Uveal melanoma (UM) exhibits recurring chromosomal abnormalities and gene driver mutations, which are related to tumor evolution/progression. Almost half of the patients with UM develop distant metastases, predominantly to the liver, and so far there are no effective adjuvant therapies. An accurate UM genetic profile could assess the individual patient's metastatic risk, and provide the basis to determine an individualized targeted therapeutic strategy for each UM patient. To investigate the presence of specific chromosomal and gene alterations, BAP1 protein expression, and their relationship with distant progression free survival (DPFS), we analyzed tumor samples from 63 UM patients (40 men and 23 women, with a median age of 64 years), who underwent eye enucleation by a single cancer ophthalmologist from December 2005 to June 2016. UM samples were screened for the presence of losses/gains in chromosomes 1p, 3, 6p, and 8q, and for mutations in GNAQ, GNA11, BAP1, SF3B1, and EIF1AX. BAP1 protein expression was detected by immunohistochemistry (IHC). Multivariate analysis showed that the presence of monosomy 3, 8q gain, and loss of BAP1 protein were significantly associated to DPFS, while BAP1 gene mutation was not, mainly due to the presence of metastatic UM cases with negative BAP1 IHC and no BAP1 mutation detected by Sanger sequencing. Loss of BAP1 protein expression and monosomy 3 represent the strongest predictors of metastases, and may have important implications for implementation of patient surveillance, properly designed clinical trials enrollment, and adjuvant therapy.

The development of adequate model systems to study human malignancies is crucial for basic and preclinical research. Here, we exploit the ''immune-privileged'' developmental time window to achieve orthotopic xenotransplantation of human brain tumor cells in wild-type (WT) mice. We find that, when transplanted in utero, human glioblastoma (GBM) cells readily integrate in the embryonic mouse brain mirroring key tumor-associated pathological features such as infiltration, vascularization, and complex tumor microenvironment including reactive astrocytes and host immune cell infiltration. Remarkably, activation of the host IBA1 tumor-associated microglia/macrophages depends on the type of glioma cell transplanted, suggesting our approach allows one to study human GBM interactions with the immune system of WT host mice. The embryonic engraftment model complements existing ones, providing a rapid and valuable alternative to study fundamental biology of human brain tumors in immune competent mice.

diseases and develop potential cures. [1] Developments across the fields of biotechnology, tissue engineering, biomaterials, and microtechnology, have led to in vitro models ranging from multilayer 3D cell cultures [2] to small self-standing cell aggregates called spheroids, [3] up to complex brain organoids derived from human pluripotent stem (hPS) cells. [4] Albeit grown in an artificial in vitro environment, the shift from conventional 2D neural cultures to 3D models was shown to better mimic the complexity of intertwined 3D networks found in the brain. [5] hPS-derived brain organoids can indeed recapitulate several aspects specific to human brain development at the level of gene expression, [6] cell-type differentiation and network formation, [7] and can express phenotypes of human brain diseases when generated from patient-derived hPS-cells. [4a,8] Following these results, 3D neural cell assemblies have raised a large interest for the study of human brain diseases and therapies. Furthermore, these models can overcome certain limitations of currently used animal models, such as low experimental accessibility for functional studies, [9] low sample size, low reproducibility and, above all, poor translational relevance of screening results to humans. [5] The routine experimental use of 3D brain tissue models, however, remains largely unpractical for applications in drugdiscovery. On one side, intermodel variability and unmonitored cellular viability can affect the reliable generation of complex 3D brain tissue model systems. For instance, as 3D models become critically sized, the low diffusion of nutrients and oxygen tends to induce the formation of a necrotic core, [1b,4a,5] with consequent losses in cellular viability. On the other side, available biosensing technologies are not yet adapted for the routine monitoring of biosignals such as neural activity inside individual 3D models. This hinders studies aiming toward a better understanding of the emergence of spontaneous neural activity in these models as well as their optimization to reliably generate electrically active brain tissue models for functional assays. Over the last few years, researchers have been working on protocols for culturing organoids with minimal variability, mainly focusing on homogenizing morphologies. [4c] As far as monitoring brain organoids, current major biosensing Brain organoids is an exciting technology proposed to advance studies on human brain development, diseases, and possible therapies. Establishing and applying such models, however, is hindered by the lack of technologies to chronically monitor neural activity. A promising new approach comprising selfstanding biosensing microdevices capable of achieving seamless tissue integration during cell aggregation and culture. To date, there is little information on how to control the aggregation of such bioartificial 3D neural assemblies. Here, the growth of hybrid neurospheroids obtained by the aggregation of silicon sham microchips (100 × 100 × 50 μm 3) with primary cortical cells ...

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Background Meningiomas are mainly benign brain tumors, although about 20% of histologically benign cases are clinically aggressive and recur after resection. We hypothesize that meningioma brain invasiveness and recurrence may be related to the presence of cancer stem cells and their high responsiveness to the CXCL12-CXCR4/CXCR7 chemokine axis. The aim of this study was to isolate meningioma stem cells from human samples, characterize them for biological features related to malignant behavior, and to identify the role of CXCR4/CXCR7 in these processes. Methods Meningioma stem cells were isolated from patient-derived primary cultures in stem cell-permissive conditions, and characterized for phenotype, self-renewal, proliferation and migration rates, vasculogenic mimicry, and in vivo tumorigenesis, in comparison with differentiated meningioma cells and stem-like cells isolated from normal meninges. These cell populations were challenged with CXCL12 and CXCL11 and receptor antagonists to define the chemokine role in stem cell-related functions. Results Stem-like cells isolated from meningioma cultures display higher proliferation and migration rates, vasculogenic mimicry, as compared to meningioma non-stem cells or cells isolated from normal meninges and were the only tumorigenic population in vivo. In meningioma cells, these stem-like functions were under the control of the CXCR4/CXCR7 chemokine axis. Conclusions We report a role for CXCL11 and CXCL12 in the control of malignant features in stem-like cells isolated from human meningioma, providing a possible basis for the aggressive clinical behavior observed in subsets of these tumors. CXCR4/CXCR7 antagonists might represent a useful approach for meningioma at high risk of recurrence and malignant progression.

In article number 2000114, Luca Berdondini and co-workers present 3D neurospheroids with self-standing silicon microdevices internalized at different levels. Results are obtained by uncovering the control capability of silicon surface engineering to drive microdevices at predefined sites during cellular aggregation and 3D growth. This work paves the way to bionic brain-tissue models with inbuilt untethered bioelectronic sensors and actuators.