Model Of Spontaneous Brain Metastasis In Small Cell Lung Cancer With Epithelial-To-Neuronal...

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. Citation Format: Shreoshi Pal Choudhuri, Thomas Salisbury, Mantre Dehnad, Bratati Mukherjee, Braeden Freitas, Kyle May, Seth Hamilton, Shruti Raghavan, Victor Stastny, Kimberley Avila, Jui Wan Loh, Urooba Nadeem, Luc Girard, Jeon Lee, Michael S. Lawrence, Genevieve Konopka, James Kim, Benjamin J. Drapkin. A model of spontaneous brain metastasis in small cell lung cancer undergoes epithelial-to-neuronal transition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6066.