Chafe Shawn C, Zhai Kui, Aghaei Nikoo, Miletic Petar, Huang Zhi, Brown Kevin R, Mobilio Daniel, Young Daniel, Suk Yujin, Grewal Shan, McKenna Dillon, Alizada Zahra, Kieliszek Agata M, Lam Fred C, Escudero Laura, Huang Qian, Huebner Ariana, Lu Jack, Ang Patrick, Anand Alisha, Custers Stefan, Apel Erika, Slassi Sarah, Brakel Benjamin, Kim Jongmyung, Liu James K C, Bassey-Archibong Blessing Iquo, Abdo Rober, Shargall Yaron, Lu Jian-Qiang, Cutz Jean-Claude, Zhang Qi, Li Shawn Shun-Cheng, Venugopal Chitra, Hynds Robert E, Dufour Antoine, Moffat Jason, Swanton Charles, Bao Shideng, Singh Sheila K
Department of Surgery, McMaster University, Hamilton, ON L8S 4L8, Canada.
Centre for Discovery in Cancer Research, McMaster University, Hamilton, ON L8S 4L8, Canada.
Sci Transl Med. 2025 Jul 2;17(805):eadu2459. doi: 10.1126/scitranslmed.adu2459.
Brain metastasis occurs in up to 40% of patients with non-small cell lung cancer (NSCLC). Considerable genomic heterogeneity exists between the primary lung tumor and respective brain metastasis; however, the identity of the genes capable of driving brain metastasis is incompletely understood. Here, we carried out an in vivo genome-wide CRISPR activation screen to identify molecular drivers of brain metastasis from an orthotopic xenograft model derived from a patient with NSCLC. We found that activating expression of the Alzheimer's disease-associated beta-secretase 1 (BACE1) led to a substantial increase in brain metastases. Furthermore, genetic and pharmacological inhibition of BACE1 blocked NSCLC brain metastasis. Mechanistically, we identified that BACE1 acts through epidermal growth factor receptor to drive this metastatic phenotype. Together, our data highlight the power of in vivo CRISPR activation screening to unveil molecular drivers and potential therapeutic targets of NSCLC brain metastasis.
脑转移发生在高达40%的非小细胞肺癌（NSCLC）患者中。原发性肺肿瘤与相应的脑转移瘤之间存在相当大的基因组异质性；然而，能够驱动脑转移的基因的特性尚未完全明确。在此，我们进行了一项体内全基因组CRISPR激活筛选，以从一名NSCLC患者的原位异种移植模型中鉴定脑转移的分子驱动因素。我们发现，激活与阿尔茨海默病相关的β-分泌酶1（BACE1）的表达会导致脑转移显著增加。此外，对BACE1的基因和药理学抑制可阻断NSCLC脑转移。从机制上讲，我们确定BACE1通过表皮生长因子受体发挥作用，以驱动这种转移表型。总之，我们的数据突出了体内CRISPR激活筛选在揭示NSCLC脑转移的分子驱动因素和潜在治疗靶点方面的作用。
