About

Daniel J. Brat, MD, PhD, is the Magerstadt Professor and Chair of the Department of Pathology at Northwestern University Feinberg School of Medicine. He also serves as the Pathologist-in-Chief at Northwestern Memorial Hospital. His role involves leading the department and overseeing its various research and clinical activities. The page highlights his leadership position and academic titles but does not provide specific details about his research focus, background, or key contributions.

Research topics

• Biology
• Medicine
• Computer Science
• Pathology
• Information Retrieval
• Genetics
• Computational biology
• Neuroscience
• Zoology
• Evolutionary biology
• Bioinformatics
• Ecology

Selected publications

• Abstract 1150: Combining CDK4/6 inhibitor with TMZ and radiation alters cell states for synergistic responses in orthotopic DIPG models

  Cancer Research · 2026-04-03

  article

  Abstract Background: To develop effective therapies for DIPG at different clinical stages, we examined efficacy and mechanisms of action of a combination therapy—abemaciclib (a CDK4/6 inhibitor), temozolomide (TMZ), and radiation (XRT)—in two patient-derived orthotopic xenograft (PDOX) models derived from treatment-naïve (IBs-9119DIPG) and autopsied (IBs-A0317DIPG) tumors. Methods: In vitro synergistic anti-tumor activities were examined in tumor organoids, and in vivo efficacy in the PDOX models treated with abemaciclib (75 mg/Kg × 14 days), TMZ (50 mg/Kg × 5 days) and XRT (2 Gy/day × 5 days) alone and in combination (n=10/group, 60 mice/model). Changes of animal survival times were analyzed with log-rank analysis. Mechanisms of treatment response and resistance were elucidated by immunohistochemistry and scRNA-seq analysis. Results: The triple therapy generated synergistic anti-tumor effects in organoids and significantly extended survival times in both PDOX models (P<0.05) despite their strong cellular state differences. scRNAseq identified reduction of oligodendrocyte-progenitor-like (OPC-like) cells in both models and astrocyte-like (AC-like) cells in IBs-A0317DIPG as response mediators; and revealed expansion of neural progenitor-like (NPC-like) cells in IBs-A0317DIPG and of mesenchymal-like (MES-like) and mitotic-like cells in IBs-9119DIPG as resistance contributors. Pseudotime trajectory analysis uncovered the exit of stemness into differentiation in oligodendrocyte-progenitor-like (OPC-like) cells as a novel mechanism of resistance in the treatment-naïve IBs-9119DIPG, in contrast to the enrichment of stem-like cells in the recurrent model IBs-A0317DIPG. A radiation-resistant subpopulation with novel candidate targets (NPAS3, TBC1D5, INPP4B) was also discovered. Conclusions: This study demonstrated strong anti-DIPG capacities of the triple therapy in both untreated and recurrent DIPG tumors by acting on distinct cellular and molecular targets, and identifies previously unrecognized mechanisms underlying DIPG therapy response and resistance. Citation Format: Zilu Huang, Tongchao Jiang, Milagros M. Suarez Palacios, Tommy Ouyang, Aalaa Abdallah, Long Niu, Jinnan Chen, Xin Zhai, Emily Ciolak, Wenan Qiang, Runxin Wu, Nitin Wadhwani, Alicia Lenzen, Michael DeCuypere, Sandi Lam, Shi-Yuan Cheng, Ching Man Wai, Brian Wray, Matthew John Schipma, Xinkun Wang, Wan-Yee Teo, Daniel J. Brat, Yuchen Du, Yunfei Xia, Xiao-Nan Li, John Kalapurakal. Combining CDK4/6 inhibitor with TMZ and radiation alters cell states for synergistic responses in orthotopic DIPG models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1150.

  PublisherDOI

• Abstract 2496: <i>In silico</i> screening of therapeutics candidates targeting minimal residual disease in glioblastoma

  Cancer Research · 2026-04-03

  article

  Abstract Background: Glioblastoma recurrence is inevitable despite aggressive surgical resection of contrast enhancing (CE) tumor. Unlike the deep molecular characterization of CE glioblastoma, unresected infiltrating tumor, representing minimal residual disease (MRD) has not been well profiled. Increasingly, clinical trials are being conducted in the MRD setting for glioblastoma patients, necessitating understanding of unresected infiltrating tumor for targeted therapeutic development. Methods: Visium HD spatial transcriptomics was used to profile a cohort of newly diagnosed, treatment-naïve glioblastoma patients that underwent supramaximal resection, with both core and infiltrating in situ components. Spatial profiles generated expression signatures of infiltrative and CE tumor. For in silico prediction of therapeutics targeting the MRD, expression signatures of infiltrative and CE tumor were compared with drug perturbation signatures from the NIH L1000 database using the sRGES method to predict reversal of disease expression patterns. IC50 data from human cell lines were aggregated from the Genomics of Drug Sensitivity in Cancer or individual study data while blood-brain barrier (BBB) penetrance was predicted using the CNS-MPO approach. Findings: Infiltrative tumor expression profiles were enriched for genes corresponding to neural and oligodendrocyte progenitor like cells. In contrast CE glioblastoma displayed mesenchymal and astrocytic programs, suggesting spatial concentration of glioblastoma states within MRD and CE tumor. For CE glioblastoma, proteasome inhibitors and glucocorticoid receptor agonists were predicted to have the highest antitumor activity. In contrast, histone deacetylase inhibitors (HDACi) were highly ranked for MRD while exhibiting low predicted efficacy in CE tumor. Synergy analysis of drug candidates provided multiple dual treatment options for both the CE and MRD contexts. Conclusions: Cumulatively, these data indicate that the resected tumor does not reflect the MRD state, providing clarity on why targeted therapeutics for glioblastoma have not been particularly successful. Spatial profiling of the MRD demonstrates vulnerability to unique drug targets, which if utilized in the correct setting could confer greater survival benefit. Citation Format: Harrshavasan Congivaram, Shashwat Tripathi, Mateo Gomez, Katy McCortney, Ching Man Wai, Ruochen Du, Thomas K. Sears, Jianzhong Zhang, Daniel J. Brat, Craig M. Horbinski, Mark W. Youngblood, Jared T. Ahrendsen, Adam M. Sonabend, Stephen T. Magill, Matthew C. Tate, Maciej S. Lesniak, Sean Sachdev, Timothy Sita, Priya Kumthekar, Karan Dixit, Robin Buerki, Ditte Primdahl, Mustafa Khasraw, John de Groot, David A. Reardon, Rimas V. Lukas, Roger Stupp, Amy B. Heimberger. In silico screening of therapeutics candidates targeting minimal residual disease in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2496.

  PublisherDOI

• Comparative pathology boards facilitate the translation of knowledge between canine and human cancer patients

  Brain Pathology · 2025-05-05

  letterOpen access

  Comparative pathology boards bring together anatomic pathologists with expertise in canine and human histology to identify shared features, including immune or TME components, tumor subtypes, or prognostic tissue biomarkers. This article summarizes feedback to improve future initiatives and enhance the translational relevance of comparative oncology for human patients. Comparative pathology boards (CPBs) bring together anatomic pathologists with expertise in canine (DVM) and human (MD) pathology to perform parallel review of canine tissue histology. CPB objectives can include characterization of tumor subtypes or identification of tissue-based biomarkers with potential relevance for human patients (Figure S1). The National Cancer Institute's Comparative Oncology Program (COP) has supported three CPBs. These efforts originated within the Comparative Brain Tumor Consortium, which aimed to establish the relevance of the tumor-bearing pet dog in human neuro-oncology research [1]. With the goal of improving future CPB initiatives, an online survey of COP CPB pathologists was conducted using Research Electronic Data Capture [2]. Twenty-one responses were received from the glioma (n = 10; seven DVM, three MD), meningioma (n = 9; six DVM, three MD), and osteosarcoma CPBs (n = 2; one MD, one DVM; Figure 1A). Because the study conditions varied, results are independently reported by CPB. Four veterinary pathologists with neuropathology expertise participated in both the glioma and meningioma CPBs. No MD pathologists were on more than one CPB. Responses from the osteosarcoma CPB are included within the text but omitted from graphs. All survey respondents agreed or strongly agreed that the mixed composition (MD + DVM) was a strength of the COP CPB process. Although human grading systems have been applied to multiple canine cancer types including meningioma [3], input from both sides allows researchers to better understand how canine cancers mimic or differ from their human counterparts. For example, MD-trained pathologists on the glioma CPB were significantly less likely to report infiltration and necrosis or to diagnose oligodendrogliomas compared to DVM-trained pathologists [4]. This may be reflective of how histologic features present in canine gliomas or differences in tumor type caseload across professions. Furthermore, MD-trained pathologists routinely incorporate molecular data in their diagnosis, which is not a standard component of the current veterinary workflow. Identifying and understanding these differences is key to defining the value of the tumor-bearing pet dog in comparative research. Engaging pathologists with varied backgrounds provides different perspectives to the CPB. Most respondents described their career focus as a mixture of diagnostic pathology and applied research (Figure S2). The glioma CPB included both board-certified pathologists and pathology residents engaged in PhD doctoral research [4]. Building a solid backbone with strong subject matter expertise is critical for CPB success and for buy-in following publication. In addition, CPB pathologists must confidently share their opinions on a tumor, which can be difficult for some, such as early career pathologists. Conversely, early career pathologists can bring a new perspective and may be more open to reevaluating their approach. Review of whole-slide images over traditional glass slides streamlines the CPB process. All CPB members reported using digital slides previously, but most reviewed them infrequently (Figure 1B), highlighting the importance of software training sessions. Slow loading time was a common challenge (Figure 1C,D). Storing scans on a publicly available database rather than using hard drives should be considered, although it would be important to have a method for pathologists to annotate tissues without biasing others. During the review, mitoses were considered the most difficult feature to assess (Figure 1E). Other features reported as difficult to evaluate included inflammation and macronuclei (meningioma CPB; Figure 1F). Access to high-resolution monitors may help. Literature review can also be invaluable; for example, mitotic figure references may help improve confidence and interpretation in digital slides [5]. Histologic features with higher subjectivity are particularly problematic, underscoring the importance of iterative case review and pre-review meetings to refine morphologic criteria, increase interobserver agreement, and improve reproducibility of grading systems. Clear messaging regarding the time commitment for CPB participation is critical for member recruitment and retention. Although reviewing different features, most CPB members reported spending 5–15 min per case (Figure 2A). This gives future CPBs a meaningful benchmark by which to request pathologists' participation. Considering that CPBs may review 100–200 cases, the review alone can take up to 50 h. This is in addition to pre-review training, post-review discussion, and publication efforts. Members of the glioma CPB, which has already published their findings [1, 4], estimated a total of >60 h (Figure 2B). However, few pathologists reported receiving time off service to support CPB activities (Figure 2C). Because the CPB requires a substantial time commitment and perseverance, it is important to consider individuals with a proven track record of productive collaborative work and an ability to complete projects in a timely manner. This is compounded by the need to complete reviews efficiently to prevent diagnostic drift. Taken together, time constraints remain a critical challenge. Methods to reduce this burden moving forward should be considered, including the use of digital pathology analyses and AI algorithms which can be developed based on consensus CPB annotations. Although the COVID19 pandemic has greatly altered the collaborative science landscape with a push toward virtual meetings, most members preferred a combination of in-person and virtual meetings (Figure 2D). In-person meetings are an opportunity to discuss the cross-species landscape of disease and outline goals which should be reiterated throughout the trajectory of the CPB. While many pathologists are familiar with individuals within their own specialty, an in-person meeting allows formal introductions of members and their backgrounds and enables interactions between fields; this facilitates research collaborations beyond the CPB. The glioma CPB convened an in-person kickoff meeting which was positively received by members as a welcomed opportunity to exchange ideas and experiences. All CPBs have utilized virtual meetings to discuss histopathology and update classification systems prior to case review. A post-review in-person meeting can also be useful for discussing disparate features or defining a CPB consensus diagnosis to evaluate against outcome or ancillary data. Compiling clinical metadata in advance of the slide review helps shape the best dataset. The suggested minimum requirement includes clinical data and immunohistochemistry (Figure 2E). Retrospective studies may have cases with different treatments and incomplete clinical details or outcome measures, which affect the study's ability to assign prognostic value to histologic features. Canine clinical trials offer a more straightforward method to examine histology against outcome. Inclusion of additional molecular adjuncts is more likely to uncover canine subpopulations with significant relevance to human patients; examples include the identification of similar subgroups in human and canine meningiomas through methylation profiling and RNA sequencing [6, 7]. All survey takers agreed or strongly agreed that they would recommend CPB participation to a colleague (Figure 2F). Most DVM-trained survey participants agreed or strongly agreed that their institution viewed their participation on the CPB favorably (Figure 2G) and included it in promotion or performance evaluations. Several also requested letters of support from the COP. In contrast, most MD-trained pathologists neither agreed nor disagreed, and none requested letters of support or specifically mentioned the CPB in performance evaluations, suggesting that CPB participation was less significant to their career development. As such, it is important that efforts are made to ensure that MD-trained pathologists benefit from their involvement, including ensuring that their views are incorporated and that CPB goals are sufficiently comparative in nature. When animals are proposed as models for human diseases, there is value in convening a CPB to assess the underlying histology and define features shared with human patients. Future CPBs should prioritize diseases for which animal models are most needed. Although our work was initiated in brain tumors [1, 4], we have expanded to osteosarcoma, which is estimated to occur 10 times more frequently in canine compared to pediatric patients, underscoring its value as a model and biospecimen resource [8]. Other canine cancers reviewed by teams of MD- and DVM-trained pathologists include melanoma [9], urothelial carcinoma [10], and soft tissue tumors [11]. Collecting feedback from additional pathologists from different institutions and in different disease contexts will be important for establishing the value of CPBs and for outlining goals for future studies in this space. These interdisciplinary efforts support the use of canine clinical trials and tissue biospecimens to further canine cancer research while enhancing the translational relevance of comparative oncology for human patients. All authors participated in the COP's CPBs. JAB wrote the initial manuscript draft. All authors reviewed and approved the final draft. We would like to acknowledge the pathologists that supported the Comparative Brain Tumor Consortium and glioma CPB (Veterinary: Jey Koehler, Andrew Miller, Brian Porter, Jessica Beck, Ingrid Cornax, Kara Corps, Chad Frank, M. Gerard O'Sullivan, Dan R. Rissi, R. Mark Simpson, Kevin Woolard; and MD-trained: C. Ryan Miller, Kenneth Aldape, Daniel Brat, Caterina Giannini, Craig Horbinski, Jason Huse), meningioma CPB (Veterinary: Molly Church, Andrew Miller, Sara Belluco, Kara Corps, Jey Koehler, Kaspar Matiasek, Daniel Rissi; and MD-trained: Kenneth Aldape, Mireille Bitar, Rati Chkheidze, Joanna Phillips, Sharika Rajan, Anat Stemmer-Rachamimov, Stephen Yip), and osteosarcoma CPB (Veterinary: Courtney Schott; MD-trained: Jonathan Bush). We would also like to thank Erika Berger for her assistance with REDCap. Figure 1C, Supplemental Figure 1, and the graphical abstract were created with BioRender.com. This work was supported by the Intramural Program of the National Cancer Institute, NIH (Z01-BC006161). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government. The authors declare that they have no competing interests. The data that support the findings of this study are available from the corresponding author upon reasonable request. Data S1. Supporting Information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

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• Development, validation, and utility of a clinically applicable methylation classifier for recurrence risk prediction in meningiomas

  Research Square · 2025-08-11

  preprintOpen access
  PublisherDOI

• 1526 Predicting Meningioma Recurrence with Methylation Profiling

  Laboratory Investigation · 2025-03-01

  articleOpen access
  PublisherOA PDFDOI

• TMIC-03. The Hypoxic Peri-necrotic Niche of Glioblastoma Drives TAM Polarization and Immunosuppression Through CLEC5A Activation by Podoplanin

  Neuro-Oncology · 2025-11-01

  articleOpen accessSenior author

  Abstract Glioblastoma, IDH-wildtype (GBM, WHO grade 4), is the most aggressive primary brain tumor in adults and is characterized by a severely hypoxia, necrosis, and a highly immunosuppressive tumor microenvironment (TME). Bone marrow-derived tumor-associated macrophages (TAMs) are the predominant immune population and accumulate within hypoxic peri-necrotic regions, where they adopt immunosuppressive phenotypes. Through integrated spatial, transcriptional, and functional analyses, we identified C-type lectin domain family 5 member A (CLEC5A) as the immune-related gene most strongly associated with poor prognosis in GBM. CLEC5A regulates immune responses in inflammatory and infectious diseases. However, its role in GBM immune regulation remain unclear. CLEC5A is upregulated in hypoxic TAMs, promotes their migration and immunosuppressive phenotype polarization, and enhances the secretion of immunosuppressive cytokines. Adoptive bone marrow transplantation from CLEC5A-deficient donors significantly extended survival in RCAS/tv-a mouse model, decreased the infiltration and immunosuppressive polarization of TAMs, further diminished the exhausted T cells, demonstrating the critical role of CLEC5A in TAM-mediated immunosuppression. Mechanistically, CLEC5A is activated via direct binding to podoplanin (PDPN) expressed on hypoxic glioma cells, which triggers Syk-JAK-STAT3 signaling in TAMs. Targeting this axis through CLEC5A or PDPN silencing, or Syk pharmacologic inhibition, reduced TAM infiltration and polarization, delayed tumor growth, improved T cell function and prolonged survival in orthotopic and genetically engineered mouse models. Co-immunoprecipitation and blocking (PDPN blocking antibody, α-PDPN) assays confirmed a direct PDPN-CLEC5A interaction. Collectively, these findings establish the PDPN-CLEC5A-Syk-JAK-STAT3 pathway as a central regulator of the immunosuppressive TME in GBM and nominate CLEC5A/Syk as promising therapeutic targets to improve patient outcomes.

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• Targeting Survivin: Now I Become Death, the Destroyer of Cells

  International Journal of Molecular Sciences · 2025-11-26

  reviewOpen access

  5) plays a key role in inhibiting apoptosis and is highly expressed in many cancers, including gliomas and breast cancer, where it contributes to tumor progression, therapeutic resistance and poor patient outcomes. With a dual function in promoting cell proliferation and survival, coupled with its potential immunogenicity, survivin is a compelling therapeutic target for cancer; yet, it has no FDA-approved agents to date. Here, we review key findings from preclinical models that emphasize how survivin contributes to chemoresistance and radioresistance; summarize the clinical landscape of survivin-targeted strategies, highlighting both the successes and limitations of these approaches; and outline next steps to optimize survivin-targeted therapies, including the need to integrate biomarker-focused patient selection and the potential for combination therapies. These insights establish survivin as a key driver of cancer progression and a promising target for future therapeutic development.

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• CNSC-83. A CHARACTERIZATION OF QUIESCENCE AND STEMNESS IN PATIENT-DERIVED GLIOBLASTOMA CELLS

  Neuro-Oncology · 2025-11-01

  articleOpen accessSenior author

  Abstract This project seeks to improve understanding of glioblastoma recurrence and resistance, which has often been linked to a population of cells that are quiescent and have stem-like properties, so that better treatment modalities can be developed for the most aggressive primary CNS cancer. In particular, this paper seeks to quantify stem cells, quiescent cells, and their overlap in normoxia, hypoxia, and under other conditions associated with the tumor microenvironment. We have utilized Fluorescent Ubiquitination-based Cell Cycle Indicator (FUCCI) along with Ki-67 and P27 staining in patient-derived glioblastoma neurospheres to identify a G0 phase along with other key points in the cell cycle, and co-stained with CD133 and CD44 to identify glioblastoma stem cells (GSCs). Using this system, we found that both quiescence and stemness were significantly increased in hypoxia and under co-culture with THP-1 monocytes. There was also a significant increase in the percentage of quiescent cells under hypoxia for the subpopulation of cells that were identified as stem cells. Interestingly, there was a significant decrease in the percentage of quiescent cells from the entire cell population compared to the subpopulation that was identified as stem cells. When various stages of the cell cycle were looked at for stem cell enrichment, there was a significantly higher percentage of stem cells in the G1/S phase as compared to all of the other stages of the cell cycle. Overall, this research shows a shift towards quiescence and stemness individually under both hypoxia and monocyte coculture, but a weak overlap between the two. The distribution of stem cells among the various stages of the cell cycle could also indicate that stemness is increased when glioblastoma cells re-enter the cell cycle, rather than co-existing with quiescence, as is commonly believed. Further work needs to follow these changes with treatment and understand their mechanistic underpinnings.

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• IMMU-07. Synergistic STING activation in meningioma neoplastic and immune populations triggers programmed necrosis and modulates the collagen-rich immunosuppressive microenvironment

  Neuro-Oncology · 2025-11-01

  articleOpen access

  Abstract Despite recent progress in elucidating the molecular events underlying meningioma aggressiveness, there remain no established adjuvant therapies for tumors that are intractable to surgery and radiation. Using integrated approaches of single-cell RNA/ATAC-seq, spatial multiprotein immunofluorescence, and bulk RNA-seq and methylation profiling, we identify widespread expression of STING across multiple cell populations within the meningioma microenvironment. In contrast to other brain tumors such as glioma, meningioma neoplastic cells exhibited increased chromatin accessibility and promoter hypomethylation, associated with robust STING expression across WHO grades and DNA methylation subgroups. Treatment of freshly resected human meningiomas with the STING agonist 8803 induced direct cytotoxicity within 72 hours, even after removal of CD45+ immune cells. Pharmacologic inhibitors and transcriptional profiling revealed an association of programmed necrotic cell death pathways with 8803 efficacy, including partial dependence on reactive oxygen species production. Proteolytic maturation of the pore-forming protein gasdermin D on meningioma cancer cells contributed to 8803-induced cytotoxicity, and resulted in release of pro-inflammatory damage-associated molecular pattern molecules that further potentiated innate immune cell activation through toll-like receptors. STING activation via 8803 reduced meningioma volume across four preclinical murine models, and significantly improved survival after intracranial tumor treatment. These therapeutic effects were associated with marked immunological tumor infiltration and cytotoxicity, tumor stromal remodeling through macrophage elaborated metalloproteinases, and downregulation of the TIM3 and LAIR1 dominant mechanisms of meningioma-mediated immune suppression. Our results reveal widespread synergistic expression of STING in neoplastic and myeloid populations in meningioma, identify novel mechanisms of STING cytotoxicity in tumor cells, suggest a role for STING activation in degradation of collagen-rich tumor microenvironments, and clarify a new treatment indication for the STING agonist 8803.

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• TMIC-95. Hypoxic Tumor Microenvironment Promotes Hippo Pathway Transcriptional Activity to Enrich Glioma Stem Cells in the Peri-necrotic Niche of Glioblastoma

  Neuro-Oncology · 2025-11-01

  articleOpen accessSenior author

  Abstract Glioblastoma (GBM) is an aggressive brain tumor with poor prognosis, marked by extensive necrosis and enrichment of tumor-associated macrophages (TAMs) and glioma stem cells (GSCs) in peri-necrotic regions. Analysis of Ivy-GAP and single-cell RNA-seq data revealed elevated Hippo pathway transcriptional activity in the hypoxic peri-necrotic niche despite low expression of canonical stemness factors like SOX2, OLIG2, and FOXM1. We hypothesize that Hippo activation supports GSC maintenance through hypoxia and TAM-derived cytokines. In patient-derived GBM neurospheres, 1% hypoxia increased nuclear YAP1/TAZ and CYR61 expression. Zyxin (Zyx), a potential upstream regulator, was upregulated and phosphorylated under hypoxia. AKT, previously known to phosphorylate Zyx and be regulated by hypoxia, was also activated, suggesting hypoxia promotes Zyx phosphorylation and YAP/TAZ nuclear translocation via AKT. AKT inhibition with Capivasertib reduced Zyx phosphorylation and Hippo transcription in hypoxia. Conditioned media from primary macrophages activated Hippo signaling in GBM cells. NicheNetR identified TGF-β1 as a hypoxia-specific TAM-derived cytokine promoting malignant gene programs. Exogenous TGF-β1 increased CYR61, while TGFBR2 expression is elevated under hypoxia. Blocking TGFBR2 with inhibitor LY2109761 abolished TGF-β1-induced Hippo activation. Hypoxia and TGF-β1 synergistically enhanced GSC maintenance in limiting dilution assays. In vivo, pharmacologic inhibition of YAP/TAZ with Verteporfin or genetic TAZ knockdown in the RCAS/tv-a mouse model reduced tumor burden and prolonged survival. Flow cytometry confirmed decreased CD133+/CD44+ GSCs in TAZ-deficient tumors. These results demonstrate hypoxia and TGF-β1 signaling to activate YAP/TAZ-driven Hippo signaling, promoting GSC maintenance in the peri-necrotic GBM niche.

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Recent grants

• NIH Grant R01NS053727

  NIH · $1.7M · 2011

• Winship Cancer Institute Cancer Center Support Grant

  NIH · $48.7M · 2009–2028

• Identification and targeting of mechanisms specific to glioma stem cells in glioblastoma

  NIH · $1.8M · 2018–2024

• NIH Grant K08NS042934

  NIH · $729k · 2006

• NIH Grant R01CA176659

  NIH · $2.3M · 2019

Frequent coauthors

• Daniel T. Chang

  400 shared

• Michael Weller

  University Hospital of Zurich

  385 shared

• Mark R. Gilbert

  University of Missouri

  359 shared

• Erik P. Sulman

  New York University

  330 shared

• Olivier Gevaert

  303 shared

• Tali Mazor

  University of California, San Francisco

  302 shared

• Lih‐Shen Chin

  Shanghai University of Traditional Chinese Medicine

  302 shared

• Robert H. Bell

  Durham University

  300 shared