Abstract 6540: Lung adenocarcinoma cancer cells that metastasize to the brain bring their own soil

Abstract Lung adenocarcinoma (LUAD) is the most common histologic subtype of non-small cell lung cancer (NSCLC). Unlike other prevalent NSCLC subtypes, LUAD is characterized by an early dissemination, most frequently to the brain, particularly in patients harboring EGFR mutations. Although the mechanisms underlying LUAD metastasis to the brain are poorly understood, tumor-associated fibroblasts (TAFs) are increasingly recognized as major drivers of tumor progression and have also been hypothesized to contribute to tumor dissemination and metastasis. However, current experimental evidence of TAFs in brain metastasis is very limited. To address this gap of knowledge, we aimed to analyze retrospectively common markers of immunosuppressive TAFs phenotypes in LUAD in patient biopsies from primary tumors and paired brain metastases (n=17). These markers included α-SMA, FAP and MYH11, and were analyzed by immunofluorescence. We confirmed the presence of TAFs that were positive for these markers in primary tumors, although α-SMA+ TAFs were dominant, in line with previous observations. Notably, our preliminary analysis in brain metastases revealed numerous cells exhibiting an elongated nuclear morphology comparable to that found in fibroblasts in LUAD primary tumors; moreover, these cells were also positive for either α-SMA, FAP and MYH11 or a mixture of these markers. In further agreement with the primary tumor, α-SMA+ TAFs were dominant, whereas FAP+ TAFs were patient dependent and MYH11+ TAFs accounted for a smaller TAF population. In contrast, these TAF-like cells were negative for standard markers of activated astrocytes and pericytes. Moreover, brain metastasis showed patterns of T-cell exclusion similar to those reported in primary tumors. Because the normal brain is devoid of fibroblasts, these preliminary observations strongly support the presence of bona fide TAFs in brain metastasis. Moreover, the striking similarities between major immunosuppressive TAFs populations in the primary tumors and brain metastases support that disseminated cancer cells from LUAD patients bring their own soil during brain metastasis. Future analysis should validate these observations to ultimately define major immunosuppressive TAFs populations in brain metastasis, which could be used to design more specific therapeutic approaches against these populations. Citation Format: Alejandro Bernardo Suárez, Gabriela Caballero, Iban Aldecoa Ansorregui, Natalia Isabel Diaz-Valdivia, Patricia Fernandez-Nogueira, Noemi Reguart, Jordi Alcaraz Casademunt. Lung adenocarcinoma cancer cells that metastasize to the brain bring their own soil [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6540.