The compression of brain tissue by a tumour mass is believed to be a major cause of the clinical symptoms seen in patients with brain cancer. However, the biological consequences of these physical stresses on brain tissue are unknown. Here, via imaging studies in patients and by using mouse models of human brain tumours, we show that a subgroup of primary and metastatic brain tumours, classified as nodular on the basis of their growth pattern, exert solid stress on the surrounding brain tissue, causing a decrease in local vascular perfusion as well as neuronal death and impaired function. We demonstrate a causal link between solid stress and neurological dysfunction by applying and removing cerebral compression, which respectively mimic the mechanics of tumour growth and of surgical resection. We also show that, in mice, treatment with lithium reduces solid-stress-induced neuronal death and improves motor coordination. Our findings indicate that brain-tumour-generated solid stress impairs neurological function in patients, and that lithium as a therapeutic intervention could counter these effects.
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The authors declare that all data supporting the findings of this study are available within the paper and its Supplementary Information. Raw RNA-Seq data from this study have been deposited in the NCBI Sequence Read Archive (SRA) under submission ID SUB4405185 and BioProject ID PRJNA486395.
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We thank A. Ivinson (UK Dementia Research Institute), M. A. Moskowitz and M. J. Whalen (MGH) for critical discussion and insightful suggestions; S. Roberge, M. Duquette, C. Smith and E. L. Jones (MGH) for technical support, H. Wakimoto (MGH) for the MGG8 cell line and O. Rapalino (MGH) for help with the pre-operative clinical study. This work was supported by the National Cancer Institute (NCI; P01-CA080124, P50-CA165962, R01-CA129371, R01-CA208205, U01-CA 224348), NCI Outstanding Investigator Award (R35-CA197743), the Lustgarten Foundation, the Ludwig Center at Harvard, the National Foundation for Cancer Research and the Gates Foundation (R.K.J), R01-HL128168 (to J.W.B., T.P.P. and L.L.M.), DP2OD008780 (T.P.P.), R01CA214913 (T.P.P.), P41EB015903 (Center for Biomedical OCT Research and Translation), NIH/NINDS P30NS045776 (EM facility core) and P30-CA14051 from NCI (Koch Institute Genomics core). This work was also supported in part by the Susan G. Komen Foundation Fellowship PDF14301739, Fondation ARC pour la recherche sur le cancer and the INSERM-CNRS ATIP-Avenir grant (G.S.), NCI F32-CA216944-01 (H.T.N.), the European Research Council (ERC) under the European Union’s Horizon 2020 (grant agreement no. 758657), the South-Eastern Norway Regional Health Authority grants 2017073, 2016102 and 2013069, the Research Council of Norway grants 261984 and ES435705, the Norwegian Cancer Society grants 6817564 and 3434180 (K.E.E.), F31HL126449 from the National Heart, Lung, and Blood Institute at the NIH (M.D.), SolidarImmun fellowship (J.K.), Feodor-Lynen Postdoctoral Fellowship from Alexander von Humboldt Foundation (M.G.) and Deutsche Forschungsgemeinschaft AS422-2/1 (V.A.).
R.K.J. received an honorarium from AMGEN and consultant fees from Pfizer, Ophthotech, Merck, SPARC, SynDevRx and XTuit. R.K.J. owns equity in Enlight, Ophthotech and SynDevRx, and serves on the Boards of Trustees of Tekla Healthcare Investors, Tekla Life Sciences Investors, the Tekla Healthcare Opportunities Fund and the Tekla World Healthcare Fund. No reagents or funding from these companies was used in these studies. K.E.E. has intellectual properties with NordicNeuroLab AS, Bergen, Norway.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Tables 1–5, Supplementary Figures 1–11, Supplementary Video Legends 1–7 and Supplementary References 1–38.
RNA-Seq of compressed/released lithium-treated cortexes.
Illustration of the mathematical model to estimate the tumour-induced solid stress in the normal brain.
Representative longitudinal MRI of archetypal post-surgery patients with a nodular GBM tumour.
Representative longitudinal MRI of archetypal post-surgery patients with an infiltrative GBM tumour.
OCT longitudinal intravital angiography of the nodular GBM U87 mouse model.
OCT longitudinal intravital angiography of the nodular BC BT474 mouse model.
Representative Rotarod test (index of motor coordination and balance) in a mouse with no compression.
OCT longitudinal intravital angiography of the decompression phase in the compression apparatus model.
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Seano, G., Nia, H.T., Emblem, K.E. et al. Solid stress in brain tumours causes neuronal loss and neurological dysfunction and can be reversed by lithium. Nat Biomed Eng 3, 230–245 (2019). https://doi.org/10.1038/s41551-018-0334-7
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