Transcriptomic Hallmarks of Tumor Plasticity and Stromal Interactions in Brain Metastasis

The brain is a major site of relapse for several cancers, yet deciphering the mechanisms of brain metastasis remains a challenge because of the complexity of the brain tumor microenvironment (TME). To define the molecular landscape of brain metastasis from intact tissue in vivo, we employ an RNA-sequencing-based approach, which leverages the transcriptome of xenografts and distinguishes tumor cell and stromal gene expression with improved sensitivity and accuracy. Our data reveal shifts in epithelial and neuronal-like lineage programs in malignant cells as they adapt to the brain TME and the reciprocal neuroinflammatory response of the stroma. We identify several transcriptional hallmarks of metastasis that are specific to particular regions of the brain, induced across multiple tumor types, and confirmed in syngeneic models and patient biopsies. These data may serve as a resource for exploring mechanisms of TME co-adaptation within, as well as across, different subtypes of brain metastasis.We thank Sally Adua for critical review of the manuscript. This work wasfunded by grants R01CA166376, R01CA191489, and W81XWH-15-1-0117and the Beatrice Kleinberg Neuwirth Fund (to D.X.N.); Yale Lung CancerSPORE grant P50CA196530 (to K.P. and D.X.N.); Yale SPORE in Skin Cancergrants P50 CA121974, K24CA172123, and R01 CA216846 (to H.M.K.);MINECO grants SAF2017-89643-R and SAF2015-62547-ERC, Bristol-MyersSquibb-MRA Young Investigator Award 2017, Fundacio ́n Ramo ́n Areces,and CLIP CRI Award 2018 (to M.V.); La Caixa-Severo Ochoa InternationalPhD Program Fellowship (to L.Z.); and FCT PhD Fellowship SFRH/BD/100089/2014 (to C.M.). M.V. is a Ramo ́n y Cajal Investigator (RYC-2013-13365) and member of EMBO YIP (4053). K.D.P. was supported by grantT32 CA193200, W.L.C. by grant DGE-1122492, and E.W. by grant T32GM100884S