Evidence map›Paper›PMID 40601773›Full record

ArticleScience translational medicine2025

A genome-wide in vivo CRISPR activation screen identifies BACE1 as a therapeutic vulnerability of lung cancer brain metastasis.

Shawn C Chafe, Kui Zhai, Nikoo Aghaei, Petar Miletic, Zhi Huang, Kevin R Brown, Daniel Mobilio, Daniel Young, Yujin Suk, Shan Grewal and 30 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Science translational medicine, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.

0numbers the graph read from it
0cells of the map it votes in
2citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

2 citing papers in PubMed.

  1. Targeting the non-coding RNA-PANoptosis axis: a novel frontier in disease diagnosis and therapy.Apoptosis : an international journal on programmed cell death · 2026
    Review
  2. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

40 authors.

Shawn C ChafeDepartment of Surgery, McMaster University, Hamilton, ON L8S 4L8, Canada.ORCID 0000-0001-8802-651X
Kui ZhaiDepartment of Surgery, McMaster University, Hamilton, ON L8S 4L8, Canada.ORCID 0000-0003-4725-190X
Nikoo AghaeiDepartment of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4L8, Canada.
Petar MileticDepartment of Surgery, McMaster University, Hamilton, ON L8S 4L8, Canada.
Zhi HuangDepartment of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
Kevin R BrownHospital for Sick Children, Toronto, ON M5G 1E8, Canada.ORCID 0000-0002-5514-2538
Daniel MobilioDepartment of Surgery, McMaster University, Hamilton, ON L8S 4L8, Canada.ORCID 0000-0003-4469-6815
Daniel YoungDepartment of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
Yujin SukDepartment of Surgery, McMaster University, Hamilton, ON L8S 4L8, Canada.
Shan GrewalDepartment of Surgery, McMaster University, Hamilton, ON L8S 4L8, Canada.
Dillon McKennaDepartment of Surgery, McMaster University, Hamilton, ON L8S 4L8, Canada.
Zahra AlizadaDepartment of Surgery, McMaster University, Hamilton, ON L8S 4L8, Canada.ORCID 0009-0009-5196-8146
Agata M KieliszekDepartment of Surgery, McMaster University, Hamilton, ON L8S 4L8, Canada.ORCID 0000-0002-5176-4890
Fred C LamDepartment of Neurosurgery, Stanford School of Medicine, Palo Alto, CA 94305, USA.ORCID 0000-0002-9801-5037
Laura EscuderoDepartment of Surgery, McMaster University, Hamilton, ON L8S 4L8, Canada.ORCID 0000-0001-7385-673X
Qian HuangDepartment of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
Ariana HuebnerCancer Evolution and Genome Instability Laboratory, Francis Crick Institute, London NW1 1AT, UK.ORCID 0000-0001-8009-4999
Jack LuDepartment of Surgery, McMaster University, Hamilton, ON L8S 4L8, Canada.
Patrick AngCentre for Discovery in Cancer Research, McMaster University, Hamilton, ON L8S 4L8, Canada.ORCID 0009-0009-1618-9905
Alisha AnandCentre for Discovery in Cancer Research, McMaster University, Hamilton, ON L8S 4L8, Canada.
Stefan CustersDepartment of Surgery, McMaster University, Hamilton, ON L8S 4L8, Canada.
Erika ApelCentre for Discovery in Cancer Research, McMaster University, Hamilton, ON L8S 4L8, Canada.
Sarah SlassiCentre for Discovery in Cancer Research, McMaster University, Hamilton, ON L8S 4L8, Canada.
Benjamin BrakelCentre for Discovery in Cancer Research, McMaster University, Hamilton, ON L8S 4L8, Canada.
Jongmyung KimDepartment of Radiation Oncology, Moffitt Cancer Center, Tampa, FL 33612, USA.ORCID 0000-0002-9625-6128
James K C LiuDepartment of Neuro-oncology, Moffitt Cancer Center, Tampa, FL 33612, USA.ORCID 0000-0002-1907-7150
Blessing Iquo Bassey-ArchibongDepartment of Biological Sciences, Concordia University of Edmonton, Edmonton, AB T5B 4E3, Canada.ORCID 0000-0002-3041-6491
Rober AbdoDepartment of Biochemistry, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 5C1, Canada.ORCID 0009-0005-7915-5025
Yaron ShargallDepartment of Surgery, McMaster University, Hamilton, ON L8S 4L8, Canada.
Jian-Qiang LuDepartment of Pathology and Laboratory Medicine, McMaster University, Hamilton, ON L8S 4L8, Canada.ORCID 0000-0003-1945-5569
Jean-Claude CutzDepartment of Pathology and Laboratory Medicine, McMaster University, Hamilton, ON L8S 4L8, Canada.ORCID 0000-0001-7895-3467
Qi ZhangDepartment of Pathology and Molecular Medicine, Western University, London, ON N6A 5C1, Canada.ORCID 0000-0003-4928-2742
Shawn Shun-Cheng LiDepartment of Biochemistry, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 5C1, Canada.ORCID 0000-0003-3610-9035
Chitra VenugopalDepartment of Surgery, McMaster University, Hamilton, ON L8S 4L8, Canada.
Robert E HyndsEpithelial Cell Biology in ENT Research Group, Developmental Biology and Cancer Department, UCL Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK.ORCID 0000-0002-2170-8791
Antoine DufourDepartment of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada.ORCID 0000-0002-3429-4188
Jason MoffatHospital for Sick Children, Toronto, ON M5G 1E8, Canada.ORCID 0000-0002-5663-8586
Charles SwantonCancer Evolution and Genome Instability Laboratory, Francis Crick Institute, London NW1 1AT, UK.ORCID 0000-0002-4299-3018
Shideng BaoDepartment of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.ORCID 0000-0002-4236-2662
Sheila K SinghDepartment of Surgery, McMaster University, Hamilton, ON L8S 4L8, Canada.ORCID 0000-0003-1272-5300

Funding

PerkinElmer IVIS Spectrum CTS10OD018205 · OD · CLEVELAND CLINIC LERNER COM-CWRU · PI DRAZBA, JUDY · 2015 to 2015
$600k
Transmission Electron MicroscopeS10RR031536 · NCRR · CLEVELAND CLINIC LERNER COM-CWRU · PI DRAZBA, JUDY · 2011 to 2011
$518k
Cancer Research UK CC2041NCRR NIH HHS S10 RR031536NIH HHS S10 OD018205Wellcome Trust CC2041
6 · The paper itself

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 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.

Indexed as

Amyloid Precursor Protein SecretasesAspartic Acid EndopeptidasesBrain NeoplasmsCarcinoma, Non-Small-Cell LungClustered Regularly Interspaced Short Palindromic RepeatsCRISPR-Cas SystemsLung NeoplasmsAnimalsCell Line, TumorErbB ReceptorsGene Expression Regulation, NeoplasticHumansMiceXenograft Model Antitumor AssaysAmyloid Precursor Protein SecretasesAspartic Acid EndopeptidasesBACE1 protein, humanErbB Receptors

Identifiers

PMID40601773
PMCPMC7617989

What OpenQuestion holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.