PRCA-06 GENOME-WIDE IN VIVO CRISPR ACTIVATION SCREEN IDENTIFIES BACE1 AS A THERAPEUTIC VULNERABILITY OF LUNG CANCER BRAIN METASTASIS
Abstract 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 (CRISPRa) screen to identify molecular drivers of brain metastasis from an orthotopic NSCLC patient-derived xenograft model. We discovered activating expression of the Alzheimer’s disease associated β-site amyloid precursor protein cleaving enzyme 1 (BACE1) led to a significant increase in brain metastasis. Furthermore, genetic and pharmacological inhibition of BACE1 blocked NSCLC brain metastasis. Mechanistically, we identified BACE1 acts through its novel substrate EGFR to drive this metastatic phenotype. Together, our data highlights the power of in vivo CRISPR screening to unveil novel molecular drivers and potential therapeutic targets of NSCLC brain metastasis.
Authors
- Chitra Venugopal (ORCID: https://orcid.org/0009-0000-2968-2971)
- Blessing Bassey‐Archibong (ORCID: https://orcid.org/0000-0002-3041-6491)
- Sheila Kumari Singh (ORCID: https://orcid.org/0000-0003-1272-5300)
- Jian‐Qiang Lu (ORCID: https://orcid.org/0000-0003-1945-5569)
- Agata Kieliszek (ORCID: https://orcid.org/0000-0002-5176-4890)
- Charles Swanton (ORCID: https://orcid.org/0000-0002-4299-3018)
- Shawn C. Chafe (ORCID: https://orcid.org/0000-0001-8802-651X)
- Qian Huang (ORCID: https://orcid.org/0000-0002-5447-2770)
- Shawn S.‐C. Li (ORCID: https://orcid.org/0000-0003-3610-9035)
- Shideng Bao (ORCID: https://orcid.org/0000-0002-4236-2662)
- Fred C. Lam
- Laura Escudero (ORCID: https://orcid.org/0000-0001-7385-673X)
- Jean‐Claude Cutz (ORCID: https://orcid.org/0000-0001-7895-3467)
- Shan Grewal
- Robert E. Hynds (ORCID: https://orcid.org/0000-0002-2170-8791)
- Benjamin A. Brakel (ORCID: https://orcid.org/0000-0003-1388-3490)
- Alisha Anand
- Dillon McKenna (ORCID: https://orcid.org/0009-0000-6803-9786)
- Kui Zhai (ORCID: https://orcid.org/0000-0003-4725-190X)
- Yaron Shargall (ORCID: https://orcid.org/0000-0001-8585-0327)
- Stefan Custers (ORCID: https://orcid.org/0009-0007-3297-8918)
- Daniel Young (ORCID: https://orcid.org/0000-0003-2542-0135)
- James K. Liu (ORCID: https://orcid.org/0000-0002-1907-7150)
- Daniel Mobilio (ORCID: https://orcid.org/0000-0003-4469-6815)
- Petar Miletic
- Ariana Huebner
- Nikoo Aghaei (ORCID: https://orcid.org/0000-0003-3394-668X)
- Qi Zhang (ORCID: https://orcid.org/0000-0003-4928-2742)
- Rober Abdo (ORCID: https://orcid.org/0009-0005-7915-5025)
- Jongmyung Kim (ORCID: https://orcid.org/0000-0002-9625-6128)
- Kevin R. Brown (ORCID: https://orcid.org/0000-0002-5514-2538)
- Jason Moffat (ORCID: https://orcid.org/0000-0002-5663-8586)
- Antoine Dufour (ORCID: https://orcid.org/0000-0002-3429-4188)
- Yujin Suk (ORCID: https://orcid.org/0000-0002-3966-3771)
- Zahra Alizada (ORCID: https://orcid.org/0009-0009-5196-8146)
- Zhi Huang
- P T Ang (ORCID: https://orcid.org/0009-0009-1618-9905)
- Junhong Lü
- Erika Apel
- Sarah Slassi
Institutions
- Western University (CA)
- Concordia University of Edmonton (CA)
- Cleveland Clinic (US)
- University of Calgary (CA)
- Hospital for Sick Children (CA)
- Moffitt Cancer Center (US)
- Stanford Medicine (US)
- University College London (GB)
- McMaster University (CA)
Publication Details
- Journal
- Neuro-Oncology Advances
- Published
- 2025-08-01
- DOI
- https://doi.org/10.1093/noajnl/vdaf123.085
- Primary Topic
- Bioinformatics and Genomic Networks
- Type
- article
- Field-Weighted Citation Impact
- 0.00