Emerging evidence supports the hypothesis that multicellular tumor clusters invade and seed metastasis. However, whether tumor-associated stroma induces epithelial-mesenchymal plasticity in tumor cell clusters, to promote invasion and metastasis, remains unknown. We demonstrate herein that carcinoma-associated fibroblasts (CAFs) frequently present in tumor stroma drive the formation of tumor cell clusters composed of two distinct cancer cell populations, one in a highly epithelial (E-cadherin^hiZEB1^lo/neg: E^hi) state and another in a hybrid epithelial/mesenchymal (E-cadherin^loZEB1^hi: E/M) state. The E^hi cells highly express oncogenic cell-cell adhesion molecules, such as carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) and CEACAM6 that associate with E-cadherin, resulting in increased tumor cell cluster formation and metastatic seeding. The E/M cells also retain associations with E^hi cells, which follow the E/M cells leading to collective invasion. CAF-produced stromal cell-derived factor 1 and transforming growth factor-β confer the E^hi and E/M states as well as invasive and metastatic traits via Src activation in apposed human breast tumor cells. Taken together, these findings indicate that invasive and metastatic tumor cell clusters are induced by CAFs via epithelial-mesenchymal plasticity.

中文翻译：

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基质成纤维细胞通过上皮间质可塑性诱导转移性肿瘤细胞簇。


新出现的证据支持多细胞肿瘤簇侵袭和种子转移的假设。然而，肿瘤相关基质是否会诱导肿瘤细胞簇的上皮-间质可塑性，从而促进侵袭和转移，仍不清楚。我们在此证明，肿瘤基质中经常存在的癌相关成纤维细胞（CAF）驱动由两种不同癌细胞群组成的肿瘤细胞簇的形成，其中一种处于高度上皮（E-钙粘蛋白^hi ZEB1 ^lo/neg ：E ^hi ）状态另一个处于混合上皮/间质（E-钙粘蛋白^lo ZEB1 ^hi ：E/M）状态。 E ^hi细胞高度表达致癌细胞间粘附分子，例如与 E-钙粘蛋白相关的癌胚抗原相关细胞粘附分子 5 (CEACAM5) 和 CEACAM6，导致肿瘤细胞簇形成和转移性种植增加。 E/M 细胞还保留与 E ^hi细胞的关联，E hi 细胞跟随 E/M 细胞导致集体入侵。 CAF 产生的基质细胞衍生因子 1 和转化生长因子-β 通过 Src 激活赋予人类乳腺肿瘤细胞 E ^hi和 E/M 状态以及侵袭性和转移性状。总而言之，这些发现表明侵袭性和转移性肿瘤细胞簇是由 CAF 通过上皮间质可塑性诱导的。