A model of spontaneous brain metastasis in small cell lung cancer undergoes epithelial-to-neuronal transition

Brain metastases (BrMs) occur in 40-60% of small cell lung cancer (SCLC) patients, causing significant morbidity and mortality. Although most patients present with extracranial metastases (EMs) at diagnosis, approximately two-thirds of BrMs arise after diagnosis and could be prevented by effective and tolerable therapies. However, SCLC models rarely form BrMs in mice, hindering translational research. We report patient-derived xenograft (PDX) models of SCLC that form recurrent, spontaneous, and symptomatic BrMs. By refining a surgical approach to generate solitary orthotopic primary (OP) tumors within the margins of the left lung parenchyma, six PDX models developed diffuse EMs within 8 weeks of OP detection by MRI. In a model harboring therapy-induced subclonal mutations, we confirmed that these EMs arose spontaneously from the left lung OP tumors, and further validated this finding with a lentiviral DNA barcode library. Model MGH1564-1A, derived from a relapsed SCLC patient shortly after the emergence of small BrMs, produced delayed ataxia and hydrocephalus in 70% of mice (median onset ~100 days). Whole brain sectioning of these mice consistently revealed BrMs up to 2 mm in diameter, whereas in mice without neurologic symptoms, BrMs were not detected. Intriguingly, when compare with the OP tumors, these spontaneous BrMs demonstrated an epithelial-to-neuronal transition (ENT) in global transcription that was confirmed by immunohistochemistry. This transition was absent from EMs within the same animals, suggesting that ENT is a BrM-specific adaptation. Two additional PDX models demonstrated recurrent BrMs, suggesting brain tropism as a property of some PDX models but not others. To our knowledge, these are the first models of human SCLC to reliably develop spontaneous BrMs that limit animal survival, providing a preclinical system for investigating the drivers of brain organotropism in SCLC and for evaluating anti-BrM therapies.