Abstract
BACKGROUNDBrain metastasis (BrM) patients treated with surgery and radiotherapy frequently experience local recurrence (LR), leptomeningeal metastasis (LM), and poor overall survival (OS). We sought to correlate the presence of invasive or circumscribed histopathological growth pattern, observed in the BrM lesion and surrounding brain, with these outcomes, and to study molecular mediators of parenchymal invasion.METHODSWe assessed the HGP of H&E-stained slides from 164 surgically resected BrM from 147 patients. HGP was correlated with incidence of LR, LM and OS. Single-cell RNA sequencing (scRNAseq) was performed on three invasive HGP patients, sampling the metastasis center (MC) and surrounding brain (SB) outside of the contrast-enhancing region. Orthotopic patient-derived xenograft models (OPDX) were established from N=30 brain metastasis via intracranial propagation.RESULTS56/164 BrM specimens (34%) showed a circumscribed growth pattern between the tumor and adjacent brain (cHGP) while 108/164 (66%) showed significant invasion of tumor lobules or single cells into the brain parenchyma (iHGP). iHGP was associated with LR, LM and shortened OS in BrM patients. OPDX models of BrM retain features of patient BrM, including HGP. scRNAseq identified abundant cancer cells in SB that overexpressed a number of genes involved in cell survival, invasion and metastasis compared to matched cancer cells in MC. Validation of these targets with immunohistochemistry in patient and OPDX tissues revealed cold-inducible RNA binding protein (CIRBP) overexpression in iHGP patient and OPDX BrM. Modulation of CIRBP expression in OPDX and cell line models of iHGP BrM delayed BrM progression and extended OS.CONCLUSIONiHGP is a poor prognostic indicator in patients with surgically resected BrM, establishing HGP as an important prognostic factor that should be considered by clinicians treating BrM patients. We identify CIRBP as a functional mediator of this process.
Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
