RASSF1C oncogene elicits amoeboid invasion, cancer stemness, and extracellular vesicle release via a SRC/Rho axis

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.

FOXD1-dependent RalA-ANXA2-Src complex promotes CTC formation in breast cancer

“…Src is highly overexpressed and activated in different epithelial cancers, especially breast cancer. It is well-documented to promote cancer cell plasticity, motility and invasion, and has been described as a key player in EMT [ 47 , 48 ]. Tyr23 Phosphorylation of ANXA2 by Src tyrosine kinase promotes proliferation, migration, and invasion of tumor cells [ 27 ].…”

Biological effects and regulation of IGFBP5 in breast cancer

“…One intracellular target of IGFBP5 is the Ras-Association Domain Family 1 C Protein (RASSF1C) ( 87 ). RASSF1C is a proto-oncogenic protein ( 88 ) that participates in driving invasion, metastasis and stem cell activity in BC ( 89 ). By physically interacting with RASSF1C, IGFBP5 may regulate ERK1/2 activity ( 87 ).…”

SRC kinase-mediated signaling pathways and targeted therapies in breast cancer

“…In addition, activated SRC/FAK module can further activate multiple other FA components to initiate a cascade of signal transduction events that regulate BC tumorigenesis and metastasis [ 66 – 68 ]. These FA components that have been reported in BC include Paxillin [ 69 , 70 ], Tensin-3 [ 71 ], TKS5 [ 72 ], CAV-1 [ 73 , 74 ], LPP [ 75 ], p130Cas [ 76 ] and p190RhoGAP [ 77 – 79 ] (Fig. 4 and Table 1 ).…”