Solid stress in brain tumours causes neuronal loss and neurological dysfunction and can be reversed by lithium

Giorgio Seano, Hadi T Nia, Kyrre E Emblem, Meenal Datta, Jun Ren, Shanmugarajan Krishnan, Jonas Kloepper, Marco C Pinho, William W Ho, Mitrajit Ghosh, Vasileios Askoxylakis, Gino B Ferraro, Lars Riedemann, Elizabeth R Gerstner, Tracy T Batchelor, Patrick Y Wen, Nancy U Lin, Alan J Grodzinsky, Dai Fukumura, Peigen Huang, James W Baish, Timothy P Padera, Lance L Munn, Rakesh K Jain, Giorgio Seano, Hadi T Nia, Kyrre E Emblem, Meenal Datta, Jun Ren, Shanmugarajan Krishnan, Jonas Kloepper, Marco C Pinho, William W Ho, Mitrajit Ghosh, Vasileios Askoxylakis, Gino B Ferraro, Lars Riedemann, Elizabeth R Gerstner, Tracy T Batchelor, Patrick Y Wen, Nancy U Lin, Alan J Grodzinsky, Dai Fukumura, Peigen Huang, James W Baish, Timothy P Padera, Lance L Munn, Rakesh K Jain

Abstract

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.

Figures

Fig. 1.. Measuring how nodular tumors mechanically…
Fig. 1.. Measuring how nodular tumors mechanically affect the surrounding brain.
(a-c) Solid stress in mouse models of nodular (patient-derived U87 cell line) and infiltrative brain tumors (patient-derived MGG8 cell line) in nude mice. (a) High-resolution ultrasound imaging of the stress-induced deformation and representative stress profiles across the tumour diameter and the normal surrounding tissue. Scale bar: 1 mm. (b-c) Estimation of the circumferential (compression; σθθ) and radial (tension; σrr) stress in the surrounding tissue obtained from mathematical model (described in Figure S1b-d and Method section). Data are mean of three independent tumors ± s.e.m. (d) Micro-anatomic deformation of the brain tissue around nodular tumors. IHC of U87 and MGG8 tumors at the interface of the normal brain tissue. Neurons (NeuN staining) and vessels (Collagen IV staining). Arrows indicate the deformed region around the tumour, neurons are packed and vessels are displaced following the circumference of the tumour margin. Representative images from a cohort of 10 mice with tumour. Scale bar: 50 μm. (e) Representative T2W and FLAIR MRI of pre-surgery pre-treatment patients with perfectly-defined margins GBM (nodular) and ill-defined GBM (infiltrative). (f) Karnofsky performance score (KPS) histograms of patients with perfectly-defined margins (nodular) or ill-defined GBM (infiltrative). Cohort of 64 pre-surgery pre-treatment GBM patients.
Fig. 2.. Reduced vessel perfusion in the…
Fig. 2.. Reduced vessel perfusion in the brain tissue around nodular tumors.
(a) Longitudinal OCT intravital angiography (perfused vessels) of the nodular Gl261 mouse model. U87 and BT474 are presented in Fig. S3B, D. Scale bar: 1 mm. (b) Longitudinal quantitative analysis of the vascular perfused volume fraction in the surrounding tissue. GBM U87: Day17 p=0.025; Day18 p=0.011; Day19 p=0.045; day20 p=0.037 vs the red-dotted time-point. BC BT474: Day14 p=0.001; Day18 p=0.024; Day21 p=0.003; day25 p=0.005; day28 p=0.001; day32 p<0.001; day38 p=0.035 vs the red-dotted time-point. Data are mean ± s.e.m. (c) Intravital longitudinal multi-photon imaging depicting changes in vessel diameter in the nodular Gl261-GFP and in the infiltrative MGG8-GFP GBM mouse models. GFP (green, tumour cells) and TAMRA-Dextran (red, 2MDa-dextran, blood flow). VA = vascular area. Scale bar: 20 μm.
Fig. 3.. Neuronal deformation and death in…
Fig. 3.. Neuronal deformation and death in the brain tissue around nodular tumors.
(a) Intravital multi-photon imaging of brain nuclei around the nodular mouse Gl261-DsRed GBM implanted in H2B-EGFP mouse (CAG::H2B-EGFP C57/BL6). GFP (green, nuclei within the brain tissue), DsRed (red, tumour cells) and BlueCascade (blue, 2MDa-dextran, blood flow). Insets are magnifications of the yellow squares. Vascular area (VA) is the quantification (%) of these exact images. Scale bar: 20 μm. (b) IHC of neuronal nuclei (NeuN) in the surrounding brain tissue of mice with the nodular U87 tumour. Representative image from a cohort of 10 mice with tumour. Insets are magnifications of the red squares. Scale bar: 50 μm. (c) Quantification of neuronal nuclear area in the brain tissue around nodular or infiltrative tumors. Data are mean ± s.e.m. p-values are vs “300–450 from the tumour edge”. (d) Apoptosis (ApopTag) at the interface between the nodular U87 tumour and the normal brain tissue. Representative image from a cohort of 10 mice with tumour. Inset is magnification of the red square. Scale bar: 100 μm.
Fig. 4.. Reduced perfusion in the surrounding…
Fig. 4.. Reduced perfusion in the surrounding normal tissues in GBM and BC brain met patients.
(a) Quantification of the local perfusion in surrounding normal brain tissue from immediately adjacent to the peri-edematous region of the GBM to the region 12 mm away from the tumor edge. The cohort of 64 pre-surgery GBM patients was divided in patients with a reduced perfusion in the surrounding tissue (“reduced perf”) and patients with no difference in perfusion (“unchanged perf”). Data are mean ± s.e.m. Point 1.72 p<0.001 vs “unchanged perf”; point 3.44 p<0.001; point 5.15 p=0.001; point 6.87 p=0.014; point 8.59 p=0.019. (b) Representative pre-surgery GBM patient from a cohort of 33 patients with local reduced perfusion and fiber tensor signal in the surrounding tissue as well as midline shift. (c) Histograms of KPS in “reduced perf” and “unchanged perf” GBM patients. (d) CE-T1 and FLAIR-T2 volumes in the two classes with “reduced perf.” or “unchanged perf.” in the surrounding brain tissue. N.S., not significant. Data are mean ± s.e.m (N = 64 patients). (e) Classification of the patients in the two perfusion subclasses in based on the edematous (FLAIR-T2) MRI margins (N = 64 patients). Comparable result with CE-T1 MRI, Fig. S6B. (f) Quantification of the local perfusion in the brain tissue immediately surrounding the BC brain mets. Cohort of 34 BC patients (26 HER2-positive; 8 HER2-negative). Data are mean ± s.e.m. Point 0 p<0.001 vs point 1.2; point 1.2 p<0.001 vs point 2.4; point 3.6 p=0.010 vs point 4.8; point 4.8 p=0.013 vs point 6. (g) Representative BC HER2-negative patient from a cohort of 34 patients with local reduction of perfusion and fiber tensor signal in the surrounding tissue.
Fig. 5.. Direct chronic compression of brain…
Fig. 5.. Direct chronic compression of brain reduces vessel perfusion and induces neuronal damage.
(a) Schematic of the intravital compression device procedure. (b) Deformation of the compressed tissue. Hematoxylin-eosin (H&E) of the whole brain gradually and chronically compressed for 14 days. Representative image from a cohort of 7 mice with compression device. Insets are magnifications of the white squares. Scale bar: 1 mm. (c) OCT longitudinal intravital angiography of the brain seen from the compression apparatus (average projection of the 3D imaging). Vascular area (VA) is the quantification (%) of the shown images. Scale bar: 1 mm. (d) Ultrastructural imaging of nuclei in uncompressed and compressed cortexes via electromicroscopy. Representative images from a cohort of 3 mice per experimental point. Scale bar: 1 μm. Quantification of the percentage of condensed chromatin area in n nuclei. Data are mean ± s.e.m. (e-f) NeuN (neuron nuclei) in the compressed cortex. Representative images from a cohort of 4 mice per experimental point and quantification of number of neurons (NeuN+ nuclei) per cortex exposed to the cranial window. Data are mean ± s.e.m. Scale bar: 100 μm. (g) Quantification of neuronal nuclear area in uncompressed or compressed cortexes. Normalized results. Data are mean ± s.e.m. (h) Rotarod endurance (index of motor coordination and balance) after 14 days of compression of the motor and somatosensory cortex. Data are mean of 3 consecutive days (1 measure/day) and 5 mice per group ± s.e.m. (i) Static gait test (index of locomotion); footprint analysis of the stride length. Footprint in Fig. S8E. Data are mean of 3 technical replicates and n mice per group ± s.e.m.
Fig. 6.. Decompression restores vessel perfusion and…
Fig. 6.. Decompression restores vessel perfusion and partially rescues motor-coordination.
(a) OCT angiography after decompression of brains with nodular U87 tumors by removing cranial window (craniotomy). Complete time-course in Figure S9B-C. (b) Schematic of the long-term compression/decompression timeline via the in vivo chronic apparatus. (c) Longitudinal OCT angiography before and after decompression. Images of a representative mouse from a cohort of 3 mice. Insets are magnifications of the red squares. See Movie S7 for the complete time-lapse. Scale bar: 1 mm. (d) Representative cortexes stained with anti-NeuN from a cohort of 3 mice. The long-term compression induces tissue loss and the decompression partly restores the micro-anatomy of the cortex. Insets are magnifications of the red squares. Scale bar: 500 μm. (e) Quantification of the NeuN+ neurons in the cortexes, decompressed or compressed and released. Data are mean ± s.e.m. (f) Rotarod endurance (index of motor coordination and balance) 24–48 hours after decompression of the motor and somatosensory cortex. Data are mean of 2 consecutive days and 12 mice per group ± s.e.m (normalized with the value before decompression).
Fig. 7.. Systemic treatment with lithium alleviates…
Fig. 7.. Systemic treatment with lithium alleviates compression-mediated neuronal damage.
(a) Schematic of the treatments in long-term compression/decompression procedure. (b) Representative cortexes stained with anti-NeuN from a cohort of 5 mice per experimental point. Chronic lithium treatment preserves the cortex micro-anatomy after decompression. Insets are magnifications of the red squares. Scale bar: 500 μm. (c) Quantification of the NeuN+ neurons in the cortexes, decompressed or compressed and released. Data are mean ± s.e.m. (d) Ultrastructural imaging of nuclei in compressed cortexes treated with vehicle or lithium via electromicroscopy. Representative images from a cohort of 3 mice per experimental point. Scale bar: 1 μm. Quantification of the percentage of condensed chromatin area in n nuclei. Data are mean ± s.e.m. (e) Longitudinal analysis of the Rotarod endurance (index of motor coordination and balance). Data are mean of 2 consecutive days and 6 mice per group ± s.e.m. (f) Static gait test (index of locomotion); footprint analysis of the stride length at the time of highest compression (day 14). Data are mean of 3 technical replicates and n mice per group ± s.e.m. 115 steps measured for vehicle-treated mice and 62 for lithium-treated ones.
Fig. 8.. Solid stress from nodular brain…
Fig. 8.. Solid stress from nodular brain tumors compresses the surrounding brain tissue, thus causing neurological dysfunction.
(a) Heatmap illustrating normalized gene expression of differentially expressed genes (FDR<0.05) from RNA-Seq analysis of compressed/released cortexes under chronic lithium treatment. (b) Quantification of the NeuN+ neurons in the cortexes, compressed and released lithium-treated with treatment start when compression and symptoms were already present. Data are mean ± s.e.m. (c) Schematic summarizing the effects of nodular tumors and their resulting solid stress on the surrounding brain tissue. The focus of the manuscript is on nodular tumors and the effects of solid stress on the surrounding tissue, while infiltrative tumors appeared to exert lower solid stress to the brain. (d) Schematic summarizing the causes, modifiers and consequences of solid stress from nodular tumors.

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