Abstract
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.
Highlights
Cell invasion and migration are essential processes during cancer progression and metastatic dissemination
We demonstrate that molecular events driven by mesenchymal-amoeboid transition (MAT) are associated with cancer stemness and that amoeboid cells express the cancer stem cell markers ALDH1, CD133, and the pluripotency marker Nanog
RASSF1C expression is maintained in tumors and emerging studies indicate a pro-oncogenic role for this isoform of the RASSF1 gene (Estrabaud et al, 2007)
Summary
Cell invasion and migration are essential processes during cancer progression and metastatic dissemination. It has been reported that enhanced Rho/ROCK signaling directly promotes phosphorylation of myosin light chain 2 (pMLCII) in vitro (Kimura et al, 1996), which in turn induces reduction of stress fibers and formation of cortical actomyosin (Kimura et al, 1996; Alvarez-Gonzalez et al, 2015). These major changes in actin architecture enable cancer cells to remodel components of the extracellular matrix and to squeeze into the surrounding tissue.
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