ELK3-CYFIP2 axis-mediated actin remodeling modulates metastasis and natural killer cell responses in triple-negative...

Triple-negative breast cancer (TNBC) is an aggressive, highly metastatic disease with a poor prognosis. E26 transformation-specific transcription factor (ELK3) is highly expressed in TNBCs, and functions as a regulator of epithelial-mesenchymal transition and immune responses. Because metastatic migration and immune evasion by TNBC cells are critical factors for successful metastasis, unravelling the underlying mechanisms and developing effective immunotherapeutic strategies is urgent. Here, TNBC cell lines MDA-MB-231 and Hs578T were examined to determine the relationship between ELK3 expression and filopodia protrusion on the cell membrane, as well as actin accumulation at contact sites with natural killer (NK) cells. RNA-sequencing analysis and molecular experiments were conducted to identify and validate downstream target genes of ELK3 associated with migration and attachment of TNBC cells. The immune response of TNBC to NK cells was evaluated through imaging and flow cytometry analyses. Clinical significance was assessed through Kaplan-Meier analysis of survival outcomes of TNBC patients. Gene expression profiling and molecular analysis revealed that oncogenic ELK3 directly suppresses expression of cytoplasmic FMR1 interacting protein2 (CYFIP2), a repressor of actin accumulation. Further molecular and pharmacological analyses confirmed that the ELK3-CYFIP2 axis serves a dual role in TNBC cell lines by (1) controlling filopodia-mediated migration and adhesion by regulating actin accumulation, and (2) regulating sensitivity to NK cells by modulating actin accumulation at contact sites. Kaplan-Meier analysis suggested that ELK3-CYFIP2 axis is associated with survival of TNBC patients, and that ELK3 suppresses transcription of CYFIP2. Thus, the ELK3-CYFIP2 axis plays a pivotal role in regulating actin, emphasizing its significance in controlling both cancer cell migration and NK cell responses in TNBC.