bims-malgli 2023-10-01 papers

bims-malgli

Biomed News

on Biology of malignant gliomas

Issue of 2023‒10‒01
twelve papers selected by
Oltea Sampetrean, Keio University

H3K27M Vaccine Appears Safe and Immunogenic in Diffuse Midline Glioma.
RANO 2.0: Update to the Response Assessment in Neuro-Oncology Criteria for High- and Low-Grade Gliomas in Adults.
Alterations in EGFR and PDGFRA are associated with the localization of contrast-enhancing lesions in glioblastoma.
Phase II trial of concurrent sunitinib, temozolomide, and radiotherapy with adjuvant temozolomide for newly diagnosed MGMT unmethylated glioblastoma.
BCAT1 regulates glioblastoma cell plasticity and contributes to immunosuppression.
Crosstalk between PARN and EGFR-STAT3 Signaling Facilitates Self-Renewal and Proliferation of Glioblastoma Stem Cells.
Multiplexed single-cell lineage tracing of mitotic kinesin inhibitor resistance in glioblastoma.
Pooled genetic screens to identify vulnerabilities in TERT-promoter-mutant glioblastoma.
Integrated molecular and multiparametric MRI mapping of high-grade glioma identifies regional biologic signatures.
Magnetic resonance imaging of iron metabolism with T2* mapping predicts an enhanced clinical response to pharmacological ascorbate in patients with GBM.
White Matter Tract Density Index Prediction Model of Overall Survival in Glioblastoma.
Metabolic and epigenetic reprogramming in the pathogenesis of glioblastoma: Toward the establishment of "metabolism-based pathology".

Cancer Discov. 2023 Sep 29. OF1

H3K27M Vaccine Appears Safe and Immunogenic in Diffuse Midline Glioma.

An H3K27M-specific vaccine was tolerable and immunogenic in patients with diffuse midline glioma (DMG).

DOI: https://doi.org/10.1158/2159-8290.CD-RW2023-155
J Clin Oncol. 2023 Sep 29. JCO2301059

RANO 2.0: Update to the Response Assessment in Neuro-Oncology Criteria for High- and Low-Grade Gliomas in Adults.

Patrick Y Wen, Martin van den Bent, Gilbert Youssef, Timothy F Cloughesy, Benjamin M Ellingson, Michael Weller, Evanthia Galanis, Daniel P Barboriak, John de Groot, Mark R Gilbert, Raymond Huang, Andrew B Lassman, Minesh Mehta, Annette M Molinaro, Matthias Preusser, Rifaquat Rahman, Lalitha K Shankar, Roger Stupp, Javier E Villanueva-Meyer, Wolfgang Wick, David R Macdonald, David A Reardon, Michael A Vogelbaum, Susan M Chang.

PURPOSE: The Response Assessment in Neuro-Oncology (RANO) criteria for high-grade gliomas (RANO-HGG) and low-grade gliomas (RANO-LGG) were developed to improve reliability of response assessment in glioma trials. Over time, some limitations of these criteria were identified, and challenges emerged regarding integrating features of the modified RANO (mRANO) or the immunotherapy RANO (iRANO) criteria.METHODS: Informed by data from studies evaluating the different criteria, updates to the RANO criteria are proposed (RANO 2.0).
RESULTS: We recommend a standard set of criteria for both high- and low-grade gliomas, to be used for all trials regardless of the treatment modalities being evaluated. In the newly diagnosed setting, the postradiotherapy magnetic resonance imaging (MRI), rather than the postsurgical MRI, will be used as the baseline for comparison with subsequent scans. Since the incidence of pseudoprogression is high in the 12 weeks after radiotherapy, continuation of treatment and confirmation of progression during this period with a repeat MRI, or histopathologic evidence of unequivocal recurrent tumor, are required to define tumor progression. However, confirmation scans are not mandatory after this period nor for the evaluation of treatment for recurrent tumors. For treatments with a high likelihood of pseudoprogression, mandatory confirmation of progression with a repeat MRI is highly recommended. The primary measurement remains the maximum cross-sectional area of tumor (two-dimensional) but volumetric measurements are an option. For IDH wild-type glioblastoma, the nonenhancing disease will no longer be evaluated except when assessing response to antiangiogenic agents. In IDH-mutated tumors with a significant nonenhancing component, clinical trials may require evaluating both the enhancing and nonenhancing tumor components for response assessment.
CONCLUSION: The revised RANO 2.0 criteria refine response assessment in gliomas.

DOI: https://doi.org/10.1200/JCO.23.01059
Neurooncol Adv. 2023 Jan-Dec;5(1):5(1): vdad110

Alterations in EGFR and PDGFRA are associated with the localization of contrast-enhancing lesions in glioblastoma.

Ryutaro Makino, Nayuta Higa, Toshiaki Akahane, Hajime Yonezawa, Hiroyuki Uchida, Tomoko Takajo, Shingo Fujio, Mari Kirishima, Taiji Hamada, Hitoshi Yamahata, Kiyohisa Kamimura, Takashi Yoshiura, Koji Yoshimoto, Akihide Tanimoto, Ryosuke Hanaya.

  Background: Glioblastoma (GBM) is a malignant brain tumor, with radiological and genetic heterogeneity. We examined the association between radiological characteristics and driver gene alterations.Methods: We analyzed the driver genes of 124 patients with IDH wild-type GBM with contrast enhancement using magnetic resonance imaging. We used a next-generation sequencing panel to identify mutations in driver genes and matched them with radiological information. Contrast-enhancing lesion localization of GBMs was classified into 4 groups based on their relationship with the subventricular zone (SVZ) and cortex (Ctx).
Results: The cohort included 69 men (55.6%) and 55 women (44.4%) with a mean age of 66.4 ± 13.3 years. EGFR and PDGFRA alterations were detected in 28.2% and 22.6% of the patients, respectively. Contrast-enhancing lesion touching both the SVZ and Ctx was excluded because it was difficult to determine whether it originated from the SVZ or Ctx. Contrast-enhancing lesions touching the SVZ but not the Ctx had significantly worse overall survival than non-SVZ lesions (441 days vs. 897 days, P = .002). GBM touching only the Ctx had a better prognosis (901 days vs. 473 days, P < .001) than non-Ctx lesions and was associated with EGFR alteration (39.4% vs. 13.2%, P = .015). Multiple contrast lesions were predominant in PDGFRA alteration and RB1-wild type (P = .036 and P = .031, respectively).
Conclusions: EGFR alteration was associated with cortical lesions. And PDGFRA alteration correlated with multiple lesions. Our results suggest that clarifying the association between driver genes and tumor localization may be useful in clinical practice, including prognosis prediction.

Keywords:  glioblastoma; multicentric glioma; multifocal glioma; neural stem cell; subventricular zone

DOI:  https://doi.org/10.1093/noajnl/vdad110
Neurooncol Adv. 2023 Jan-Dec;5(1):5(1): vdad106

Phase II trial of concurrent sunitinib, temozolomide, and radiotherapy with adjuvant temozolomide for newly diagnosed MGMT unmethylated glioblastoma.

Mame Daro Faye, Jacob Easaw, Paula De Robles, Raman Agnihotram, Alexander Torres-Vasquez, Frederic Lamonde, Kevin Petrecca, Scott Owen, Valerie Panet-Raymond, George Shenouda, Luis Souhami, Maryam Azam, Bushra Hossain, Jad Alkass, Siham Sabri, Bassam Abdulkarim.

  Background: The overall prognosis of glioblastoma (GBM) remains dismal, particularly for patients with unmethylated O6-methylguanine-DNA-methyltransferase (MGMT) promoter. In this phase II trial, we tested the combination of the antiangiogenic agent sunitinib with radiotherapy and temozolomide (TMZ) for newly diagnosed unmethylated MGMT GBM patients.Methods: We enrolled 37 patients with unmethylated MGMT promoter GBM, age 18-70, and KPS ≥70. Patients received 12.5 mg of daily sunitinib for 7 days, followed by concurrent chemoradiation plus 12.5 mg sunitinib, then adjuvant TMZ. The primary endpoint was progression-free survival (PFS), and secondary endpoints were overall survival (OS), safety, and neutrophil-to-lymphocyte ratio (NLR) biomarker.
Results: At a median follow-up time of 15.3 months (range: 3.1-71.3 months), the median PFS was 7.15 months (95% CI: 5.4-10.5) and the 6-month PFS was 54.0%. Median OS was 15.0 months (95% CI: 13.8-19.4) and 2-year OS rate was 17.1%. Patients receiving >3 cycles of adjuvant TMZ, undergoing surgery at progression, and presenting a post-concurrent NLR ≤6 experienced a significant improved OS with hazard ratios of 0.197 (P = .001), 0.46 (P = .049), and 0.38 (P = .021), respectively, on multivariable analysis. Age >65 years predicted for worse OS with hazard ratio of 3.92 (P = .037). Grade ≥3 thrombocytopenia occurred in 22.9%, grade ≥3 neutropenia in 20%, and grade ≥3 thromboembolic events in 14.3% of patients. There were no grade 5 events.
Conclusion: Our findings suggest a potential benefit of combining sunitinib with chemoradiation in newly diagnosed GBM patients with unmethylated MGMT status and provide a strong rationale to test this combination in future studies.

Keywords:  glioblastoma; radiation therapy; sunitinib; temozolomide; unmethylated MGMT

DOI:  https://doi.org/10.1093/noajnl/vdad106
Neuro Oncol. 2023 Sep 28. pii: noad190. [Epub ahead of print]

BCAT1 regulates glioblastoma cell plasticity and contributes to immunosuppression.

Pavle Boskovic, Nathalie Wilke, Ka-Hou Man, Peter Lichter, Liliana Francois, Bernhard Radlwimmer.

  Glioblastoma is the most common malignant brain tumor in adults. Cellular plasticity and the poorly differentiated features result in a fast relapse of the tumors following treatment. Moreover, the immunosuppressive microenvironment proved to be a major obstacle to immunotherapeutic approaches. Branched-chain amino acid transaminase 1 (BCAT1) is a metabolic enzyme that converts branched-chain amino acids into branched-chain keto acids, depleting cellular α-ketoglutarate and producing glutamate. BCAT1 was shown to drive the growth of glioblastoma and other cancers; however, its oncogenic mechanism remains poorly understood. Here, we show that BCAT1 is crucial for maintaining the poorly differentiated state of glioblastoma cells and that its low expression correlates with a more differentiated glioblastoma phenotype. Furthermore, orthotopic tumor injection into immunocompetent mice demonstrated that the brain microenvironment is sufficient to induce differentiation of Bcat1-KO tumors in vivo. We link the transition to a differentiated cell state to the increased activity of TET demethylases and the hypomethylation and activation of neuronal differentiation genes. In addition, the knockout of Bcat1 attenuated immunosuppression, allowing for an extensive infiltration of CD8 + cytotoxic T-cells and complete abrogation of tumor growth. Further analysis in immunodeficient mice revealed that both tumor cell differentiation and immunomodulation following BCAT1-KO contribute to the long-term suppression of tumor growth. In summary, our study unveils BCAT1's pivotal role in promoting glioblastoma growth by inhibiting tumor cell differentiation and sustaining an immunosuppressive milieu. These findings offer a novel therapeutic avenue for targeting glioblastoma through the inhibition of BCAT1.

Keywords:  BCAT1; differentiation; immunosuppression; neurooncology

DOI:  https://doi.org/10.1093/neuonc/noad190
Cancer Res. 2023 Sep 25.

Crosstalk between PARN and EGFR-STAT3 Signaling Facilitates Self-Renewal and Proliferation of Glioblastoma Stem Cells.

Jinlong Yin, Yoona Seo, Jiho Rhim, Xiong Jin, Tae Hoon Kim, Sung Soo Kim, Jun-Hee Hong, Ho-Shin Gwak, Heon Yoo, Jong Bae Park, Jong Heon Kim.

Glioblastoma is the most common type of malignant primary brain tumor and displays highly aggressive and heterogeneous phenotypes. The transcription factor STAT3 has been reported to play a key role in glioblastoma malignancy. Thus, discovering targets and functional downstream networks regulated by STAT3 that govern glioblastoma pathogenesis may lead to improved treatment strategies. In this study, we identified that poly(A)-specific ribonuclease (PARN), a key modulator of RNA metabolism, activates EGFR-STAT3 signaling to support glioblastoma stem cells (GSCs). Functional integrative analysis of STAT3 found PARN as the top-scoring transcriptional target involved in RNA processing in glioblastoma patients, and PARN expression was strongly correlated with poor patient survival and elevated malignancy. PARN positively regulated self-renewal and proliferation of GSCs through its 3'-5' exoribonuclease activity. EGFR was identified as a clinically relevant target of PARN in GSCs. PARN positively modulated EGFR by negatively regulating the EGFR-targeting miRNA miR-7, and increased EGFR expression created a positive feedback loop to increase STAT3 activation. PARN depletion in GSCs reduced infiltration and prolonged survival in orthotopic brain tumor xenografts; similar results were observed using siRNA nanocapsule-mediated PARN targeting. Pharmacological targeting of STAT3 also confirmed PARN regulation by STAT3 signaling. In sum, these results suggest that a STAT3-PARN regulatory network plays a pivotal role in tumor progression and thus may represent a target for glioblastoma therapeutics.

DOI: https://doi.org/10.1158/0008-5472.CAN-22-3965
bioRxiv. 2023 Sep 12. pii: 2023.09.09.557001. [Epub ahead of print]

Multiplexed single-cell lineage tracing of mitotic kinesin inhibitor resistance in glioblastoma.

Yim Ling Cheng, Matei A Banu, Wenting Zhao, Steven S Rosenfeld, Peter Canoll, Peter A Sims.

Glioblastoma (GBM) is a deadly brain tumor, and the kinesin motor KIF11 is an attractive therapeutic target because of its dual roles in proliferation and invasion. The clinical utility of KIF11 inhibitors has been limited by drug resistance, which has mainly been studied in animal models. We used multiplexed lineage tracing barcodes and scRNA-seq to analyze drug resistance time courses for patient-derived GBM neurospheres treated with ispinesib, a potent KIF11 inhibitor. Similar to GBM progression in patients, untreated cells lost their neural lineage identity and transitioned to a mesenchymal phenotype, which is associated with poor prognosis. In contrast, cells subjected to long-term ispinesib treatment exhibited a proneural phenotype. We generated patient-derived xenografts to show that ispinesib-resistant cells form less aggressive tumors in vivo , even in the absence of drug. Finally, we used lineage barcodes to nominate drug combination targets by retrospective analysis of ispinesib-resistant clones in the drug-naïve setting and identified drugs that are synergistic with ispinesib.

DOI: https://doi.org/10.1101/2023.09.09.557001
Oncogene. 2023 Sep 23.

Pooled genetic screens to identify vulnerabilities in TERT-promoter-mutant glioblastoma.

Kevin J Tu, Connor E Stewart, Peter G Hendrickson, Joshua A Regal, So Young Kim, David M Ashley, Matthew S Waitkus, Zachary J Reitman.

Pooled genetic screens represent a powerful approach to identify vulnerabilities in cancer. Here we used pooled CRISPR/Cas9-based approaches to identify vulnerabilities associated with telomerase reverse transcriptase (TERT) promoter mutations (TPMs) found in >80% of glioblastomas. We first developed a platform to detect perturbations that cause long-term growth defects in a TPM-mutated glioblastoma cell line. However, we could not detect dependencies on either TERT itself or on an E-twenty six transcription (ETS) factor known to activate TPMs. To explore this finding, we cataloged TPM status for 441 cell lines and correlated this with genome-wide screening data. We found that TPM status was not associated with differential dependency on TERT, but that E-twenty six (ETS) transcription factors represent key dependencies in both TPM+ and TPM- lines. Further, we found that TPMs are associated with expression of gene programs regulated by a wide array of ETS-factors in both cell lines and primary glioblastoma tissues. This work contributes a unique TPM cell line reagent, establishes TPM status for many deeply-profiled cell lines, and catalogs TPM-associated vulnerabilities. The results highlight challenges in executing genetic screens to detect TPM-specific vulnerabilities, and suggest redundancy in the genetic network that regulates TPM function with therapeutic implications.

DOI: https://doi.org/10.1038/s41388-023-02845-w
Nat Commun. 2023 Sep 28. 14(1): 6066

Integrated molecular and multiparametric MRI mapping of high-grade glioma identifies regional biologic signatures.

Leland S Hu, Fulvio D'Angelo, Taylor M Weiskittel, Francesca P Caruso, Shannon P Fortin Ensign, Mylan R Blomquist, Matthew J Flick, Lujia Wang, Christopher P Sereduk, Kevin Meng-Lin, Gustavo De Leon, Ashley Nespodzany, Javier C Urcuyo, Ashlyn C Gonzales, Lee Curtin, Erika M Lewis, Kyle W Singleton, Timothy Dondlinger, Aliya Anil, Natenael B Semmineh, Teresa Noviello, Reyna A Patel, Panwen Wang, Junwen Wang, Jennifer M Eschbacher, Andrea Hawkins-Daarud, Pamela R Jackson, Itamar S Grunfeld, Christian Elrod, Gina L Mazza, Sam C McGee, Lisa Paulson, Kamala Clark-Swanson, Yvette Lassiter-Morris, Kris A Smith, Peter Nakaji, Bernard R Bendok, Richard S Zimmerman, Chandan Krishna, Devi P Patra, Naresh P Patel, Mark Lyons, Matthew Neal, Kliment Donev, Maciej M Mrugala, Alyx B Porter, Scott C Beeman, Todd R Jensen, Kathleen M Schmainda, Yuxiang Zhou, Leslie C Baxter, Christopher L Plaisier, Jing Li, Hu Li, Anna Lasorella, C Chad Quarles, Kristin R Swanson, Michele Ceccarelli, Antonio Iavarone, Nhan L Tran.

Sampling restrictions have hindered the comprehensive study of invasive non-enhancing (NE) high-grade glioma (HGG) cell populations driving tumor progression. Here, we present an integrated multi-omic analysis of spatially matched molecular and multi-parametric magnetic resonance imaging (MRI) profiling across 313 multi-regional tumor biopsies, including 111 from the NE, across 68 HGG patients. Whole exome and RNA sequencing uncover unique genomic alterations to unresectable invasive NE tumor, including subclonal events, which inform genomic models predictive of geographic evolution. Infiltrative NE tumor is alternatively enriched with tumor cells exhibiting neuronal or glycolytic/plurimetabolic cellular states, two principal transcriptomic pathway-based glioma subtypes, which respectively demonstrate abundant private mutations or enrichment in immune cell signatures. These NE phenotypes are non-invasively identified through normalized K2 imaging signatures, which discern cell size heterogeneity on dynamic susceptibility contrast (DSC)-MRI. NE tumor populations predicted to display increased cellular proliferation by mean diffusivity (MD) MRI metrics are uniquely associated with EGFR amplification and CDKN2A homozygous deletion. The biophysical mapping of infiltrative HGG potentially enables the clinical recognition of tumor subpopulations with aggressive molecular signatures driving tumor progression, thereby informing precision medicine targeting.

DOI: https://doi.org/10.1038/s41467-023-41559-1
Clin Cancer Res. 2023 Sep 29.

Magnetic resonance imaging of iron metabolism with T2* mapping predicts an enhanced clinical response to pharmacological ascorbate in patients with GBM.

Michael S Petronek, Varun Monga, Kellie L Bodeker, Michael Kwofie, Chu-Yu Lee, Kranti A Mapuskar, Jeffrey M Stolwijk, Amira Zaher, Brett A Wagner, Mark C Smith, Sandy Vollstedt, Heather Brown, Meghan L Chandler, Amanda C Lorack, Jared S Wulfekuhle, Jann N Sarkaria, Ryan T Flynn, Jeremy D W Greenlee, Matthew A Howard, Brian J Smith, Karra A Jones, Garry R Buettner, Joseph J Cullen, Joel St-Aubin, John M Buatti, Vincent A Magnotta, Douglas R Spitz, Bryan G Allen.

PURPOSE: Pharmacological ascorbate (P-AscH-) is hypothesized to be an Fe-dependent tumor-specific adjuvant to chemo-radiation in treating glioblastoma (GBM). The current study determined the efficacy of combining P-AscH- with radiation and temozolomide in a phase 2 clinical trial while simultaneously investigating a mechanism-based, non-invasive biomarker in T2* mapping to predict GBM response to P-AscH- in humans.PATIENTS AND METHODS: The single-arm phase 2 clinical trial (NCT02344355) enrolled 55 subjects with analysis performed 12 months following the completion of treatment. Overall survival (OS) and progression-free survival (PFS) were estimated with the Kaplan-Meier method and compared across patient subgroups with log-rank tests. 49 of 55 subjects were evaluated using T2*-based MRI to assess its utility as an Fe-dependent biomarker.
RESULTS: Median OS was estimated to be 19.6 months (90% CI: 15.7 - 26.5 months), a statistically significant increase compared to historic control patients (14.6 months). Subjects with initial T2* relaxation < 50 ms were associated with a significant increase in PFS compared to T2*high subjects (11.2 months vs. 5.7 months, p<0.05) and a trend towards increased OS (26.5 months vs. 17.5 months). These results were validated in pre-clinical in vitro and in vivo model systems.
CONCLUSIONS: P-AscH- combined with temozolomide and radiotherapy has the potential to significantly enhance GBM survival. T2*-based MRI assessment of tumor iron content is a prognostic biomarker for GBM clinical outcomes.

DOI: https://doi.org/10.1158/1078-0432.CCR-22-3952
JAMA Neurol. 2023 Sep 25.

White Matter Tract Density Index Prediction Model of Overall Survival in Glioblastoma.

Alessandro Salvalaggio, Lorenzo Pini, Matteo Gaiola, Aron Velco, Giulio Sansone, Mariagiulia Anglani, Lucius Fekonja, Franco Chioffi, Thomas Picht, Michel Thiebaut de Schotten, Vittorina Zagonel, Giuseppe Lombardi, Domenico D'Avella, Maurizio Corbetta.

Importance: The prognosis of overall survival (OS) in patients with glioblastoma (GBM) may depend on the underlying structural connectivity of the brain.Objective: To examine the association between white matter tracts affected by GBM and patients' OS by means of a new tract density index (TDI).
Design, Setting, and Participants: This prognostic study in patients with a histopathologic diagnosis of GBM examined a discovery cohort of 112 patients who underwent surgery between February 1, 2015, and November 30, 2020 (follow-up to May 31, 2023), in Italy and 70 patients in a replicative cohort (n = 70) who underwent surgery between September 1, 2012, and November 30, 2015 (follow-up to May 31, 2023), in Germany. Statistical analyses were performed from June 1, 2021, to May 31, 2023. Thirteen and 12 patients were excluded from the discovery and the replicative sets, respectively, because of magnetic resonance imaging artifacts.
Exposure: The density of white matter tracts encompassing GBM.
Main Outcomes and Measures: Correlation, linear regression, Cox proportional hazards regression, Kaplan-Meier, and prediction analysis were used to assess the association between the TDI and OS. Results were compared with common prognostic factors of GBM, including age, performance status, O6-methylguanine-DNA methyltransferase methylation, and extent of surgery.
Results: In the discovery cohort (n = 99; mean [SD] age, 62.2 [11.5] years; 29 female [29.3%]; 70 male [70.7%]), the TDI was significantly correlated with OS (r = -0.34; P < .001). This association was more stable compared with other prognostic factors. The TDI showed a significant regression pattern (Cox: hazard ratio, 0.28 [95% CI, 0.02-0.55; P = .04]; linear: t = -2.366; P = .02). and a significant Kaplan-Meier stratification of patients as having lower or higher OS based on the TDI (log-rank test = 4.52; P = .03). Results were confirmed in the replicative cohort (n = 58; mean [SD] age, 58.5 [11.1] years, 14 female [24.1%]; 44 male [75.9%]). High (24-month cutoff) and low (18-month cutoff) OS was predicted based on the TDI computed in the discovery cohort (accuracy = 87%).
Conclusions and Relevance: In this study, GBMs encompassing regions with low white matter tract density were associated with longer OS. These findings indicate that the TDI is a reliable presurgical outcome predictor that may be considered in clinical trials and clinical practice. These findings support a framework in which the outcome of GBM depends on the patient's brain organization.

DOI: https://doi.org/10.1001/jamaneurol.2023.3284
Pathol Int. 2023 Sep 27.

Metabolic and epigenetic reprogramming in the pathogenesis of glioblastoma: Toward the establishment of "metabolism-based pathology".

Kenta Masui, Paul S Mischel.

  Molecular genetic approaches are now mandatory for cancer diagnostics, especially for brain tumors. Genotype-based diagnosis has predominated over the phenotype-based approach, with its prognostic and predictive powers. However, comprehensive genetic testing would be difficult to perform in the clinical setting, and translational research is required to histologically decipher the peculiar biology of cancer. Of interest, recent studies have demonstrated discrete links between oncogenotypes and the resultant metabolic phenotypes, revealing cancer metabolism as a promising histologic surrogate to reveal specific characteristics of each cancer type and indicate the best way to manage cancer patients. Here, we provide an overview of our research progress to work on cancer metabolism, with a particular focus on the genomically well-characterized malignant tumor glioblastoma. With the use of clinically relevant animal models and human tissue, we found that metabolic reprogramming plays a major role in the aggressive cancer biology by conferring therapeutic resistance to cancer cells and rewiring their epigenomic landscapes. We further discuss our future endeavor to establish "metabolism-based pathology" on how the basic knowledge of cancer metabolism could be leveraged to improve the management of patients by linking cancer cell genotype, epigenotype, and phenotype through metabolic reprogramming.

Keywords:  cancer metabolism; epigenome; glioblastoma; metabolism-based pathology; molecular genetics

DOI:  https://doi.org/10.1111/pin.13379