Petti Eleonora, Di Vito Serena, Dinami Roberto, Porru Manuela, Marchesi Stefano, Lohuis Jeroen, Zizza Pasquale, Iachettini Sara, Salvati Erica, D'Angelo Carmen, Rizzo Angela, Maresca Carmen, Ascione Flora, Di Benedetto Anna, Buglioni Simonetta, Sacconi Andrea, Ostano Paola, Li Qingsen, Stoppacciaro Antonella, Leonetti Carlo, van Rheenen Jacco, Maiuri Paolo, Scita Giorgio, Biroccio Annamaria
Translational Oncology Research Unit, IRCCS-Regina Elena National Cancer Institute, Rome, Italy.
Department of Ecological and Biological Sciences (DEB), University of Tuscia, Viterbo, Italy.
Cell Death Dis. 2025 Mar 30;16(1):224. doi: 10.1038/s41419-025-07415-4.
The Telomere Repeat-Binding factor 2 (TRF2) contributes to cancer progression by both telomere-dependent and independent mechanisms, including immune escape and angiogenesis. Here, we found that TRF2, through its Basic domain, directly interacts with Emerin forming a complex, including Lamin A/C, Lamin B1, SUN1, and SUN2. Importantly, TRF2 association with the inner nuclear membrane is functional to the proper establishment of cell polarity, finally promoting productive 1D and 3D migration in triple negative breast cancer cells (TNBC). In line with this, a spontaneous model of TNBC metastasis, combined with intravital imaging, allowed us to demonstrate that TRF2 promotes cell migration at the primary tumor site and is required for the early steps of the metastatic cascade. In human breast cancers, aberrantly elevated TRF2 expression positively correlates with cancer progression, metastasis, and poor prognosis, identifying TRF2 as a potential target for novel therapeutic strategies against TNBC.
端粒重复结合因子2（TRF2）通过端粒依赖性和非依赖性机制促进癌症进展，包括免疫逃逸和血管生成。在此，我们发现TRF2通过其碱性结构域直接与Emerin相互作用形成复合物，该复合物包括核纤层蛋白A/C、核纤层蛋白B1、SUN1和SUN2。重要的是，TRF2与内核膜的结合对于细胞极性的正确建立具有功能性作用，最终促进三阴性乳腺癌细胞（TNBC）的有效一维和三维迁移。与此一致，TNBC转移的自发模型与活体成像相结合，使我们能够证明TRF2促进原发性肿瘤部位的细胞迁移，并且是转移级联早期步骤所必需的。在人类乳腺癌中，异常升高的TRF2表达与癌症进展、转移和不良预后呈正相关，确定TRF2为针对TNBC的新型治疗策略的潜在靶点。
