Cell plasticity is a crucial hallmark leading to cancer metastasis. Upregulation of Rho/ROCK pathway drives actomyosin contractility, protrusive forces, and contributes to the occurrence of highly invasive amoeboid cells in tumors. Cancer stem cells are similarly associated with metastasis, but how these populations arise in tumors is not fully understood. Here, we show that the novel oncogene RASSF1C drives mesenchymal-to-amoeboid transition and stem cell attributes in breast cancer cells. Mechanistically, RASSF1C activates Rho/ROCK via SRC-mediated RhoGDI inhibition, resulting in generation of actomyosin contractility. Moreover, we demonstrate that RASSF1C-induced amoeboid cells display increased expression of cancer stem-like markers such as CD133, ALDH1, and Nanog, and are accompanied by higher invasive potential in vitro and in vivo. Further, RASSF1C-induced amoeboid cells employ extracellular vesicles to transfer the invasive phenotype to target cells and tissue. Importantly, the underlying RASSF1C-driven biological processes concur to explain clinical data: namely, methylation of the RASSF1C promoter correlates with better survival in early-stage breast cancer patients. Therefore, we propose the use of RASSF1 gene promoter methylation status as a biomarker for patient stratification.

中文翻译：

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RASSF1C 癌基因通过 SRC/Rho 轴引发阿米巴入侵、癌症干性和细胞外囊泡释放


细胞可塑性是导致癌症转移的重要标志。 Rho/ROCK 通路的上调可驱动肌动球蛋白收缩性、突出力，并有助于肿瘤中高度侵袭性变形细胞的出现。癌症干细胞同样与转移相关，但这些细胞群如何在肿瘤中产生尚不完全清楚。在这里，我们展示了新的癌基因 RASSF1C 驱动乳腺癌细胞中的间充质到变形虫的转变和干细胞属性。从机制上讲，RASSF1C 通过 SRC 介导的 RhoGDI 抑制激活 Rho/ROCK，从而产生肌动球蛋白收缩性。此外，我们证明RASSF1C诱导的变形细胞表现出癌症干细胞样标记物（例如CD133、ALDH1和Nanog）表达增加，并且伴随着更高的体外和体内侵袭潜力。此外，RASSF1C 诱导的变形细胞利用细胞外囊泡将侵袭表型转移到靶细胞和组织。重要的是，RASSF1C 驱动的生物过程与临床数据相一致：即 RASSF1C 启动子的甲基化与早期乳腺癌患者的更好生存相关。因此，我们建议使用RASSF1基因启动子甲基化状态作为患者分层的生物标志物。