TY - JOUR AU - Kovács, Hilda AU - Jakusch, Tamás AU - May, Nóra Veronika AU - Tóth, Szilárd AU - Szakács, Gergely AU - Enyedy, Éva Anna TI - Complex formation of ML324, the histone demethylase inhibitor, with essential metal ions: Relationship between solution chemistry and anticancer activity JF - JOURNAL OF INORGANIC BIOCHEMISTRY J2 - J INORG BIOCHEM VL - 255 PY - 2024 SP - 112540 SN - 0162-0134 DO - 10.1016/j.jinorgbio.2024.112540 UR - https://m2.mtmt.hu/api/publication/34761990 ID - 34761990 LA - English DB - MTMT ER - TY - JOUR AU - Ubhi, Tajinder AU - Zaslaver, Olga AU - Quaile, Andrew T. AU - Plenker, Dennis AU - Cao, Pinjiang AU - Pham, Nhu-An AU - Békési, Angéla AU - Jang, Gun-Ho AU - O’Kane, Grainne M. AU - Notta, Faiyaz AU - Moffat, Jason AU - Wilson, Julie M. AU - Gallinger, Steven AU - Vértessy, Beáta (Grolmuszné) AU - Tuveson, David A. AU - Röst, Hannes L. AU - Brown, Grant W. TI - Cytidine deaminases APOBEC3C and APOBEC3D promote DNA replication stress resistance in pancreatic cancer cells JF - NATURE CANCER J2 - NAT CANCER PY - 2024 SN - 2662-1347 DO - 10.1038/s43018-024-00742-z UR - https://m2.mtmt.hu/api/publication/34735982 ID - 34735982 N1 - Department of Biochemistry, University of Toronto, Toronto, ON, Canada Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, United States Living Biobank, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada Department of Applied Biotechnology and Food Science, Faculty of Chemical Technology and Biotechnology, BME Budapest University of Technology and Economics, Budapest, Hungary Genome Metabolism Research Group, Institute of Molecular Life Sciences, Research Centre for Natural Sciences, Hungarian Research Network, Budapest, Hungary Ontario Institute for Cancer Research, Toronto, ON, Canada Wallace McCain Centre for Pancreatic Cancer, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada Division of Research, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada Hepatobiliary/Pancreatic Surgical Oncology Program, University Health Network, Toronto, ON, Canada Xilis Inc., Durham, NC, United States Export Date: 18 March 2024 Correspondence Address: Brown, G.W.; Department of Biochemistry, Canada; email: grant.brown@utoronto.ca Funding details: National Institutes of Health, NIH, 1R01CA188134, 1R01CA190092, 5P30CA45508, R01CA229699, U01CA210240, U01CA224013 Funding details: Simons Foundation, SF, 552716, FRN 166094 Funding details: Lustgarten Foundation Funding details: Princess Margaret Cancer Foundation, PMCF Funding details: Ontario Institute for Cancer Research, OICR Funding details: Cold Spring Harbor Laboratory, CSHL Funding details: Government of Ontario Funding details: Thompson Foundation Funding details: Canadian Friends of Hebrew University, CFHU Funding details: Canadian Cancer Society Research Institute, CCSRI Funding details: Canadian Institutes of Health Research, CIHR, PJT-463531 Funding details: Canada Foundation for Innovation, CFI, 37660 Funding details: Canadian Cancer Society, CCS, 706293, FDN-159913, P.CTIP.1005 Funding details: Canada Research Chairs Funding details: Magyar Tudományos Akadémia, MTA, BO/726/22/8, ÚNKP-22-5-BME-295 Funding details: Terry Fox Research Institute, TFRI Funding details: Hospital for Sick Children, SickKids, FK137867 Funding details: Nemzeti Kutatási Fejlesztési és Innovációs Hivatal, NKFI, K135231, NKP-2018-1.2.1-NKP-2018-00005, TKP2021-EGA-02 Funding details: Nemzeti Kutatási, Fejlesztési és Innovaciós Alap, NKFIA Funding details: Innovációs és Technológiai Minisztérium Funding text 1: D.A.T. receives stock options from Leap Therapeutics, Surface Oncology, Sonata Therapeutics and Mestag Therapeutics outside of the published work. D.A.T. is scientific cofounder of Mestag Therapeutics. D.A.T. has received research grant support from the Fibrogen, Mestag and ONO Therapeutics. D.A.T. receives grant funding from the Lustgarten Foundation, the National Institutes of Health and the Thompson Foundation. None of this work is related to the publication. T.U. and G.W.B. were consultants for Repare Therapeutics. G.W.B. received research support from Repare Therapeutics. The other authors report no competing interests. Funding text 2: We thank S. Angers (University of Toronto) for the Cas9 stable HPAF-II, AsPC-1 and BxPC-3 cell lines, D. Durocher (Lunenfeld-Tanenbaum Research Institute) for the RPE1–hTERT–Cas9 p53 cell line and the lentiGuide–NLS–eGFP and lentiGuide–NLS–mCherry plasmids, H. Wyatt (University of Toronto) for the Sf9 and Hi5 insect cell lines, L. Chelico (University of Saskatchewan) for A3C purification advice and the Donnelly Sequencing Centre (University of Toronto) for performing Illumina sequencing. Pancreatic tumor RNA expression data from the ICGC PACA-CA and COMPASS trial cohorts were generated by the Ontario Institute for Cancer Research (PanCuRx Translational Research Initiative) through funding provided by the Government of Ontario, the Wallace McCain Centre for Pancreatic Cancer supported by the Princess Margaret Cancer Foundation, the Terry Fox Research Institute, the Canadian Cancer Society Research Institute, Pancreatic Cancer Canada and a charitable donation from the Canadian Friends of the Hebrew University (A.U. Soyka). T.U. was supported by an Ontario Graduate Scholarship and a Frederick Banting and Charles Best Canadian Institutes of Health Research Doctoral Award. J.M. was supported by the Canadian Institutes of Health Research (PJT-463531) and holds the GlaxoSmithKline Chair in Genetics and Genome Biology at the Hospital for Sick Children. Project no. FK137867 for A.B. has been implemented with support provided by the Ministry for Culture and Innovation of Hungary from the National Research, Development and Innovation Fund, financed under the OTKA_FK_21 funding scheme. A.B. was also supported by the János Bolyai Research Scholarship of the Hungarian Academy of Science (BO/726/22/8) and by the ÚNKP-22-5-BME-295 New National Excellence Program of the Ministry for Culture and Innovation from the source of the National Research, Development and Innovation Fund. B.G.V. was supported by the National Research, Development and Innovation Fund of Hungary (K135231, NKP-2018-1.2.1-NKP-2018-00005) and the TKP2021-EGA-02 grant, implemented with support provided by the Ministry for Innovation and Technology of Hungary from the National Research, Development and Innovation Fund. D.A.T. is supported by the Lustgarten Foundation, where D.A.T. is a distinguished scholar and Director of the Lustgarten Foundation–designated Laboratory of Pancreatic Cancer Research. D.A.T. is also supported by the Thompson Foundation, the Cold Spring Harbor Laboratory and Northwell Health Affiliation, the Northwell Health Tissue Donation Program, the Cold Spring Harbor Laboratory Association, the National Institutes of Health (5P30CA45508, U01CA210240, R01CA229699, U01CA224013, 1R01CA188134 and 1R01CA190092) and by a gift from the Simons Foundation (552716). H.L.R. was funded by the Canadian Institutes of Health Research (FRN 166094) and Canada Foundation for Innovation (grant 37660). G.W.B. is a Tier I Canada Research Chair and was supported by the Canadian Cancer Society (Innovate grant 706293), the Canadian Institutes of Health Research (FDN-159913) and the Ontario Institute for Cancer Research (P.CTIP.1005). We are grateful to work on the lands of the Mississaugas of the Credit, the Anishnaabeg, the Haudenosaunee and the Wendat peoples, land that is now home to many diverse First Nations, Inuit and Métis peoples. −/− AB - Gemcitabine is a potent inhibitor of DNA replication and is a mainstay therapeutic for diverse cancers, particularly pancreatic ductal adenocarcinoma (PDAC). However, most tumors remain refractory to gemcitabine therapies. Here, to define the cancer cell response to gemcitabine, we performed genome-scale CRISPR–Cas9 chemical–genetic screens in PDAC cells and found selective loss of cell fitness upon disruption of the cytidine deaminases APOBEC3C and APOBEC3D. Following gemcitabine treatment, APOBEC3C and APOBEC3D promote DNA replication stress resistance and cell survival by deaminating cytidines in the nuclear genome to ensure DNA replication fork restart and repair in PDAC cells. We provide evidence that the chemical–genetic interaction between APOBEC3C or APOBEC3D and gemcitabine is absent in nontransformed cells but is recapitulated across different PDAC cell lines, in PDAC organoids and in PDAC xenografts. Thus, we uncover roles for APOBEC3C and APOBEC3D in DNA replication stress resistance and offer plausible targets for improving gemcitabine-based therapies for PDAC. © The Author(s), under exclusive licence to Springer Nature America, Inc. 2024. LA - English DB - MTMT ER - TY - JOUR AU - Brampton, Christopher AU - Pomozi, Viola AU - Le Corre, Yannick AU - Zoll, Janna AU - Kauffenstein, Gilles AU - Ma, Chi AU - Hoffmann, Peter R. AU - Martin, Ludovic AU - Le Saux, Olivier TI - Bone Marrow–Derived ABCC6 Is an Essential Regulator of Ectopic Calcification In Pseudoxanthoma Elasticum JF - JOURNAL OF INVESTIGATIVE DERMATOLOGY J2 - J INVEST DERMATOL PY - 2024 SN - 0022-202X DO - 10.1016/j.jid.2024.01.026 UR - https://m2.mtmt.hu/api/publication/34735956 ID - 34735956 LA - English DB - MTMT ER - TY - JOUR AU - Gál, Luca AU - Fóthi, Ábel AU - Orosz, Gergő AU - Nagy, Sándor AU - Than, Nándor Gábor AU - Orbán, Tamás I. TI - Exosomal small RNA profiling in first-trimester maternal blood explores early molecular pathways of preterm preeclampsia JF - FRONTIERS IN IMMUNOLOGY J2 - FRONT IMMUNOL VL - 15 PY - 2024 PG - 14 SN - 1664-3224 DO - 10.3389/fimmu.2024.1321191 UR - https://m2.mtmt.hu/api/publication/34669504 ID - 34669504 LA - English DB - MTMT ER - TY - GEN AU - Spisák, Sándor AU - Chen, David AU - Likasitwatanakul, Pornlada AU - Doan, Paul AU - Li, Zhixin AU - Bala, Pratyusha AU - Vizkeleti, Laura AU - Tisza, Viktoria AU - De Silva, Pushpamail AU - Giannakis, Marios AU - Wolpin, Brian AU - Qi, Jun AU - Sethi, Nilay S TI - Utilizing a dual endogenous reporter system to identify functional regulators of aberrant stem cell and differentiation activity in colorectal cancer. PY - 2024 UR - https://m2.mtmt.hu/api/publication/34577433 ID - 34577433 AB - Aberrant stem cell-like activity and impaired differentiation are central to the development of colorectal cancer (CRC). To identify functional mediators that regulate these key cellular programs in CRC, we developed an endogenous reporter system by genome-editing human CRC cell lines with knock-in fluorescent reporters at the SOX9 and KRT20 locus to report aberrant stem cell-like activity and differentiation, respectively, and then performed pooled genetic perturbation screens. Constructing a dual reporter system that simultaneously monitored aberrant stem cell-like and differentiation activity in the same CRC cell line improved our signal to noise discrimination. Using a focused-library CRISPR screen targeting 78 epigenetic regulators with 542 sgRNAs, we identified factors that contribute to stem cell-like activity and differentiation in CRC. Perturbation single cell RNA sequencing (Perturb-seq) of validated hits nominated SMARCB1 of the BAF complex (also known as SWI/SNF) as a negative regulator of differentiation across an array of neoplastic colon models. SMARCB1 is a dependency in CRC and required for in vivo growth of human CRC models. These studies highlight the utility of a biologically designed endogenous reporter system to uncover novel therapeutic targets for drug development. LA - English DB - MTMT ER - TY - JOUR AU - Bence, Melinda AU - Jankovics, Ferenc AU - Kristó, Ildikó AU - Gyetvai, Akos AU - Vértessy, Beáta (Grolmuszné) AU - Erdélyi, Miklós TI - Direct interaction of Su(var)2-10 via the SIM-binding site of the Piwi protein is required for transposon silencing in Drosophila melanogaster JF - FEBS JOURNAL J2 - FEBS J PY - 2024 PG - 21 SN - 1742-464X DO - 10.1111/febs.17073 UR - https://m2.mtmt.hu/api/publication/34575637 ID - 34575637 N1 - Funding Agency and Grant Number: National Research, Development and Innovation Office [K132384, PD124446]; Janos Bolyai Fellowship of Hungarian Academy of Sciences [BO/00599/17]; UNKP New National Excellence Program of the Ministry of Human Capacities of Hungary [UNKP-19-4-SZTE-5]; National Research, Development and Innovation Office (National Laboratory for Biotechnology) [2022-2.1.1-NL-2022-00008]; National Research, Development and Innovation Office [K135231, K146890, FK137867, VEKOP-2.3.2-16-2017-00013, NKP-2018-1.2.1-NKP-2018-00005]; Ministry for Innovation and Technology of Hungary from the National Research, Development and Innovation Fund; [TKP2021-EGA-02] AB - Nuclear Piwi/Piwi-interacting RNA complexes mediate co-transcriptional silencing of transposable elements by inducing local heterochromatin formation. In Drosophila, sumoylation plays an essential role in the assembly of the silencing complex; however, the molecular mechanism by which the sumoylation machinery is recruited to the transposon loci is poorly understood. Here, we show that the Drosophila E3 SUMO-ligase Su(var)2-10 directly binds to the Piwi protein. This interaction is mediated by the SUMO-interacting motif-like (SIM-like) structure in the C-terminal domain of Su(var)2-10. We demonstrated that the SIM-like structure binds to a special region found in the MID domain of the Piwi protein, the structure of which is highly similar to the SIM-binding pocket of SUMO proteins. Abrogation of the Su(var)2-10-binding surface of the Piwi protein resulted in transposon derepression in the ovary of adult flies. Based on our results, we propose a model in which the Piwi protein initiates local sumoylation in the silencing complex by recruiting Su(var)2-10 to the transposon loci. LA - English DB - MTMT ER - TY - JOUR AU - Kaci, Hana AU - Dombi, Ágnes AU - Gömbös, Patrik AU - Szabó, András AU - Bakos, Éva AU - Laczka, Csilla AU - Poór, Miklós TI - Interaction of mycotoxins zearalenone, α-zearalenol, and β-zearalenol with cytochrome P450 (CYP1A2, 2C9, 2C19, 2D6, and 3A4) enzymes and organic anion transporting polypeptides (OATP1A2, OATP1B1, OATP1B3, and OATP2B1) JF - TOXICOLOGY IN VITRO J2 - TOXICOL IN VITRO VL - 96 PY - 2024 PG - 8 SN - 0887-2333 DO - 10.1016/j.tiv.2024.105789 UR - https://m2.mtmt.hu/api/publication/34575448 ID - 34575448 LA - English DB - MTMT ER - TY - JOUR AU - Tóth, Eszter AU - Györffy, Dániel AU - Posta, Máté AU - Hupuczi, Petronella AU - Balogh, Andrea AU - Szalai, Gábor AU - Orosz, Gergő Balázs AU - Orosz, László AU - Szilágyi, András AU - Oravecz, Orsolya AU - Veress, Lajos AU - Nagy, Sándor AU - Török, Olga AU - Murthi, Padma AU - Erez, Offer AU - Papp, Zoltán AU - Ács, Nándor AU - Than, Nándor Gábor TI - Decreased Expression of Placental Proteins in Recurrent Pregnancy Loss: Functional Relevance and Diagnostic Value JF - INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES J2 - INT J MOL SCI VL - 25 PY - 2024 IS - 3 PG - 23 SN - 1661-6596 DO - 10.3390/ijms25031865 UR - https://m2.mtmt.hu/api/publication/34563187 ID - 34563187 N1 - Funding Agency and Grant Number: Hungarian Academy of Sciences; Thermo Fisher Scientific Funding text: Pascaline Caruhel, Kathrin Matischak, Elena Uliyanova, and Arnaud Vernier from Thermo Fisher Scientific (Hennigsdorf, Germany) for providing the daily medians of the related proteins. AB - Miscarriages affect 50–70% of all conceptions and 15–20% of clinically recognized pregnancies. Recurrent pregnancy loss (RPL, ≥2 miscarriages) affects 1–5% of recognized pregnancies. Nevertheless, our knowledge about the etiologies and pathophysiology of RPL is incomplete, and thus, reliable diagnostic/preventive tools are not yet available. Here, we aimed to define the diagnostic value of three placental proteins for RPL: human chorionic gonadotropin free beta-subunit (free-β-hCG), pregnancy-associated plasma protein-A (PAPP-A), and placental growth factor (PlGF). Blood samples were collected from women with RPL (n = 14) and controls undergoing elective termination of pregnancy (n = 30) at the time of surgery. Maternal serum protein concentrations were measured by BRAHMS KRYPTOR Analyzer. Daily multiple of median (dMoM) values were calculated for gestational age-specific normalization. To obtain classifiers, logistic regression analysis was performed, and ROC curves were calculated. There were differences in changes of maternal serum protein concentrations with advancing healthy gestation. Between 6 and 13 weeks, women with RPL had lower concentrations and dMoMs of free β-hCG, PAPP-A, and PlGF than controls. PAPP-A dMoM had the best discriminative properties (AUC = 0.880). Between 9 and 13 weeks, discriminative properties of all protein dMoMs were excellent (free β-hCG: AUC = 0.975; PAPP-A: AUC = 0.998; PlGF: AUC = 0.924). In conclusion, free-β-hCG and PAPP-A are valuable biomarkers for RPL, especially between 9 and 13 weeks. Their decreased concentrations indicate the deterioration of placental functions, while lower PlGF levels indicate problems with placental angiogenesis after 9 weeks. LA - English DB - MTMT ER - TY - JOUR AU - Menyhart, Otilia AU - Fekete, János Tibor AU - Győrffy, Balázs TI - Resistance to Combined Anthracycline–Taxane Chemotherapy Is Associated with Altered Metabolism and Inflammation in Breast Carcinomas JF - INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES J2 - INT J MOL SCI VL - 25 PY - 2024 IS - 2 PG - 15 SN - 1661-6596 DO - 10.3390/ijms25021063 UR - https://m2.mtmt.hu/api/publication/34561052 ID - 34561052 AB - Approximately 30% of early-stage breast cancer (BC) patients experience recurrence after systemic chemotherapy; thus, understanding therapy resistance is crucial in developing more successful treatments. Here, we investigated the mechanisms underlying resistance to combined anthracycline–taxane treatment by comparing gene expression patterns with subsequent therapeutic responses. We established a cohort of 634 anthracycline–taxane-treated patients with pathological complete response (PCR) and a separate cohort of 187 patients with relapse-free survival (RFS) data, each having transcriptome-level expression data of 10,017 unique genes. Patients were categorized as responders and non-responders based on their PCR and RFS status, and the expression for each gene was compared between the two groups using a Mann–Whitney U-test. Statistical significance was set at p < 0.05, with fold change (FC) > 1.44. Altogether, 224 overexpressed genes were identified in the tumor samples derived from the patients without PCR; among these, the gene sets associated with xenobiotic metabolism (e.g., CYP3A4, CYP2A6) exhibited significant enrichment. The genes ORAI3 and BCAM differentiated non-responders from responders with the highest AUC values (AUC > 0.75, p < 0.0001). We identified 51 upregulated genes in the tumor samples derived from the patients with relapse within 60 months, participating primarily in inflammation and innate immune responses (e.g., LYN, LY96, ANXA1). Furthermore, the amino acid transporter SLC7A5, distinguishing non-responders from responders, had significantly higher expression in tumors and metastases than in normal tissues (Kruskal–Wallis p = 8.2 × 10−20). The identified biomarkers underscore the significance of tumor metabolism and microenvironment in treatment resistance and can serve as a foundation for preclinical validation studies. © 2024 by the authors. LA - English DB - MTMT ER - TY - JOUR AU - Zhou, W. AU - Zhao, Z. AU - Lin, A. AU - Yang, J.Z. AU - Xu, J. AU - Wilder-Romans, K. AU - Yang, A. AU - Li, J. AU - Solanki, S. AU - Speth, J.M. AU - Walker, N. AU - Scott, A.J. AU - Wang, L. AU - Wen, B. AU - Andren, A. AU - Zhang, L. AU - Kothari, A.U. AU - Yao, Y. AU - Peterson, E.R. AU - Korimerla, N. AU - Werner, C.K. AU - Ullrich, A. AU - Liang, J. AU - Jacobson, J. AU - Palavalasa, S. AU - O'Brien, A.M. AU - Elaimy, A.L. AU - Ferris, S.P. AU - Zhao, S.G. AU - Sarkaria, J.N. AU - Győrffy, Balázs AU - Zhang, S. AU - Al-Holou, W.N. AU - Umemura, Y. AU - Morgan, M.A. AU - Lawrence, T.S. AU - Lyssiotis, C.A. AU - Peters-Golden, M. AU - Shah, Y.M. AU - Wahl, D.R. TI - GTP Signaling Links Metabolism, DNA Repair, and Responses to Genotoxic Stress JF - CANCER DISCOVERY J2 - CANCER DISCOV VL - 14 PY - 2024 IS - 1 SP - 158 EP - 175 PG - 18 SN - 2159-8274 DO - 10.1158/2159-8290.CD-23-0437 UR - https://m2.mtmt.hu/api/publication/34544300 ID - 34544300 N1 - Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, United States Department of Oncology, the Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China Cell Signaling Technology, Inc, Danvers, MA, United States Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, United States Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, United States Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, United States Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI, United States Department of Oncology, the First Affiliated Hospital of Nanchang University, Nanchang, China Department of Pathology, Division of Neuropathology, University of Michigan, Ann Arbor, MI, United States Department of Human Oncology, University of Wisconsin, Madison, MA, United States Mayo Clinic, Rochester, MN, United States Department of Bioinformatics, Semmelweis University, Budapest, Hungary TTK Cancer Biomarker Research Group, Institute of Enzymology, Budapest, Hungary Department of Neurosurgery, University of Michigan, Ann Arbor, MI, United States Department of Neurology, University of Michigan, Ann Arbor, MI, United States Department of Molecular and Integrative Physiology, Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI, United States Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI, United States Export Date: 7 February 2024 Correspondence Address: Zhou, W.; Department of Radiation Oncology, 1301 Catherine Street, Room 4433D, Medical Science Building 1, United States; email: zhouweih@umich.edu Correspondence Address: Wahl, D.R.; Department of Radiation Oncology, 1500 E Medical Center Dr, United States; email: dwahl@med.umich.edu Chemicals/CAS: 2',3' dideoxyguanosine triphosphate, 68726-28-3; bleomycin, 11056-06-7, 9041-93-4; guanosine triphosphate, 86-01-1; hydroxyproline, 51-35-4, 6912-67-0; phosphoprotein phosphatase, 9025-75-6; protein phosphatase 2c; serine, 56-45-1, 6898-95-9; vincristine, 57-22-7; Guanosine Triphosphate Funding details: U083054 Funding details: National Institutes of Health, NIH, R01CA148828, R01CA244931, R01CA245546, R01CA248160, R01DK095201, R35HL144979, R37CA237421 Funding details: National Cancer Institute, NCI, K08CA234416, R37CA258346 Funding details: National Institute of Neurological Disorders and Stroke, NINDS, R01NS129123 Funding details: Alex's Lemonade Stand Foundation for Childhood Cancer, ALSF, 63/416,146 Funding details: Sontag Foundation Funding details: AbbVie Funding details: Boehringer Ingelheim Funding details: A. Alfred Taubman Medical Research Institute Funding details: Crohn's and Colitis Foundation, CCF, 623914, DP2 OD030734, F32CA260735 Funding details: University of Michigan Comprehensive Cancer Center, P30CA046592 Funding details: Nemzeti Kutatási Fejlesztési és Innovációs Hivatal, NKFI, R01CA240515, RRF-2.3.1-21-2022-00015, TKP2021-NVA-15 Funding text 1: S.G. Zhao reports unrelated patents licensed to Veracyte, Tempus, and that a family member is an employee of Artera and holds stock in Exact Sciences. J.N. Sarkaria reports grants from Forma, AbbVie, Boehringer Ingelheim, Bayer, Wayshine, Boston Scientific, AstraZeneca, Black Diamond, Karyopharm, Rain Therapeutics, KLT Health, Sumitomo Dainippon Pharma Oncology, ABL Bio, Modi-fiBio, SK Biopharmaceuticals, and Wugen outside the submitted work. Y. Umemura reports grants from Gateway for Cancer Research during the conduct of the study; personal fees from Servier and Oncoboard outside the submitted work. M.A. Morgan reports grants and personal fees from AstraZeneca outside the submitted work. C.A. Lyssiotis reports personal fees from Odyssey Therapeutics, Third Rock Ventures, Astellas Pharmaceuticals, and T-Knife Therapeutics outside the submitted work; in addition, C.A. Lyssiotis has US Patent No. 2015126580-A1 issued, US Patent No. 20190136238 issued, and International Patent No. WO2013177426-A2 issued. D.R. Wahl reports grants from NIH/NCI during the conduct of the study; personal fees from Agios/Servier, Innocrin Inc, Admare, Bruker, grants from Damon Runyon Cancer Foundation, Sontag Foundation, Ben and Catherine Ivy Glioblastoma Foundation, Chad Tough Defeat DIPG Foundation, Alex’s Lemonade Stand Foundation, and Forbes Institute for Cancer Discovery outside the submitted work; in addition, D.R. Wahl has a patent for “methods of assessing metabolic flux” (No. 63/416,146) pending. No disclosures were reported by the other authors. Funding text 2: We thank Steven Krongenberg for his assistance with illustrations. D.R. Wahl was supported by grants from the Forbes Institute for Cancer Discovery, the NCI (R37CA258346; K08CA234416), the National Institute of Neurological Disorders and Stroke (R01NS129123), the Damon Runyon Cancer Foundation, the Sontag Foundation, the Ivy Glioblastoma Foundation, Alex’s Lemonade Stand Foundation, and the Chad Tough Defeat DIPG foundation. D.R. Wahl is also funded through the Emerging Scholars program of the Taubman Institute via a gift from William Parfet. W. Zhou was supported by the University of Michigan Medical School Pandemic Research Recovery grant (U083054). S. Solanki was supported by a Crohn’s and Colitis Foundation Research fellow award (623914). A.J. Scott was supported by NCI (F32CA260735). S.G. Zhao was supported by DP2 OD030734. B. Győrffy was supported by the National Research, Development and Innovation Office RRF-2.3.1-21-2022-00015 and TKP2021-NVA-15. M.A. Morgan was supported by NCI (R01CA240515) and the University of Michigan Comprehensive Cancer Center (UMCCC) Core Grant (P30CA046592). M. Peters-Golden was supported by NIH (R35HL144979). C.A. Lyssiotis was supported by NIH/NCI grants (R37CA237421, R01CA248160, and R01CA244931) and UMCCC Core Grant (P30CA046592). Y.M. Shah was supported by NIH grants (R01CA148828, R01CA245546, and R01DK095201) and UMCCC Core Grant (P30CA046592). LA - English DB - MTMT ER -