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Table containing all brain metastatic cell lines in the BrMPanel

Spread of cancer to the brain remains an unmet clinical need in spite of the increasing number of cases among patients with lung, breast cancer, and melanoma most notably. Although research on brain metastasis was considered a minor aspect in the past due to its untreatable nature and invariable lethality, nowadays, limited but encouraging examples have questioned this statement, making it more attractive for basic and clinical researchers. Evidences of its own biological identity (i.e., specific microenvironment) and particular therapeutic requirements (i.e., presence of blood–brain barrier, blood–tumor barrier, molecular differences with the primary tumor) are thought to be critical aspects that must be functionally exploited using preclinical models. We present the coordinated effort of 19 laboratories to compile comprehensive information related to brain metastasis experimental models. Each laboratory has provided details on the cancer cell lines they have generated or characterized as being capable of forming metastatic colonies in the brain, as well as principle methodologies of brain metastasis research. The Brain Metastasis Cell Lines Panel (BrMPanel) represents the first of its class and includes information about the cell line, how tropism to the brain was established, and the behavior of each model in vivo. These and other aspects described are intended to assist investigators in choosing the most suitable cell line for research on brain metastasis. The main goal of this effort is to facilitate research on this unmet clinical need, to improve models through a collaborative environment, and to promote the exchange of information on these valuable resources.

Contains experimental therapies tested on brain metastatic cell lines and associated clinical trials

Altres ajuts: acords transformatius de la UAB Hypothesis: The easy aggregation of superparamagnetic iron oxide nanoparticles (SPION) greatly reduces their adsorption performance for removing arsenic (As) from polluted water. We propose to exploit the porosity and good diffusion properties of a cube-shaped cellulose sponge for loading SPION to reduce the aggregation and to develop a composite adsorbent in the cm-scale that could be used for industrial applications. Experiments: SPION were in-situ synthesized by co-precipitation using a commercial cube-shaped sponge (MetalZorb®) as support. The morphology, iron-oxide phase, adsorption performance and thermodynamic parameters of the composite adsorbent were determined to better understand the adsorption process. X-ray absorption spectroscopy (XAS) was used to investigate the chemical state of the adsorbed As(III). Findings: The adsorption of the supported SPION outperforms the unsupported SPION (ca. 14 times higher adsorption capacity). The modelling of the adsorption isotherms and the kinetic curves indicated that chemisorption is controlling the adsorption process. The thermodynamic analysis shows that the adsorption retains the spontaneous and endothermic character of the unsupported SPION. The XAS results revealed an adsorption-oxidation mechanism in which the adsorbed As(III) was partially oxidized to less toxic As(V) by the hydroxyl free radical (•OH) generated from Fe(III) species and by the hydroxyl groups.

The application of azimuthal plot analysis of tts-μXRD results allows us to discriminate the origin of calcium oxalate nephrolith formation.

Wheat can be biofortified with different inorganic selenium (Se) forms, selenite or selenate. The choice of Se source influences the physiological response of the plant and the Se metabolites produced. We looked at selenium uptake, distribution and metabolization in wheat exposed to selenite, selenate and a 1:1 molar mixture of both to determine the impact of each treatment on the Se speciation in roots, shoots, and grains. To achieve a comprehensive quantification of the Se species, the complementarity of high-performance liquid chromatography coupled with inductively coupled plasma mass spectrometry and X-ray absorption spectroscopy was exploited. This approach allowed the identification of the six main selenium species: selenomethionine, selenocysteine, selenocystine, selenite, selenate, and elemental selenium. The three treatments resulted in similar total selenium concentration in grains, 90-150 mg Se kg

Altres ajuts: acords transformatius de la UAB Altres ajuts: This work has been funded by ALBA Synchrotron through granted proposal (grant reference: 2020024303) Olivetol (OLV), as a cannabidiol (CBD) analog, was incorporated in γ-cyclodextrin metal-organic frameworks (γ-CD-MOFs) and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) liposomes as potential analgesic drug delivery systems (DDS) for dental hypersensitivity (DH) treatment. These DDS have been scarcely employed in oral health, being the frst time in case of MOFs loaded with cannabinoids. In vitro experiments using bovine teeth were performed to verify if the drug is able to reach the dentin, where it can fow to the pulp tissues and exert its analgesic efect; enamel and dentin regions were analyzed by synchrotron radiation-based FTIR microspectroscopy. Principal component analysis (PCA) was used to process the spectroscopic data as a powerful chemometric tool, and it revealed a similar behavior in both regions. The studied DDS have been characterized by diferent techniques, and is was demonstrated that DDS is an efcient way to carry the drug through dental tissues without compromising theirstructure.

We propose a low-invasive method to enable implantable, large volume Raman spectroscopy in arbitrarily deep brain regions of the mouse brain. Using a single tapered fiber as thin as 1 μm at the tip, we identified diagnostic markers of brain metastasis - the most frequent brain tumor in human adults - with overall accuracy ≥ 90%. We view our approach as a promising complement to the existing palette of tools for optical interrogation of the brain.

Brain metastasis is an unmet clinical need, affecting between 10-30% of cancer patients with 200000 to 400000 newly diagnosis per annum in the US. Recently, several clinical trials have reported benefits using immunotherapy to treat brain metastasis. However, variability of the responses is broad and high benefit is found mainly in asymptomatic brain metastasis, while the benefit is dramatically reduced in the clinically relevant stage. Thus, it is currently unknown how to effectively target symptomatic brain metastases with immunotherapy. We previously reported a clinically relevant protumoral program driven by STAT3 activation in a subpopulation of reactive astrocytes in these advanced stages of the disease. Our current study further exploited the heterogeneity within the metastasis-associated microenvironment as a resource to identify novel therapeutic vulnerabilities to improve the benefits of immunotherapies based on immune checkpoint blocking antibodies (ICB) in symptomatic brain metastasis. Our results demonstrate that reactive astrocytes are strong immunomodulatory cells in brain tumors. We have identified the molecular profile of disease-associated glial cells and defined its connection to modulatory activities on specific lymphocyte populations in experimental brain metastasis as well as human-derived samples. scRNASeq and high content multiplex immunofluorescence allowed us to report a novel local immunomodulatory axis dependent on TIMP1 (astrocytes)/CD63 (CD8 T cells), which is present in brain metastasis patients with high immunoscore and would imply an additional immunosuppressive signal for potential ICB responders in brain metastasis. Genetic and pharmacologic approaches targeting this STAT3-dependent local immunomodulatory axis have allowed us to define the rationale to combine immune checkpoint blockade with a STAT3 inhibitor, which we previously used in patients. We proved that such combined immunotherapy boost the systemic activation of T cells while also preventing the local blockade. Additionally, our comprehensive strategy includes the possibility to stratify patients that are best qualified to benefit from this therapy by measuring TIMP1 in liquid biopsies from CSF. Even more, our data using Patient Derived Organotypic Cultures (PDOC) from fresh brain metastasis neurosurgeries confirms that our therapeutic strategy might benefit brain metastases generated from any primary source. In conclusion, we describe an immunosuppressive mechanism in the brain microenvironment that could explain the lack of response to ICB in patients with advanced brain metastasis. Our finding provides the rationale to implement complementary approaches targeting local immunosuppression to increase the benefit of immunotherapy in symptomatic brain metastasis. Citation Format: Neibla Priego, Pedro García-Gómez, Ana de Pablos-Aragoneses, María Perea-García, Laura Álvaro-Espinosa, Carolina Hernández-Oliver, Elena Martínez-Saez, Ángel Pérez-Núñez, Aurelio Hernández-Laín, Rebeca Sanz-Pamplona, Marc Schmitz, Stephen J. Crocker, Diego Serrano, Asís Palazón, RENACER Red Nacional de Metástasis Cerebral, Manuel Valiente. TIMP1 mediates astrocyte-dependent local immunosuppression in brain metastasis. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5105.

The physical interaction between metastasis-initiating cells and the pre-existing capillary network (a process known as vascular co-option) is critical during the initial stages of multi-organ metastasis in cancer. As such, this process might provide an opportunity to prevent metastasis. As part of the process of vascular co-option, we observed that brain metastatic cells in the perivascular niche temporarily enter into a novel cell state characterized by a decreased proliferation before resuming their aggressive growth to colonize the organ. Transcriptomic analysis of co-opting metastatic cells confirmed downregulation of MYC signatures, mitotic cell cycle and increased stemness properties. By focusing on one of the top upregulated transcription factors in co-opting cells: MXD4, a MYC antagonist; we have been able to dissect the relevance of this cellular state, that we termed proliferative pause, both respect to the maintenance of the interaction with the vasculature and to the ability to generate macrometastases. As such, targeting MXD4 in lung adenocarcinoma and triple-negative breast cancer metastatic models reduced multi-organ metastases to a level that translates into increased overall survival. Mechanistically, this obliged proliferative pause is linked to a cellular response to the increasing environmental pressure involved in organ colonization. For instance, we found that crossing the blood-brain barrier induced an increased DNA damage due to mechanical constrains leading to nuclear deformation. However, the MXD4-dependent proliferative pause during vascular co-option allows metastatic cells to repair this damage to continue the colonization process. Given the enormous potential to prevent metastasis and our findings dissecting the proliferative pause status, we developed a therapeutic strategy to target vascular co-opting cells. As part of the molecular profile of co-opting cells, we validated their high dependency on Bcl proteins. As such, we have used a Bcl-2 inhibitor (obatoclax) permeable to the blood-brain barrier to target these cells in preventive scenarios. Beyond the preventive therapeutic assays in vivo, we have applied additional clinically-relevant models where preventive strategies could easily translate into the clinical practice. As such, obatoclax post-surgery provided a survival benefit by preventing relapse, as the cells left behind after the local therapy are vascular co-opting cells. Furthermore, our national network of brain metastasis (RENACER) provided us with fresh neurosurgeries and, in a limited cohort of 10 surgeries with extended resections, we were able to identify invasive fronts with metastatic cells co-opting the vasculature. The use of obatoclax to target these cancer cells, which are the seeds of relapse post-surgery, confirmed that targeting vascular co-option could be a novel strategy to prevent metastasis in a clinically relevant situation. Citation Format: Pedro García-Gómez, Diana Retana, Pablo Sanz-Martínez, Irene Salgado-Crespo, Carolina Hernández-Oliver, Maria Isabel García, Oliva Sánchez, Kevin Troulé-Lozano, Verona Villar-Cerviño, Miguel Lafarga-Coscojuela, Fátima Al-Shahrour, RENACER Red Nacional de Metástasis Cerebral, Manuel Valiente. Metastatic colonization requires a proliferative pause linked to vascular co-option [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3516.

BACKGROUND STAT3 expression in peritumoral reactive astrocytes (RA) of brain metastases (BM) from breast cancer (BC) may favor a pro-metastatic environment. MATERIAL AND METHODS Eighty-five BM specimens from BC were identified from the biobank of Pathology Unit of University of Turin and Spanish national BrM network (RENACER). pSTAT3 expression was scored in RA of peritumoral tissue according to Priego et al. (Nat Med 2018). Clinical, molecular data, and intracranial progression (i-PFS) were retrospectively retrieved. RESULTS Median age was of 54 years (range 30–81). Immunohistochemistry for GFAP and pSTAT3 was feasible in 68/85 (80%). 15/68 patients (21.1%) had BM from luminal BC, 27/68 (39.7%) from HER2-positive BC, and 26/68 (39.2%) from TNBC. 56/68 (82.4%) showed positive staining of pSTAT3, of which 9/68 (13.3%) scored with 3, 26/68 (38.2%) with 2, 21/68 (30.9%%) with 1, and 12/68 (17.6%) with 0 (negative). High pSTAT3 expression (score 2-3) was observed in 17/27 (62.9%) BM from HER2-positive BC and in 15/26 (57.7%) BM from TNBC, while most of BM from luminal BC (12/15 – 80%) had low or absent pSTAT3 (score 0-1) (p=0.021). Overall i-PFS was 16 months (range 7-41): low pSTAT3 BM (score 0-1) had a median i-PFS of 21 months versus 12 months for high pSTAT3 BM (score 2-3). A shorter median i-PFS was observed in high pSTAT3 BM from TNBC (4 months) as compared with low pSTAT3 BM (11 months). Conversely, i-PFS of high pSTAT3 BM (7 months) was similar to low pSTAT3 BM (6 months) in HER2-positive BC. CONCLUSION pSTAT3 expression in RA of peritumoral tissue of BM from TNBC and HER2-positive BC is higher than in BM from luminal BC. Of note, patients with high pSTAT3 BM from TNBC progressed earlier in comparison with those with low pSTAT3, suggesting that pSTAT3 expression has an influence on the outcome.

Selenium (Se) can induce stress in plants. Our main purpose is to assess the effect of a biostimulant, based on hetero-polyoxometalates mixed with humic acids, on Se bio-fortified wheat plants. Secondly, to evaluate a possible modification of the Se species in the plant tissues and to investigate the response of phytohormones. Wheat plants were grown hydroponically and exposed to either selenite (Se(IV)), selenate (Se(VI)) or a mixture of both species (Se(MIX)) in the presence or absence of the biostimulant (foliar, FA; or root application, RA). Biomass, mineral nutrient concentration, phytohormones and Se speciation were investigated. The biostimulant FA did not modify the plant biomass but RA significantly increased the root biomass in all treatments as well as the shoot biomass of plants exposed to Se(VI) and Se(MIX) even when both modes of application caused a severe reduction of IAA levels in shoots. The biostimulant accelerated the translocation of Se from roots to shoots in the presence of Se(VI) and Se(MIX), and it only had a noticeable influence on the Se speciation in roots, but not significant in shoots. X-ray absorption spectroscopy allowed to identify organic Se as the main Se species formed in the shoots. The biostimulant has a mild effect on the Se speciation. The biostimulant has a remarkable influence on both the uptake and accumulation of certain mineral nutrients and the plant metabolism by increasing the biomass under Se exposure. This indicates the potential of this biostimulant that also will prevent the possible Se-induced plant stress.

Most physical and other natural systems are complex entities composed of a large number of interacting individual elements. It is a surprising fact that they often obey the so-called scaling laws relating an observable quantity with a measure of the size of the system. Here we describe the discovery of universal superlinear metabolic scaling laws in human cancers. This dependence underpins increasing tumour aggressiveness, due to evolutionary dynamics, which leads to an explosive growth as the disease progresses. We validated this dynamic using longitudinal volumetric data of different histologies from large cohorts of cancer patients. To explain our observations we put forward increasingly-complex biologically-inspired mathematical models that captured the key processes governing tumor growth. Our models predicted that the emergence of superlinear allometric scaling laws is an inherently three-dimensional phenomenon. Moreover, the scaling laws thereby identified allowed us to define a set of metabolic metrics with prognostic value, thus providing added clinical utility to the base findings. This research has been supported by the James S. McDonnell Foundation 21st Century Science Initiative in Mathematical and Complex Systems Approaches for Brain Cancer (collaborative awards 220020560 and 220020450), Ministerio de Economia y Competitividad/FEDER, Spain (grant no. MTM2015-71200-R), Junta de Comunidades de Castilla-La Mancha (grant no. SBPLY/17/180501/000154). Research in the Brain Metastasis Group is supported by MINECO grant MINECO-Retos SAF2017-89643-R (M.V.), Bristol-Myers Squibb Melanoma Research Alliance Young Investigator Award 2017 (498103) (M.V.), Beug Foundation's Prize for Metastasis Research 2017 (M.V.), Fundacion Ramon Areces (CIVP19S8163) (M.V.), Worldwide Cancer Research (19-0177) (M.V.), H2020-FETOPEN (828972) (M.V.), Fundacio La Marato de tv3 (141), Clinic and Laboratory Integration Program CRI Award 2018 (54545) (M.V.), AECC Coordinated Translational Groups 2017 (GCTRA16015SEOA) (M.V.), LAB AECC 2019 (LABAE19002VALI) (M.V.), La Caixa INPhINIT Fellowship (LCF/BQ/IN17/11620028) (P.G.-G.), La Caixa-Severo Ochoa International PhD Program Fellowship (LCF/BQ/SO16/52270014) (L.Z.). M.V. is a member of the European Molecular Biology Organization Young Investigators programme (4053). We would like to acknowledge J. Cervera and J. C. Penalver from the IVO Foundation (Valencia, Spain). No

Tumor growth is the result of the interplay of complex biological processes in huge numbers of individual cells living in changing environments. Effective simple mathematical laws have been shown to describe tumor growth in vitro, or simple animal models with bounded-growth dynamics accurately. However, results for the growth of human cancers in patients are scarce. Our study mined a large dataset of 1133 brain metastases (BMs) with longitudinal imaging follow-up to find growth laws for untreated BMs and recurrent treated BMs. Untreated BMs showed high growth exponents, most likely related to the underlying evolutionary dynamics, with experimental tumors in mice resembling accurately the disease. Recurrent BMs growth exponents were smaller, most probably due to a reduction in tumor heterogeneity after treatment, which may limit the tumor evolutionary capabilities. In silico simulations using a stochastic discrete mesoscopic model with basic evolutionary dynamics led to results in line with the observed data.

Altres ajuts: acords transformatius de la UAB In this study, a commercial cube-shaped open-celled cellulose sponge adsorbent was modified by in-situ co-precipitation of superparamagnetic iron oxide nanoparticles (SPION) and used to remove As(V) from aqueous solutions. Fe K-edge X-ray absorption spectroscopy (XAS) and TEM identified maghemite as the main iron phase of the SPION nanoparticles with an average size 13 nm. Batch adsorption experiments at 800 mg/L showed a 63% increase of adsorption capacity when loading 2.6 wt.% mass fraction of SPION in the cube-sponge. Experimental determination of the adsorption thermodynamic parameters indicated that the As(V) adsorption on the composite material is a spontaneous and exothermic process. As K-edge XAS results confirmed that the adsorption enhancement on the composite can be attributed to the nanoparticles loaded. In addition, adsorbed As(V) did not get reduced to more toxic As(III) and formed a binuclear corner-sharing complex with SPION. The advantageous cube-shape of the sponge-loaded SPION composite together with its high affinity and good adsorption capacity for As(V), good regeneration capability and the enhanced-diffusion attributed to its open-celled structure make this adsorbent a good candidate for industrial applications.

Altres ajuts: acords transformatius de la UAB Altres ajuts: Sandra Diez-García acknowledges the FI-2017 fellowship from Agència de Gestió d'Ajuts Universitaris i de Recerca (Generalitat de Catalunya). This study aims to develop an innovative dental product to remineralize dental enamel by a proper combination of ion-exchange resins as controlled release of mineral ions that form dental enamel, in the presence of amelogenin to guide the appropriate crystal growth. The novel product proposed consists of a combination of ion-exchange resins (weak acid and weak base) individually loaded with the remineralizing ions: Ca, PO and F, also including Zn in a minor amount as antibacterial, together with the protein amelogenin. Such cocktail provides onsite controlled release of the ions necessary for enamel remineralization due to the weak character of the resins and at the same time, a guiding tool for related crystal growth by the indicated protein. Amelogenin protein is involved in the structural development of natural enamel and takes a key role in controlling the crystal growth morphology and alignment at the enamel surface. Bovine teeth were treated by applying the resins and protein together with artificial saliva. Treated teeth were evaluated with nanoindentation, scanning electron microscopy and energy-dispersive X-ray spectroscopy. The innovative material induces the dental remineralization creating a fluorapatite layer with a hardness equivalent to sound enamel, with the appropriate alignment of corresponding nanocrystals, being the fluorapatite more acid resistant than the original mineral. Our results suggest that the new product shows potential for promoting long-term remineralization leading to the inhibition of caries and protection of dental structures.

Altres ajuts: acords transformatius de la UAB The limitations to assess dental enamel remineralization have been overcome by a methodology resulting from the appropriate combination of synchrotron radiation-based techniques on both, infrared microspectroscopy and micro X-ray diffraction, with the help of specific data mining. Since amelogenin plays a key role in modulating the mineralization of tooth enamel, we propose a controlled ion release for fluorapatite structural ions (Ca 2+, PO 3-, and F -, also including Zn 2+) by using weak acid and weak base ion-exchange resins in the presence of amelogenin to remineralize the surface of etched teeth. This combination provides the necessary ions for enamel remineralization and a guide for crystal growth due to the protein. Remineralized tooth samples were analyzed by applying the indicated methodology. The synchrotron data were treated using principal component analysis and multivariate curve resolution to analyze the mineral layer formed in the presence and absence of amelogenin. The remineralizing treatment created a fluorapatite layer free of carbonate impurities and with a similar orientation to that of the natural enamel thanks to amelogenin contribution.

Altres ajuts: acords transformatius de la UAB Altres ajuts: Jorge Rodríguez-Martínez acknowledges Agència de Gestió d'Ajuts Universitaris i de Recerca from Generalitat de Catalunya (Sapin) for the FI-2018 fellowship. γ-Cyclodextrin-metal-organic frameworks (γ-CD-MOFs) are developed as a new promising and biocompatible material, which shows a great potential for drug delivery system (DDS) applications. γ-CD-MOFs were successfully synthesized using microwave-assisted technique from different potassium sources (KOH, KCl and KNO3). The encapsulation of olivetol (OLV) into these materials was investigated as an innovative model of DDS for cannabinoids. Loading of OLV in γ-CD-MOFs was performed by impregnation and co-crystallization methods. Scanning electron microscopy (SEM) and X-ray powder diffraction (XRPD) were employed to study the structural properties of γ-CD-MOF samples, showing the typical cubic crystals in case of KOH and trigonal morphologies in case of KCl and KNO3. Olivetol content was determined using UV-Vis spectrophotometry and its interaction with γ-CD-MOFs was investigated by Attenuated Total Reflection-Fourier Transform Infrared Spectroscopy analysis (ATR-FTIR). OLV content was significantly higher when KCl or KNO3 were employed in combination with a cocrystallization method, while the drug encapsulation using KOH and the impregnation method was really poor. For the first time, γ-CD-MOFs loaded with cannabinoids were developed and they could be considered a novel strategy as DDS of these compounds.

Nephrolithiasis is a multifactor disease that produces nephrolites in the kidneys. Calcium oxalate hydrate (dihydrated, COD, or monohydrated, COM) stones are the most common ones with more than sixty percent incidence worldwide. They are related to different pathologies, COD with hypercalciuria and COM with hyperoxaluria. COD is an unstable species and transforms into COM (herein named TRA to distinguish the origin of the monohydrated species). TRA and COM are chemically and crystallographically identical leading to misdiagnosis and recurrence increase. In the current study, the composition and crystalline structures of several calcium oxalate stones, classified by morpho-constitutional analysis, were examined by IR and synchrotron through-the-substrate micro-X-ray diffraction (tts-μXRD). Both IR and linear diffractogram studies were able to distinguish between the monohydrated and dihydrated phases but not between COM and TRA, as expected. The analysis of 2D diffraction patterns revealed that TRA showed a lower degree of crystallinity and less texture with respect to COM which can be used as a signature to distinguish between the two. This study confirms that despite the subtle differences between COM and TRA, the origin of the monohydrate oxalates can be unraveled using tts-μXRD. This valuable information should be taken into account in order to improve patients' diagnosis and reduce recurrence by considering and treating the origin of the formed stones.

Modeling of metastatic disease in animal models is a critical resource to study the complexity of this multi-step process in a relevant system. Available models of metastatic disease to the brain are still far from ideal but they allow to address specific aspects of the biology or mimic clinically relevant scenarios. We not only review experimental models and their potential improvements but also discuss specific answers that could be obtained from them on unsolved aspects of clinical management.

The uncontrolled release of pharmaceutical drugs into the environment raised serious concerns in the last decades as they can potentially exert adverse effects on living organisms even at the low concentrations at which they are typically found. Among them, platinum based cytostatic drugs (Pt CDs) are among the most used drugs in cancer treatments which are administered via intravenous infusion and released partially intact or as transformation products. In this review, the studies on environmental occurrence, transformation, potential ecotoxicity, and possible treatment for the removal of platinum cytostatic compounds are revised. The analysis of the literature highlighted the generally low total platinum concentration values (from a few tens of ng L−1 to a few hundred μg L−1) found in hospital effluents. Additionally, several studies highlighted how hospitals are sources of a minor fraction of the total Pt CDs found in the environment due to the slow excretion rate which is longer than the usual treatment durations. Only some data about the impact of the exposure to low levels of Pt CDs on the health of flora and fauna are present in literature. In some cases, adverse effects have been shown to occur in living organisms, even at low concentrations. Further ecotoxicity data are needed to support or exclude their chronic effects on the ecosystem. Finally, fundamental understanding is required on the platinum drugs removal by MBR, AOPs, technologies, and adsorption.

BACKGROUND The diagnosis of brain metastasis involves high morbidity and mortality and remains an unmet clinical need in spite of being the most common tumor in the brain. Exclusion of these cancer patients from clinical trials is a major cause of their limited therapeutic options. MATERIAL AND METHODS We report a novel drug-screening platform (METPlatform) based on organotypic cultures which allows identifying effective anti-metastasis agents in the presence of the organ microenvironment. We have applied this approach to clinically relevant stages of brain metastasis using both experimental models and human tumor tissue (by performing patient-derived organotypic cultures - PDOCs -). We have also used METPlatform to perform unbiased proteomics of brain metastases in situ to identify potential novel mediators of this disease and explore resistance mechanisms to targeted therapy. Finally, we have exploited METPlatform as “avatars” to predict response to therapy in patients with primary brain tumors. RESULTS We identified heat shock protein 90 (HSP90) as a promising therapeutic target for brain metastasis. DEBIO-0932, a blood-brain barrier permeable HSP90 inhibitor, shows high potency against mouse and human brain metastases from different primary origin and oncogenomic profile at clinically relevant stages of the disease, including a novel model of local relapse after neurosurgery. Furthermore, in situ proteomic analysis of brain metastases treated with the chaperone inhibitor revealed non-canonical clients of HSP90 as potential novel mediators of brain metastasis and actionable mechanisms of resistance driven by autophagy. Combined therapy using HSP90 and autophagy inhibitors showed synergistic effects compared to sublethal concentrations of each monotherapy, demonstrating the potential of METPlatform to design and test rationale combination therapies to target metastasis more effectively. Finally, we show that brain tumor PDOCs predict the response of the corresponding patient to standard of care, thus proving the potential of METPlatform for improving personalized care in cancer. CONCLUSION Our work validates METPlatform as a potent resource for metastasis research integrating drug-screening and unbiased omic approaches that is fully compatible with human samples and questions the rationale of excluding patients with brain metastasis from clinical trials. We envision that METPlatform will be established as a clinically relevant strategy to personalize the management of metastatic disease in the brain and elsewhere.

Pathogenesis of Peritumoral Hyperexcitability in an Immunocompetent CRISPR-Based Glioblastoma Model Hatcher A, Yu K, Meyer J, Aiba I, Deneen B, Noeb JL. J Clin Invest. 2020;130(5):2286-2300. doi:10.1172/JCI133316Seizures often herald the clinical appearance of gliomas or appear at later stages. Dissecting their precise evolution and cellular pathogenesis in brain malignancies could inform the development of staged therapies for these highly pharmacoresistant epilepsies. Studies in immunodeficient xenograft models have identified local interneuron loss and excess glial glutamate release as chief contributors to network disinhibition, but how hyperexcitability in the peritumoral microenvironment evolves in an immunocompetent brain is unclear. We generated gliomas in WT mice via in utero deletion of key tumor suppressor genes and serially monitored cortical epileptogenesis during tumor infiltration with in vivo electrophysiology and GCAMP7 calcium imaging, revealing a reproducible progression from hyperexcitability to convulsive seizures. Long before seizures, coincident with loss of inhibitory cells and their protective scaffolding, gain of glial glutamate antiporter xCT expression, and reactive astrocytosis, we detected local Iba1+ microglial inflammation that intensified and later extended far beyond tumor boundaries. Hitherto unrecognized episodes of cortical spreading depolarization that arose frequently from the peritumoral region may provide a mechanism for transient neurological deficits. Early blockade of glial xCT activity inhibited later seizures, and genomic reduction of host brain excitability by deleting microtubule-associated protein Tau suppressed molecular markers of epileptogenesis and seizures. Our studies confirmed xenograft tumor–driven pathobiology and revealed early and late components of tumor-related epileptogenesis in a genetically tractable, immunocompetent mouse model of glioma, allowing the complex dissection of tumor versus host pathogenic seizure mechanisms.