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

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Cancer-associated fibroblast heterogeneity in axillary lymph nodes drives metastases in breast cancer through complementary mechanisms.
Nature Communications ( IF 14.7 ) Pub Date : 2020-01-21 , DOI: 10.1038/s41467-019-14134-w
Floriane Pelon _{1,

2} , Brigitte Bourachot _{1,

2} , Yann Kieffer _{1,

2} , Ilaria Magagna _{1,

2} , Fanny Mermet-Meillon ₃ , Isabelle Bonnet ₄ , Ana Costa _{1,

2} , Anne-Marie Givel _{1,

2} , Youmna Attieh ₅ , Jorge Barbazan ₅ , Claire Bonneau _{1,

2} , Laetitia Fuhrmann ₆ , Stéphanie Descroix ₇ , Danijela Vignjevic ₅ , Pascal Silberzan ₄ , Maria Carla Parrini ₃ , Anne Vincent-Salomon ₆ , Fatima Mechta-Grigoriou _{1,

2}

Affiliation

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.

中文翻译：

腋窝淋巴结中与癌症相关的成纤维细胞异质性通过互补机制驱动乳腺癌转移。

尽管在原发性肿瘤中发现了成纤维细胞异质性，但其在转移中的特征及其对转移的影响仍然未知。在这里，结合流式细胞术、免疫组织化学和对乳腺癌样本的 RNA 测序，我们鉴定了转移淋巴结 (LN) 中的四种癌症相关成纤维细胞 (CAF) 亚群。两种肌纤维母细胞亚群 CAF-S1 和 CAF-S4 在 LN 中积累并与癌细胞侵袭相关。通过对原代培养物进行功能测定，我们证明这些亚群通过不同的功能促进转移。 CAF-S1 刺激癌细胞迁移并通过 CXCL12 和 TGFβ 途径启动上皮间质转化，而高度收缩的 CAF-S4 通过 NOTCH 信号传导诱导癌细胞在 3 维侵袭。诊断时淋巴结中 CAF（尤其是 CAF-S4）水平较高的患者容易发生晚期远处转移。我们的研究结果表明，CAF 子集在 LN 中的积累是一个预后标志物，这表明诊断时可以在腋窝 LN 中检查 CAF 子集。

更新日期：2020-01-22

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