A genome-wide in vivo CRISPR activation screen identifies BACE1 as a therapeutic vulnerability of lung cancer brain metastasis
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 a NSCLC patient-derived xenograft model.  We discovered activation of the Alzheimer's disease associated ?-site amyloid precursor protein cleaving enzyme 1 (BACE1) led to a significant increase in brain metastasis.   Furthermore, BACE1 knockout or inhibition with MK-8931 treatment blocked NSCLC brain metastasis.  Mechanistically, we identified BACE1 cleaves an N-terminal fragment of EGFR to activate downstream signalling through MEK and ERK and 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. Overall design: Samples include 13 NSG mouse lungs and 12 NSG mouse brains and a T0 cell pellet