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There has been considerable scientific effort dedicated to understanding the biologic consequence and therapeutic implications of aberrant tryptophan metabolism in brain tumors and neurodegenerative diseases. A majority of this work has focused on the upstream metabolism of tryptophan; however, this has resulted in limited clinical application. Using global metabolomic profiling of patient-derived brain tumors, we identify the downstream metabolism of tryptophan and accumulation of quinolinate (QA) as a metabolic node in glioblastoma and demonstrate its critical role in promoting immune tolerance. QA acts as a metabolic checkpoint in glioblastoma by inducing NMDA receptor activation and Foxo1/PPARγ signaling in macrophages, resulting in a tumor supportive phenotype. Using a genetically-engineered mouse model designed to inhibit production of QA, we identify kynureninase as a promising therapeutic target to revert the potent immune suppressive microenvironment in glioblastoma. These findings offer an opportunity to revisit the biologic consequence of this pathway as it relates to oncogenesis and neurodegenerative disease and a framework for developing immune modulatory agents to further clinical gains in these otherwise incurable diseases. The upstream metabolism of tryptophan has been described as a metabolic node in glioblastoma. Here the authors show that the downstream metabolism of tryptophan, resulting in the accumulation of quinolinate in glioblastoma, contributes to pro-tumorigenic immune suppressive activation of macrophages.

Glioblastoma (GBM) tumor-associated macrophages (TAMs) provide a major immune cell population contributing to growth and immunosuppression via the production of proinflammatory factors, including IL-1. In this issue of the JCI, Chen, Giotti, and colleagues investigated loss of ll1b in the immune tumor microenvironment (TME) in GBM models driven by PDGFB expression and Nf1 knockdown. Survival was only improved in PDGFB-driven GBM models, suggesting that tumor cell genotype influenced the immune TME. IL-1β in the TME increased PDGFB-driven GBM growth by increasing tumor-derived NF-κB, expression of monocyte chemoattractants, and increased infiltration of bone marrow-derived myeloid cells (BMDMs). In contrast, no requirement for IL-1β was evident in Nf1-silenced tumors due to high basal levels of NF-κB and monocyte chemoattractants and increased infiltration of BMDM and TAMs. Notably, treatment of mice bearing PDGFB-driven GBM with anti-IL-1β or an IL1R1 antagonist extended survival. These findings suggest that effective clinical immunotherapy may require differential targeting strategies.

Mutational inactivation of the SWI/SNF chromatin regulator ATRX occurs frequently in gliomas, the most common primary brain tumors. Whether and how ATRX deficiency promotes oncogenesis by epigenomic dysregulation remains unclear, despite its recent implication in both genomic instability and telomere dysfunction. Here we report that Atrx loss recapitulates characteristic disease phenotypes and molecular features in putative glioma cells of origin, inducing cellular motility although also shifting differentiation state and potential toward an astrocytic rather than neuronal histiogenic profile. Moreover, Atrx deficiency drives widespread shifts in chromatin accessibility, histone composition, and transcription in a distribution almost entirely restricted to genomic sites normally bound by the protein. Finally, direct gene targets of Atrx that mediate specific Atrx-deficient phenotypes in vitro exhibit similarly selective misexpression in ATRX -mutant human gliomas. These findings demonstrate that ATRX deficiency and its epigenomic sequelae are sufficient to induce disease-defining oncogenic phenotypes in appropriate cellular and molecular contexts. ATRX inactivation frequently occurs in glioma. Here, the authors explore the role of ATRX inactivation in oncogenesis, highlighting ATRX deficiency driven epigenomic changes that influence the expression of genes crucial to the oncogenic phenotype.

Abstract The National Cancer Institute-led multidisciplinary Comparative Brain Tumor Consortium (CBTC) convened a glioma pathology board, comprising both veterinarian and physician neuropathologists, and conducted a comprehensive review of 193 cases of canine glioma. The immediate goal was to improve existing glioma classification methods through creation of a histologic atlas of features, thus yielding greater harmonization of phenotypic characterization. The long-term goal was to support future incorporation of clinical outcomes and genomic data into proposed simplified diagnostic schema, so as to further bridge the worlds of veterinary and physician neuropathology and strengthen validity of the dog as a naturally occurring, translationally relevant animal model of human glioma. All cases were morphologically reclassified according to a new schema devised by the entire board, yielding a majority opinion diagnosis of astrocytoma (43, 22.3%), 19 of which were low-grade and 24 high-grade, and oligodendroglioma (134, 69.4%), 35 of which were low-grade and 99 were high-grade. Sixteen cases (8.3%) could not be classified as oligodendroglioma or astrocytoma based on morphology alone and were designated as undefined gliomas. The simplified classification scheme proposed herein provides a tractable means for future addition of molecular data, and also serves to highlight histologic similarities and differences between human and canine glioma.

How malignant gliomas arise in a mature brain remains a mystery, hindering the development of preventive and therapeutic interventions. We previously showed that oligodendrocyte precursor cells (OPCs) can be transformed into glioma when mutations are introduced perinatally. However, adult OPCs rarely proliferate compared with their perinatal counterparts. Whether these relatively quiescent cells have the potential to transform is unknown, which is a critical question considering the late onset of human glioma. Additionally, the premalignant events taking place between initial mutation and a fully developed tumor mass are particularly poorly understood in glioma. Here we used a temporally controllable Cre transgene to delete p53 and NF1 specifically in adult OPCs and demonstrated that these cells consistently give rise to malignant gliomas. To investigate the transforming process of quiescent adult OPCs, we then tracked these cells throughout the premalignant phase, which revealed a dynamic multistep transformation, starting with rapid but transient hyperproliferative reactivation, followed by a long period of dormancy, and then final malignant transformation. Using pharmacological approaches, we discovered that mammalian target of rapamycin signaling is critical for both the initial OPC reactivation step and late-stage tumor cell proliferation and thus might be a potential target for both glioma prevention and treatment. In summary, our results firmly establish the transforming potential of adult OPCs and reveal an actionable multiphasic reactivation process that turns slowly dividing OPCs into malignant gliomas. Significance How malignant gliomas arise in a mature brain remains a mystery, which hinders the development of effective treatments. Which cell types can escape their quiescent, adult state and how they do so is unknown. Additionally, because gliomas are only detected at advanced stages, the full course of transformation remains uncharacterized. Here we report that adult oligodendrocyte precursor cells, despite their relatively quiescent properties, can be reactivated to a highly proliferative state by p53 and NF1 mutations and give rise to malignant gliomas. Furthermore, we describe the early phase of gliomagenesis for the first time, revealing a multistep process of reactivation, dormancy, and final transformation in which mammalian target of rapamycin signaling plays a critical role at both early and late steps.

Glioblastoma (GBM) represents an aggressive and immune-resistant cancer. Preclinical investigations have identified anti-tumor activity of a ketogenic diet (KD) potentially being used to target GBM’s glycolytic phenotype. Since immune cells in the microenvironment have a similar reliance upon nutrients to perform their individual functions, we sought to determine if KD influenced the immune landscape of GBM. Consistent with previous publications, KD improved survival in GBM in an immune-competent murine model. Immunophenotyping of tumors identified KD-influenced macrophage polarization, with a paradoxical 50% increase in immune-suppressive M2-like-macrophages and a decrease in pro-inflammatory M1-like-macrophages. We recapitulated KD in vitro using a modified cell culture based on metabolomic profiling of serum in KD-fed mice, mechanistically linking the observed changes in macrophage polarization to PPARγ-activation. We hypothesized that parallel increases in M2-macrophage polarization tempered the therapeutic benefit of KD in GBM. To test this, we performed investigations combining KD with the CSF-1R inhibitor (BLZ945), which influences macrophage polarization. The combination demonstrated a striking improvement in survival and correlative studies confirmed BLZ945 normalized KD-induced changes in macrophage polarization. Overall, KD demonstrates antitumor activity in GBM; however, its efficacy is attenuated by promoting an immunosuppressive phenotype in macrophages. Combinatorial strategies designed to modulate macrophage polarization represent a rational approach to improve the anti-tumor activity of KD in GBM.

Transdifferentiation (TD) is a recent advancement in somatic cell reprogramming. The direct conversion of TD eliminates the pluripotent intermediate state to create cells that are ideal for personalized cell therapy. Here we provide evidence that TD-derived induced neural stem cells (iNSCs) are an efficacious therapeutic strategy for brain cancer. We find that iNSCs genetically engineered with optical reporters and tumouricidal gene products retain the capacity to differentiate and induced apoptosis in co-cultured human glioblastoma cells. Time-lapse imaging shows that iNSCs are tumouritropic, homing rapidly to co-cultured glioblastoma cells and migrating extensively to distant tumour foci in the murine brain. Multimodality imaging reveals that iNSC delivery of the anticancer molecule TRAIL decreases the growth of established solid and diffuse patient-derived orthotopic glioblastoma xenografts 230- and 20-fold, respectively, while significantly prolonging the median mouse survival. These findings establish a strategy for creating autologous cell-based therapies to treat patients with aggressive forms of brain cancer. Neural stem cells have a tropism for glioblastoma. Here the authors employ fibroblasts directly reprogrammed into induced neural stem cells and loaded with cytotoxic molecules to migrate to xenotransplanted brain tumours in mice, achieving tumour shrinkage and prolonged survival.

Features of eosinophilic esophagitis (EoE) and gastroesophageal reflux disease (GERD) overlap. We aimed to determine whether staining for tissue biomarkers would differentiate EoE from GERD, suggesting utility for diagnosis of EoE. In this case-control study, EoE patients defined by consensus guidelines were compared to GERD patients with eosinophils on esophageal biopsy. Immunohistochemistry was performed for major basic protein (MBP), eotaxin-3, leukotriene A4 hydrolase (LTA4H), and leukotriene C4 synthase (LTC4S). After masking, the maximum staining density (cells per mm(2)) was quantified for each marker and compared between groups. Receiver operator characteristic curves were constructed, and the area under the curve (AUC) calculated to assess the diagnostic utility of each of the biomarkers alone and in combination with eosinophil counts. There were 51 EoE cases (mean age 24; mean 143 eosinophils per high-power field (eos per h.p.f.)) and 54 GERD controls (mean age 34; mean 20 eos per h.p.f.). The MBP density was higher in EoE than in GERD (1479 vs. 59 cells per mm(2); P<0.001), as was the eotaxin-3 density (2219 vs. 479; P<0.001). There were no differences for LTA4H and LTC4S. MBP density and eosinophil count correlated (R=0.81; P<0.001); correlation with eotaxin-3 was weaker (R=0.25; P=0.01). The AUC for diagnosis of EoE was 0.96 for MBP, 0.87 for eotaxin-3, 0.58 for LTA4H, 0.66 for LTC4S, and 0.99 for the combination of MBP, eotaxin-3, and eosinophil count. Patients with EoE had substantially higher levels of MBP and eotaxin-3 staining than GERD patients. These markers may have utility as a diagnostic assay for EoE.

Almost all Glioblastoma (GBM) are either intrinsically resistant to the chemotherapeutical drug temozolomide (TMZ) or acquire therapy-induced mutations that cause chemoresistance and recurrence. The genome maintenance mechanisms responsible for GBM chemoresistance and hypermutation are unknown. We show that the E3 ubiquitin ligase RAD18 (a proximal regulator of TLS) is activated in a Mismatch repair (MMR)-dependent manner in TMZ-treated GBM cells, promoting post-replicative gap-filling and survival. An unbiased CRISPR screen provides an aerial map of RAD18-interacting DNA damage response (DDR) pathways deployed by GBM to tolerate TMZ genotoxicity. Analysis of mutation signatures from TMZ-treated GBM reveals a role for RAD18 in error-free bypass of O 6 mG (the most toxic TMZ-induced lesion), and error-prone bypass of other TMZ-induced lesions. Our analyses of recurrent GBM patient samples establishes a correlation between low RAD18 expression and hypermutation. Taken together we define molecular underpinnings for the hallmark tumorigenic phenotypes of TMZ-treated GBM. Glioblastoma (GBM) is refractory to the chemotherapeutic genotoxin temozolomide (TMZ). Here, the authors show that GBM cells deploy RAD18-mediated Trans-Lesion Synthesis to promote error-free repair of TMZ-induced O 6 mG DNA lesions and avert lethality.

The C-terminal binding protein (CtBP) is a NADH-dependent transcriptional repressor that links carbohydrate metabolism to epigenetic regulation by recruiting diverse histone-modifying complexes to chromatin. Here global profiling of CtBP in breast cancer cells reveals that it drives epithelial-to-mesenchymal transition, stem cell pathways and genome instability. CtBP expression induces mesenchymal and stem cell-like features, whereas CtBP depletion or caloric restriction reverses gene repression and increases DNA repair. Multiple members of the CtBP-targeted gene network are selectively downregulated in aggressive breast cancer subtypes. Differential expression of CtBP-targeted genes predicts poor clinical outcome in breast cancer patients, and elevated levels of CtBP in patient tumours predict shorter median survival. Finally, both CtBP promoter targeting and gene repression can be reversed by small molecule inhibition. These findings define broad roles for CtBP in breast cancer biology and suggest novel chromatin-based strategies for pharmacologic and metabolic intervention in cancer. Diabetes and obesity pose an increased risk for breast cancer; however, the reasons for this link remain unclear. Di et al. provide evidence that CtBP, a metabolically regulated transcriptional repressor, regulates a gene network that is selectively downregulated in more aggressive forms of breast cancer.