型的特征及其对肿瘤转移的影响尚不明确。

　　2020年1月21日，英国《自然》旗下《自然通讯》在线发表法国居里研究中心、巴黎文理研究大学、索邦大学、居里研究中心附属医院、皮埃尔-吉勒·德热纳研究中心的研究报告，探讨了癌症相关成纤维细胞不同亚型的特征及其对乳腺癌转移的影响。

　　该研究结合流式细胞仪、免疫组织化学、核糖核酸（RNA）测序，对乳腺癌腋窝转移淋巴结标本进行分析，确定了4种癌症相关成纤维细胞亚型：S1、S2、S3、S4。其中，乳腺癌腋窝转移淋巴结的癌症相关成纤维细胞S1和S4比例最高，并与癌细胞浸润密切相关。

　　通过对原代培养细胞的功能测定，该研究证实这些亚型细胞通过独特的互补机制促进乳腺癌转移：癌症相关成纤维细胞S1通过基质细胞衍生趋化因子CXCL12和转化生长因子TGFβ两条信号通路刺激癌细胞转移，并启动上皮细胞向间质细胞转化；高度收缩的癌症相关成纤维细胞S4以三维形式通过NOTCH信号通路诱导癌细胞浸润。

　　乳腺癌诊断时，淋巴结癌症相关成纤维细胞（尤其S4）较多与较少的患者相比，迟发远处转移比例显著较高。

　　因此，该研究结果表明，淋巴结癌症相关成纤维细胞亚型具有预后作用，乳腺癌诊断时可以通过检查腋窝淋巴结癌症相关成纤维细胞亚型预测患者结局，并且有望成为抑制原发性乳腺癌转移的新靶点。

Nat Commun. 2020 Jan 21. [Epub ahead of print]

Cancer-associated fibroblast heterogeneity in axillary lymph nodes drives metastases in breast cancer through complementary mechanisms.

Floriane Pelon, Brigitte Bourachot, Yann Kieffer, Ilaria Magagna, Fanny Mermet-Meillon, Isabelle Bonnet, Ana Costa, Anne-Marie Givel, Youmna Attieh, Jorge Barbazan, Claire Bonneau, Laetitia Fuhrmann, Stéphanie Descroix, Danijela Vignjevic, Pascal Silberzan, Maria Carla Parrini, Anne Vincent-Salomon, Fatima Mechta-Grigoriou.

Institut Curie, PSL Research University, Paris, France; Institut Curie, PSL Research University, Sorbonne Université, Paris, France; Institut Curie Hospital, Paris, France; Institut Curie, Institut Pierre-Gilles de Gennes, Paris, France.

Although fibroblast heterogeneity is recognized in primary tumors, both its characterization in and its impact on metastases remain unknown. Here, combining flow cytometry, immunohistochemistry and RNA-sequencing on breast cancer samples, we identify four Cancer-Associated Fibroblast (CAF) subpopulations in metastatic lymph nodes (LN). Two myofibroblastic subsets, CAF-S1 and CAF-S4, accumulate in LN and correlate with cancer cell invasion. By developing functional assays on primary cultures, we demonstrate that these subsets promote metastasis through distinct functions. While CAF-S1 stimulate cancer cell migration and initiate an epithelial-to-mesenchymal transition through CXCL12 and TGFβ pathways, highly contractile CAF-S4 induce cancer cell invasion in 3-dimensions via NOTCH signaling. Patients with high levels of CAFs, particularly CAF-S4, in LN at diagnosis are prone to develop late distant metastases. Our findings suggest that CAF subset accumulation in LN is a prognostic marker, suggesting that CAF subsets could be examined in axillary LN at diagnosis.

DOI: 10.1038/s41467-019-14134-w