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 amoeboid cells display the cancer stem cell markers CD133, ALDH1 and the pluripotent marker Nanog; are accompanied by higher invasive potential in vitro and in vivo; and 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致癌基因通过新型SRC / Rho轴引发类癌侵袭，癌干和侵袭性电动汽车

细胞可塑性是导致癌症转移的关键标志。Rho / ROCK通路的上调驱动肌动球蛋白的收缩力，突出力，并促进肿瘤中高度侵袭性的变形虫细胞的发生。癌症干细胞也与转移有关，但是这些群体如何在肿瘤中产生尚不完全清楚。在这里，我们显示了新型致癌基因RASSF1C可以驱动乳腺癌细胞中的间充质向类癌过渡以及干细胞的属性。从机理上讲，RASSF1C通过SRC介导的RhoGDI抑制作用激活Rho / ROCK，从而导致产生肌动球蛋白收缩性。此外，我们证明了变形虫细胞显示出癌症干细胞标记CD133，ALDH1和多能性标记Nanog。伴随着更高的体外和体内侵袭潜力；并利用细胞外囊泡将侵袭性表型转移至靶细胞和组织。重要的是，潜在的RASSF1C驱动的生物学过程同意解释临床数据：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记。