Dataset Information

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 b-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.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Daniel Young

LAB HEAD: Antoine Dufour

PROVIDER: PXD060790 | Pride | 2025-08-25

REPOSITORIES: Pride

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			Action	DRS
	2024-11-6-Shawn-atoms.zip	Other
	S17334_846_Shawn_ATOMS_1_241009.raw	Raw
	S17335_847_Shawn_ATOMS_2_241009.raw	Raw
	S17336_848_Shawn_ATOMS_3_241009.raw	Raw
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A genome-wide in vivo CRISPR activation screen identifies BACE1 as a therapeutic vulnerability of lung cancer brain metastasis.

Chafe Shawn C SC Zhai Kui K Aghaei Nikoo N Miletic Petar P Huang Zhi Z Brown Kevin R KR Mobilio Daniel D Young Daniel D Suk Yujin Y Grewal Shan S McKenna Dillon D Alizada Zahra Z Kieliszek Agata M AM Lam Fred C FC Escudero Laura L Huang Qian Q Huebner Ariana A Lu Jack J Ang Patrick P Anand Alisha A Custers Stefan S Apel Erika E Slassi Sarah S Brakel Benjamin B Kim Jongmyung J Liu James K C JKC Bassey-Archibong Blessing Iquo BI Abdo Rober R Shargall Yaron Y Lu Jian-Qiang JQ Cutz Jean-Claude JC Zhang Qi Q Li Shawn Shun-Cheng SS Venugopal Chitra C Hynds Robert E RE Dufour Antoine A Moffat Jason J Swanton Charles C Bao Shideng S Singh Sheila K SK

Science translational medicine 20250702 805

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 ac ...[more]

PMID: 40601773

Similar Datasets

Project description:In 2020, lung cancer remains the most diagnosed entity among men and third most among women, causing approximately 1.8 million deaths worldwide with an estimated 31.5% of new cases in men and 14.6% in women, respectively (1). Moreover, metastasized non-small cell lung cancer (NSCLC) continues to be one of the cancer entities with the worst prognosis as well as disease-free and overall survival despite the recent introduction of immunotherapy, with the patients’ 5-year-survival rate ranging still only between 10-20% (1). The development of cancer and metastasis is considered a multi-step process in which many factors are the topic of ongoing investigation. Thus, the identification of novel markers and targets, which are involved in disease progression, is an essential step in improving the survival of lung cancer patients. Previously, we identified HECT and RLD domain containing E3 ubiquitin protein ligase 5 (HERC5) gene as the main target gene on 4q (6). Loss of 4q has been associated with advanced disease stage and worse prognosis in several cancer entities including lung, colorectal, pancreatic, and hepatocellular cancer (2–5). We showed that in NSCLC, HERC5 downregulation via promoter hypermethylation leads to an increase in disseminated tumor cells (DTCs) and occurrence of brain metastases in NSCLC as well as poorer overall survival (OS) (6). In hepatocellular cancer, low mRNA expression levels of HERC5 could similarly be correlated with shorter OS, which led to immune evasion by indirectly increasing infiltration by regulatory T-cells (5). It was thus postulated that HERC5 might serve as a novel metastasis suppressor gene. Originally described in the context of innate immune responses, HERC5 is known to serve as the cellular main E3 ligase of ubiquitin-like modifier interferon-stimulated gene 15 (ISG15) (7,8), thereby catalyzing the transfer of ISG15 onto target proteins – a process called ISGylation. ISGylation is not only an important primary defense mechanism against viruses and other pathogens (9,10), but also associated with various diseases such as immunodeficiencies, neurodegenerative disorders and different types of cancer (11–14). Lately, energy metabolism has been proven to have a strong influence on tumorigenesis and metastasization (15–17). Given the enhanced energy demand of highly proliferating cells, tumor cells can undergo a change in energy consumption mechanisms – such as the well-described Warburg-effect, leading to a switch between ATP production through glycolysis rather than oxidative phosphorylation (OXPHOS) (18). Despite the lower yield in ATP through glycolysis, malignant cells often prefer this pathway even in the presence of oxygen, leading to an increase in metabolic byproducts which are necessary for the elevated demand of metabolites required due to their high proliferation rates (15,16). Deregulation of ISG15 have been linked to dysfunctional mitochondria as well as altered OXPHOS activity (19–22). In this study, we aimed at further elucidating the potential metastasis suppressing role of HERC5 in NSCLC. We therefore assessed the malignant potential of HERC5 loss in in vitro and in vivo NSCLC models and could confirm its capacity to transform NSCLC cells both in vitro and in vivo into a more aggressive phenotype. We furthermore performed mass spectrometry analyses to identify the main pathways altered by differential HERC5 expression in modified NSCLC cell lines and could show that HERC5 has an influence on mitochondrial composition, and energy metabolism pathways such as OXPHOS, leading to better adaptation and survival under prolonged inhibition of oxidative phosphorylation.

Project description:Background: There is a paucity of non-invasive markers for early detection of brain metastasis (BM) in patients with non-small cell lung cancer (NSCLC). Secretory proteomic approach based on quantitative tandem mass tag is believed to offer bright prospects for screening potential serum biomarkers for diseases. Methods: We used the secretory proteomics to identify up-regulated proteins in the highly brain metastatic cell line compared to the parental lung cancer cell line. Enzyme linked immunoassay and immunohistochemistry were performed on non-small cell lung cancer patients with brain metastasis and control samples from each cohort to verify the expression levels of candidate proteins. A logistic regression model was used to develop a biomarker panel composed of Cathepsin F (CTSF) and Fibulin-1 (FBLN1), and then an independent validation data set was used for verification. The diagnostic accuracy was evaluated by receiver operating characteristic (ROC) curve analysis. Changes in serum CTSF levels of patients were tracked to monitor the effect of treatment, and progression-free survival (PFS) and overall survival (OS) were analyzed to assess their prognostic relevance. Results: CTSF and FBLN1 levels were specifically upregulated in sera and tissues of patients with NSCLC BM. Importantly, the combined diagnostic performance of CTSF and FBLN1 was superior to their individual diagnostic performance (sensitivity and specificity). CTSF serum changes were found to reflect the therapeutic response of patients with NSCLC BM and the trends of resistance and progression were detected earlier than the MRI changes. Elevated expression of CTSF in NSCLC BM tissues was associated with poor PFS. Moreover, CTSF tissue expression was found to be an independent prognostic factor. Conclusions: CTSF and FBLN1 are potential novel and specific serum markers for early diagnosis of BM in patients with NSCLC. CTSF can also be used as a biomarker for monitoring therapeutic efficacy and prognostic assessment.