Abstract
The deadly complication of brain metastasis (BM) is largely confined to a relatively narrow cross-section of systemic malignancies, suggesting a fundamental role for biological mechanisms shared across commonly brain metastatic tumor types. To identify and characterize such mechanisms, we performed genomic, transcriptional, and proteomic profiling using whole-exome sequencing, mRNA-seq, and reverse-phase protein array analysis in a cohort of the lung, breast, and renal cell carcinomas consisting of BM and patient-matched primary or extracranial metastatic tissues. While no specific genomic alterations were associated with BM, correlations with impaired cellular immunity, upregulated oxidative phosphorylation (OXPHOS), and canonical oncogenic signaling pathways including phosphoinositide 3-kinase (PI3K) signaling, were apparent across multiple tumor histologies. Multiplexed immunofluorescence analysis confirmed significant T cell depletion in BM, indicative of a fundamentally altered immune microenvironment. Moreover, functional studies using in vitro and in vivo modeling demonstrated heightened oxidative metabolism in BM along with sensitivity to OXPHOS inhibition in murine BM models and brain metastatic derivatives relative to isogenic parentals. These findings demonstrate that pathophysiological rewiring of oncogenic signaling, cellular metabolism, and immune microenvironment broadly characterizes BM. Further clarification of this biology will likely reveal promising targets for therapeutic development against BM arising from a broad variety of systemic cancers.
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Acknowledgements
We thank our patients and their families who provided samples for this research. We thank the Translational Molecular Pathology-Immunoprofiling lab (TMP-IL) at the Department Translational Molecular Pathology, University of Texas MD Anderson Cancer Center for multiplex immunofluorescence staining. This study was supported by NIH/National Cancer Institute Cancer Center Support Grant P30 CA016672 to the University of Texas MD Anderson Cancer Center (Advanced Technology Genomics Core Facility, RPPA Core Facility, Cytogenetics and Cell Authentication Core); MD Anderson Multidisciplinary Research Program; MD Anderson Multi-investigator Research Program; the American Cancer Society-Melanoma Research Alliance Team Award; a Taiho Pharmaceutical grant. J.T.H. is supported by the American Cancer Society and philanthropic contributions to the Melanoma Moon Shots Program of the University of Texas MD Anderson Cancer Center. M.A.D. is supported by the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, the AIM at Melanoma Foundation, Cancer Fighters of Houston, philanthropic contributions to the Melanoma Moon Shots Program of MD Anderson, and the Anne and John Mendelsohn Chair in Cancer Research. B.G.D. is supported by the Susan G. Komen Career Catalyst Research grant.
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KF and JTH conceptualized the study and designed the experiments. KF, PBM, GMF, XH, XM, XS, XH-FZ, JZ, SDH, ERP, DY, BGD, MAD, and JTH performed the experiments and/or analyzed data. JTH supervised the study. KF, PBM, ERP, BGD, MAD, and JTH wrote and/or revised the manuscript. All authors reviewed the manuscript.
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M.A.D. receives commercial research grants from AstraZeneca, Roche/Genentech, GlaxoSmithKline, Myriad, Oncothyreon, and Sanofi-Aventis and is a consultant/advisory board member for GlaxoSmithKline, Novartis, Roche/Genentech, Array, Bristol-Myers Squibb, Sanofi-Aventis, Vaccinex, Syndax, and NanoString. All other authors declare no conflict of interest.
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Fukumura, K., Malgulwar, P.B., Fischer, G.M. et al. Multi-omic molecular profiling reveals potentially targetable abnormalities shared across multiple histologies of brain metastasis. Acta Neuropathol 141, 303–321 (2021). https://doi.org/10.1007/s00401-020-02256-1
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DOI: https://doi.org/10.1007/s00401-020-02256-1