Homophilic CD44 Interactions Mediate Tumor Cell Aggregation and Polyclonal Metastasis in Patient-Derived Breast Cancer Models.
Homophilic CD44 Interactions Mediate Tumor Cell Aggregation and Polyclonal Metastasis in Patient-Derived Breast Cancer Models.
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DOI：
10.1158/2159-8290.cd-18-0065
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发表时间：
2019-01
期刊：
影响因子：
28.2
通讯作者：
Liu H
中科院分区：
文献类型：
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作者：
Liu X;Taftaf R;Kawaguchi M;Chang YF;Chen W;Entenberg D;Zhang Y;Gerratana L;Huang S;Patel DB;Tsui E;Adorno-Cruz V;Chirieleison SM;Cao Y;Harney AS;Patel S;Patsialou A;Shen Y;Avril S;Gilmore HL;Lathia JD;Abbott DW;Cristofanilli M;Condeelis JS;Liu H
循环肿瘤细胞（CTC）种子癌症转移;然而，潜在的细胞和分子机制仍不清楚。CTC簇的检测频率较低，但比三阴性乳腺癌患者和代表性患者来源的异种移植物（PDX）模型的单个CTC更具转移性。使用活体多光子显微成像，我们发现聚集在迁移和循环中的肿瘤细胞是由于单个肿瘤细胞的聚集而不是集体迁移和内聚脱落。聚集的肿瘤细胞表现出乳腺癌干细胞标志物CD 44的富集表达，并促进肿瘤发生和多克隆转移。CD 44的消耗有效地防止了肿瘤细胞聚集并降低了PAK 2水平。细胞间CD 44-CD 44的嗜同性相互作用引导多细胞聚集，需要其N-末端结构域，并启动CD 44-PAK 2相互作用以进一步激活FAK信号传导。我们的研究强调，CD 44 + CTC簇的存在与乳腺癌患者的不良预后相关，可以作为多克隆转移的新的治疗靶点。
Circulating tumor cells (CTCs) seed cancer metastases; however, the underlying cellular and molecular mechanisms remain unclear. CTC clusters were less frequently detected but more metastatic than single CTCs of triple negative breast cancer patients and representative patient-derived-xenograft (PDX) models. Using intravital multiphoton microscopic imaging, we found that clustered tumor cells in migration and circulation resulted from aggregation of individual tumor cells rather than collective migration and cohesive shedding. Aggregated tumor cells exhibited enriched expression of the breast cancer stem cell marker CD44 and promoted tumorigenesis and polyclonal metastasis. Depletion of CD44 effectively prevented tumor cell aggregation and decreased PAK2 levels. The intercellular CD44-CD44 homophilic interactions directed multicellular aggregation, requiring its N-terminal domain, and initiated CD44-PAK2 interactions for further activation of FAK signaling. Our studies highlight that CD44+ CTC clusters, whose presence is correlated with a poor prognosis of breast cancer patients, can serve as novel therapeutic targets of polyclonal metastasis.