p53失活通过SCD1上调和脂肪酸代谢增加驱动乳腺癌向脑部转移，这一成果由特拉维夫大学Uri Ben-David研究组经过不懈努力而取得。2025年12月29日出版的《自然—遗传学》发表了这项成果。

研究人员发现p53失活是BCBM的驱动因素，揭示了p53依赖和星形胶质细胞依赖的FAS调节，并强调FAS是治疗上可靶向的BCBM脆弱性。

研究人员表示，脑转移预后不佳，但脑向性的分子基础尚不清楚。对乳腺癌BM （BCBM）的分析显示，p53通过突变和/或非整倍体普遍失活，而在原发肿瘤中已经存在通路破坏。功能上，p53失活显著增加BCBM在体内的形成和生长，将p53的扰动与BM联系起来。机制上，p53失活上调SCD1和脂肪酸合成（FAS），这是脑转移细胞所必需的；SCD1敲除消除了p53依赖性生长优势。在分子上，p53通过启动子结合直接抑制SCD1，并通过下调其共激活子DEPDC1间接抑制SCD1。星形胶质细胞通过分泌以p53依赖方式代谢的因子进一步增强FAS，促进肿瘤存活、增殖和迁移。最后，p53缺陷肿瘤在体内和体外均对FAS抑制敏感。

附：英文原文

Title: p53 inactivation drives breast cancer metastasis to the brain through SCD1 upregulation and increased fatty acid metabolism

Author: Laue, Kathrin, Pozzi, Sabina, Zerbib, Johanna, Bertolio, Rebecca, Eliezer, Yonatan, Cohen-Sharir, Yael, Winkler, Tom, Caputo, Manuel, Ricci, Alessia A., Adler, Lital, Khoury, Rami, Longobardi, Giuseppe, Slutsky, Rachel, Leikin-Frenkel, Alicia I., Ovadia, Shai, Lange, Katharina, Rustighi, Alessandra, Piazza, Silvano, Sacconi, Andrea, Magesh, Rayna Y., Keller, Faith N., Berthelet, Jean, Schffer, Alexander, Saad, Ron, Israeli Dangoor, Sahar, Szczepanowska, Karolina, Barshack, Iris, Liao, Yang, Malitsky, Sergey, Brandis, Alexander, Broggini, Thomas, Czabanka, Marcus, Shi, Wei, Merino, Delphine, Watson, Emma V., Blandino, Giovanni, Erez, Ayelet, Ashery-Padan, Ruth, Medyouf, Hind, Bertero, Luca, Del Sal, Giannino, Satchi-Fainaro, Ronit, Ben-David, Uri

Issue&Volume: 2025-12-29

Abstract: Brain metastasis (BM) carries a poor prognosis, yet the molecular basis of brain tropism remains unclear. Analysis of breast cancer BM (BCBM) revealed pervasive p53 inactivation through mutations and/or aneuploidy, with pathway disruption already present in primary tumors. Functionally, p53 inactivation markedly increased BCBM formation and growth in vivo, causally linking p53 perturbation to BM. Mechanistically, p53 inactivation upregulated SCD1 and fatty acid synthesis (FAS), essential for brain-metastasizing cells; SCD1 knockout abolished the p53-dependent growth advantage. Molecularly, p53 suppressed SCD1 directly through promoter binding and indirectly by downregulating its co-activator DEPDC1. Astrocytes further enhanced FAS by secreting factors that were metabolized in a p53-dependent manner, promoting tumor survival, proliferation and migration. Finally, p53-deficient tumors were sensitive to FAS inhibition ex vivo and in vivo. Thus, we identify p53 inactivation as a driver of BCBM, reveal p53-dependent and astrocyte-dependent FAS modulation and highlight FAS as a therapeutically targetable BCBM vulnerability.

DOI: 10.1038/s41588-025-02446-1

Source: https://www.nature.com/articles/s41588-025-02446-1