Article
Multidisciplinary Sciences
Donghai Wang, Zhinang Yin, Honghong Wang, Liyuan Wang, Tianyu Li, Ruijing Xiao, Ting Xie, Ruyi Han, Rui Dong, Hudan Liu, Kaiwei Liang, Guoliang Qing
Summary: MYCN amplification in neuroblastoma leads to aberrant expression of MYCN oncoprotein, which activates active genes and enhances transcriptional elongation. Super elongation complex (SEC) is identified as a vulnerability in MYCN-amplified neuroblastomas and is recruited by MYCN to enhance processive transcription elongation. Inhibition of SEC leads to global reduction in transcription elongation and selective apoptosis of MYCN-amplified neuroblastoma cells, and synergistically enhances the therapeutic efficacy of BCL-2 antagonist ABT-199 in MYCN-amplified neuroblastomas.
Review
Biochemistry & Molecular Biology
Soraya Epp, Shin Mei Chuah, Melinda Halasz
Summary: This review examines the intricate interplay between MYCN and known epigenetic mechanisms in neuroblastoma, and provides insights into emerging therapeutic strategies targeting these mechanisms to improve patient outcomes.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Daniele Mercatelli, Nicola Balboni, Alessandro Palma, Emanuela Aleo, Pietro Paolo Sanna, Giovanni Perini, Federico Manuel Giorgi
Summary: The study investigated two cell lines, BE2C and Kelly, of neuroblastoma, showing distinct transcriptional network activities with BE2C having more mesenchymal characteristics compared to Kelly. Single-cell data revealed that MYCN is not constantly active in these cells, and highlighted higher variance in metallothionein transcripts in Kelly cells.
Article
Multidisciplinary Sciences
Mark W. Zimmerman, Adam D. Durbin, Shuning He, Felix Oppel, Hui Shi, Ting Tao, Zhaodong Li, Alla Berezovskaya, Yu Liu, Jinghui Zhang, Richard A. Young, Brian J. Abraham, A. Thomas Look
Summary: Retinoids can reprogram enhancer landscape to down-regulate MYCN expression and establish a new retino-sympathetic CRC, causing proliferative arrest and inducing differentiation.
Article
Oncology
Tao Liu, Lubing Gu, Zhongzhi Wu, Najah Albadari, Wei Li, Muxiang Zhou
Summary: Amplification of MYCN gene leads to overexpression of MYCN mRNA and protein, which plays a role in promoting neuroblastoma. A small molecule compound MX25-1 can bind to the 3'UTR of MYCN mRNA and induce its degradation, resulting in cell growth inhibition and cell death specifically in MYCN-amplified neuroblastoma cells. The activation of tumor suppressor miRNA let-7 is associated with the anticancer activity of MX25-1.
FRONTIERS IN ONCOLOGY
(2022)
Article
Multidisciplinary Sciences
Hai-Feng Zhang, Alberto Delaidelli, Sumreen Javed, Busra Turgu, Taylor Morrison, Christopher S. Hughes, Xiaqiu Yang, Manideep Pachva, Michael M. Lizardo, Gurdeep Singh, Jennifer Hoffmann, Yue Zhou Huang, Khushbu Patel, Rawan Shraim, Sonia H. Y. Kung, Gregg B. Morin, Samuel Aparicio, Daniel Martinez, John M. Maris, Kristopher R. Bosse, Karla C. Williams, Poul H. Sorensen
Summary: This study reveals that GREB1 gene, located near MYCN locus, is frequently coexpressed with MYCN and promotes cell survival in high-risk neuroblastoma (NB). The research also identifies MYO1B gene as a crucial regulator of invasion and metastasis in MYCN amplified NB. Furthermore, MYO1B is found to regulate secretome reprogramming and the cytokine MIF mediates its pro-invasive and pro-metastatic activity.
Article
Oncology
Danny Misiak, Sven Hagemann, Jessica L. Bell, Bianca Busch, Marcell Lederer, Nadine Bley, Johannes H. Schulte, Stefan Huttelmaier
Summary: MYCN gene amplification and upregulated expression are critical in high-risk neuroblastoma progression. MYCN is tightly regulated in neuroblastoma, including post-transcriptional control and modulation of microRNA expression. Dysregulation of MYCN expression and miRNAs is associated with neuroblastoma pathogenesis, with potential implications for therapeutic targeting.
FRONTIERS IN ONCOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Xu Pan, Xin Li, Jie Sun, Zhiying Xiong, Haoyu Hu, Shangwei Ning, Hui Zhi
Summary: This study reveals that DNA methylation can drive tissue-specific enhancer basal transcription and target gene expression in human cancers. By integrating methylome, transcriptome, and 3D genomic data, enhancer methylation triplets were identified and regulatory patterns within them were dissected. Cancer-specific core TFs regulated by enhancers were observed to shape enhancer methylation forming enhancer methylation-driven CRCs (emCRCs).
Article
Oncology
Kezhe Tan, Jialin Mo, Meng Li, Yu Dong, Yujie Han, Xi Sun, Yingxuan Ma, Kai Zhu, Wei Wu, Li Lu, Jiangbin Liu, Kewen Zhao, Lei Zhang, Yujie Tang, Zhibao Lv
Summary: This study reveals the important role of SMAD9 in neuroblastoma and its positive transcriptional feedback loop with MYCN, representing a unique tumor dependency for MYCN-amplified neuroblastoma.
JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
(2022)
Article
Oncology
Felix Schmitt-Hoffner, Sjoerd van Rijn, Umut H. Toprak, Monika Mauermann, Felix Rosemann, Anke Heit-Mondrzyk, Jens-Martin Hubner, Aylin Camgoz, Sabine Hartlieb, Stefan M. Pfister, Kai-Oliver Henrich, Frank Westermann, Marcel Kool
Summary: Activation of FOXR2 identifies a subset of neuroblastoma tumors with unfavorable outcomes, potentially related to MYCN; The study confirms the importance of FOXR2 in neuroblastoma through data analysis and cell experiments, indicating its involvement in cell cycle, growth, and death; FOXR2 stabilizes MYCN protein, impacting patient clinical outcomes.
JOURNAL OF CLINICAL ONCOLOGY
(2021)
Article
Oncology
Adam D. Durbin, Tingjian Wang, Virangika K. Wimalasena, Mark W. Zimmerman, Deyao Li, Neekesh Dharia, Luca Mariani, Noha A. M. Shendy, Stephanie Nance, Anand G. Patel, Ying Shao, Maya Mundada, Lily Maxham, Paul M. C. Park, Logan H. Sigua, Ken Morita, Amy Saur Conway, Amanda L. Robichaud, Antonio R. Perez-Atayde, Melissa J. Bikowitz, Taylor R. Quinn, Olaf Wiest, John Easton, Ernst Schonbrunn, Martha L. Bulyk, Brian J. Abraham, Kimberly Stegmaier, A. Thomas Look, Jun Qi
Summary: Gene expression is regulated by histone modifications, and EP300 plays a significant role in high-risk neuroblastoma. The compound JQAD1, which targets EP300, effectively induces cell apoptosis in neuroblastoma cells with limited toxicity to normal cells.
Article
Oncology
Birte Arlt, Christin Zasada, Katharina Baum, Jasmin Wuenschel, Guido Mastrobuoni, Marco Lodrini, Kathy Astrahantseff, Annika Winkler, Johannes H. Schulte, Sabine Finkler, Martin Forbes, Patrick Hundsdoerfer, Dennis Guergen, Jens Hoffmann, Jana Wolf, Angelika Eggert, Stefan Kempa, Hedwig E. Deubzer
Summary: This study identified a correlation between MYCN amplification and PHGDH protein as well as de novo serine synthesis. MYCN-amplified cells showed independence from exogenous serine and glycine, and PHGDH knockout or inhibition slowed proliferation but did not kill the cells, leading to chemotherapy resistance in neuroblastoma treatment. The limited attractiveness of PHGDH inhibition with small molecules in neuroblastoma patients was also discussed.
INTERNATIONAL JOURNAL OF CANCER
(2021)
Article
Cell Biology
Zhihui Liu, Xiyuan Zhang, Man Xu, Haiyan Lei, Jack F. Shern, Carol J. Thiele
Summary: The neural crest lineage regulatory transcription factors (TFs) play a crucial role in neuroblastoma (NB) by forming a core regulatory circuitry (CRC) to specify a specific tumor phenotype. This study focuses on the tumor suppressor CASZ1, which is silenced in NB tumor cells while the CRC components are highly expressed. The research findings indicate that the CRC component HAND2 directly represses CASZ1 expression. Restoring CASZ1 function upregulates noradrenergic neuronal genes and represses CRC component expression by remodeling enhancer activity, forming a negative feedback regulatory circuit with the established NB CRC to induce noradrenergic neuronal differentiation.
CELL DEATH & DISEASE
(2022)
Article
Multidisciplinary Sciences
Bieke Decaesteker, Amber Louwagie, Siebe Loontiens, Fanny De Vloed, Sarah-Lee Bekaert, Juliette Roels, Suzanne Vanhauwaert, Sara De Brouwer, Ellen Sanders, Alla Berezovskaya, Geertrui Denecker, Eva D'haene, Stephane Van Haver, Wouter Van Loocke, Jo Van Dorpe, David Creytens, Nadine Van Roy, Tim Pieters, Christophe Van Neste, Matthias Fischer, Pieter Van Vlierberghe, Stephen S. Roberts, Johannes Schulte, Sara Ek, Rogier Versteeg, Jan Koster, Johan van Nes, Mark Zimmerman, Katleen De Preter, Frank Speleman
Summary: SOX11 is identified as a potential epigenetic master regulator upstream of the core regulatory circuitry in adrenergic high-risk neuroblastoma.
NATURE COMMUNICATIONS
(2023)
Article
Medicine, Research & Experimental
Kausik Bishayee, Uddin Md. Nazim, Vijay Kumar, Jieun Kang, Jaebong Kim, Sung-Oh Huh, Ali Sadra
Summary: In MYCN-amplified neuroblastoma, treatment with the HDAC inhibitor vorinostat leads to a reprogramming of the glycolytic pathway, increasing fatty acid oxidation and oxidative phosphorylation. This reprogramming is correlated with reduced levels of MYCN and increased levels of PPARD transcription factors. Additionally, the combination of HDAC and mTORC1 inhibitors increases reactive oxygen species levels. The glycolytic enzymes HK2 and GPI are most affected by this combination. Overall, this combination treatment shows promising results without causing significant toxicity in mice.
BIOMEDICINE & PHARMACOTHERAPY
(2022)
Article
Biochemistry & Molecular Biology
Joshua Pan, Jason J. Kwon, Jessica A. Talamas, Ashir A. Borah, Francisca Vazquez, Jesse S. Boehm, Aviad Tsherniak, Marinka Zitnik, James M. McFarland, William C. Hahn
Summary: In high-throughput functional genomic screens, single gene perturbations can induce multiple cascading functional outcomes, known as pleiotropy. Our approach successfully recovered pleiotropic functions, untangled signaling pathways, and predicted unknown protein complex subunit stoichiometry using fitness screen data alone.
Meeting Abstract
Oncology
Lisa D. Cervia, Tsukasa Shibue, Benjamin Gaeta, Ashir A. Borah, Lisa Leung, Naomi Li, Nancy Dumont, Alfredo Gonzalez, Nolan Bick, Mariya Kazachkova, Joshua M. Dempster, John M. Krill-Burger, Federica Piccioni, Namrata D. Udeshi, Meagan E. Olive, Steven A. Carr, David E. Root, James M. McFarland, Francisca Vazquez, William C. Hahn
Article
Biochemistry & Molecular Biology
Chenlu Wang, Qiqin Xu, Xianhong Zhang, Daniel S. Day, Brian J. Abraham, Kehuan Lun, Liang Chen, Jie Huang, Xiong Ji
Summary: This study investigates the functions of BET protein BRD2 in transcription and its relationship with other BET proteins. The results show that BRD2 is involved in the initiation and elongation of Pol II and plays a role in regulating cell state.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2022)
Article
Cell Biology
Diana Y. Y. Lu, Jana M. Ellegast, Kenneth N. Ross, Clare F. Malone, Shan Lin, Nathaniel W. Mabe, Neekesh V. Dharia, Ashleigh Meyer, Amy Conway, Angela H. H. Su, Julia Selich-Anderson, Cenny Taslim, Andrea K. Byrum, Bo Kyung A. Seong, Biniam Adane, Nathanael S. Gray, Miguel N. Rivera, Stephen L. Lessnick, Kimberly Stegmaier
Summary: Transcription factors (TFs) are often mutated in cancer, but pediatric cancers exhibit few genome-wide mutations yet frequently have sentinel mutations affecting TFs. This study describes an alternative, central transcriptional mechanism in Ewing sarcoma wherein the constraint of the fusion TF EWS-FLI's activity supports cancer growth. ETV6 is identified as a crucial TF in this disease, repressing the transcriptional output of EWS-FLI.
NATURE CELL BIOLOGY
(2023)
Article
Oncology
Lisa D. Cervia, Tsukasa Shibue, Ashir A. Borah, Benjamin Gaeta, Linh He, Lisa Leung, Naomi Li, Sydney M. Moyer, Brian H. Shim, Nancy Dumont, Alfredo Gonzalez, Nolan R. Bick, Mariya Kazachkova, Joshua M. Dempster, John Michael Krill-Burger, Federica Piccioni, Namrata D. Udeshi, Meagan E. Olive, Steven A. Carr, David E. Root, James M. McFarland, Francisca Vazquez, William C. Hahn
Summary: By measuring gene essentiality in 1,086 cancer cell lines, we identified a ubiquitin ligase complex composed of UBA6, BIRC6, KCMF1, and UBR4 that is crucial for the survival of a subset of epithelial tumors with high aneuploidy. Inhibiting BIRC6 in cell lines dependent on this complex significantly reduced cell fitness in vitro and resulted in tumor regression in vivo. Mechanistically, BIRC6 suppression activated the integrated stress response (ISR) by stabilizing the heme-regulated inhibitor, which is a direct ubiquitination target of the UBA6/BIRC6/KCMF1/UBR4 complex. This discovery provides insights into the regulation of ISR and offers a potential therapeutic strategy.
Biographical-Item
Oncology
Gary S. Stein, Carlo M. Croce
Article
Oncology
Alessandro La Ferlita, Nipin Sp, Marina Goryunova, Giovanni Nigita, Raphael E. Pollock, Carlo M. Croce, Joal D. Beane
Summary: Soft-tissue sarcomas (STS), a rare and diverse group of tumors, have various subtypes characterized by differences in tumor biology and clinical outcomes. Small non-coding RNAs (sncRNAs), including miRNAs and tRNA-derived ncRNAs, play important roles in STS tumorigenesis and differentiation. However, the translation of these findings into clinical applications, such as biomarkers or therapeutic targets, remains challenging. This review summarizes the current understanding of sncRNAs in STS, with a focus on liposarcoma, and discusses their potential as novel biomarkers and therapeutic targets.
MOLECULAR CANCER RESEARCH
(2023)
Article
Multidisciplinary Sciences
Megan L. Insco, Brian J. Abraham, Sara J. Dubbury, Ines H. Kaltheuner, Sofia Dust, Constance Wu, Kevin Y. Chen, David Liu, Stanislav Bellaousov, Anna M. Cox, Benjamin J. E. Martin, Tongwu Zhang, Calvin G. Ludwig, Tania Fabo, Rodsy Modhurima, Dakarai E. Esgdaille, Telmo Henriques, Kevin M. Brown, Stephen J. Chanock, Matthias Geyer, Karen Adelman, Phillip A. Sharp, Richard A. Young, Paul L. Boutz, Leonard I. Zon
Summary: RNA surveillance pathways detect and degrade defective transcripts to maintain RNA fidelity. Disruption of nuclear RNA surveillance is found to be oncogenic, with CDK13 mutation causing aberrant RNA stabilization and failed activation of nuclear RNA surveillance. Activating nuclear RNA surveillance is crucial to prevent the accumulation of aberrant RNAs and their consequences in development and disease.
Article
Oncology
Ricardo de Matos Simoes, Ryosuke Shirasaki, Sondra L. Downey-Kopyscinski, Geoffrey M. Matthews, Benjamin G. Barwick, Vikas A. Gupta, Daphne Dupere-Richer, Shizuka Yamano, Yiguo Hu, Michal Sheffer, Eugen Dhimolea, Olga Dashevsky, Sara Gandolfi, Kazuya Ishiguro, Robin M. Meyers, Jordan G. Bryan, Neekesh V. Dharia, Paul J. Hengeveld, Johanna B. Bruggenthies, Huihui Tang, Andrew J. Aguirre, Quinlan L. Sievers, Benjamin L. Ebert, Brian J. Glassner, Christopher J. Ott, James E. Bradner, Nicholas P. Kwiatkowski, Daniel Auclair, Joan Levy, Jonathan J. Keats, Richard W. J. Groen, Nathanael S. Gray, Aedin C. Culhane, James M. McFarland, Joshua M. Dempster, Jonathan D. Licht, Lawrence H. Boise, William C. Hahn, Francisca Vazquez, Aviad Tsherniak, Constantine S. Mitsiades
Summary: Clinical progress in multiple myeloma has been limited due to the lack of therapies targeting specific oncogenic mutations. However, a study using CRISPR technology identified 116 genes that significantly affect the fitness of MM cells compared to other malignancies. These genes encode various factors critical for MM cell biology and provide new therapeutic targets not easily identifiable by standard genomic analysis.
Article
Biochemistry & Molecular Biology
Henry R. Kilgore, Peter G. Mikhael, Kalon J. Overholt, Ann Boija, Nancy M. Hannett, Catherine Van Dongen, Tong Ihn Lee, Young-Tae Chang, Regina Barzilay, Richard A. Young
Summary: This research reveals that different types of intracellular condensates have distinct chemical environments that affect molecular distribution. Machine learning approaches can predict the selective partitioning of molecules in condensates, providing insights for the development of small molecule therapeutics with optimal subcellular distribution and therapeutic benefits.
NATURE CHEMICAL BIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Yuxiang Zhang, David Remillard, Ugoma Onubogu, Barbara Karakyriakou, Joshua N. Asiaban, Anissa R. Ramos, Kirsten Bowland, Timothy R. Bishop, Paige A. Barta, Stephanie Nance, Adam D. Durbin, Christopher J. Ott, Michalina Janiszewska, Benjamin F. Cravatt, Michael A. Erb
Summary: The authors discovered a genetic interaction between HDAC1 and HDAC2, with each paralog being synthetically lethal with hemizygous deletion of the other. Targeting HDAC2 suppresses the growth of HDAC1-deficient neuroblastoma by degrading the NuRD complex, leading to diminished chromatin accessibility and impaired control of enhancer-associated transcription. The degraded NuRD complex subunits are dependencies in neuroblastoma and multiple myeloma, suggesting a potential therapeutic target.
NATURE STRUCTURAL & MOLECULAR BIOLOGY
(2023)
Article
Multidisciplinary Sciences
Jie Fang, Shivendra Singh, Changde Cheng, Sivaraman Natarajan, Heather Sheppard, Ahmed Abu-Zaid, Adam D. Durbin, Ha Won Lee, Qiong Wu, Jacob Steele, Jon P. Connelly, Hongjian Jin, Wenan Chen, Yiping Fan, Shondra M. Pruett-Miller, Jerold E. Rehg, Selene C. Koo, Teresa Santiago, Joseph Emmons, Stefano Cairo, Ruoning Wang, Evan S. Glazer, Andrew J. Murphy, Taosheng Chen, Andrew M. Davidoff, Carolina Armengol, John Easton, Xiang Chen, Jun Yang
Summary: A improved MYC-driven hepatoblastoma-like murine model is developed and characterized in this study, which recapitulates the pathological features of embryonal type of hepatoblastoma and shows transcriptomics resembling the high-risk gene signatures of the human disease. Single-cell RNA-sequencing and CRISPR-Cas9 screening are used to identify distinct subpopulations of hepatoblastoma cells and druggable targets shared with human hepatoblastoma. The study also reveals genetic modifiers of chemotherapy response and suggests a potential therapeutic strategy for human hepatoblastoma.
NATURE COMMUNICATIONS
(2023)
Review
Cell Biology
Noha A. M. Shendy, Mark W. Zimmerman, Brian J. Abraham, Adam D. Durbin
Summary: Cell state is controlled by master transcription factors that determine gene expression program, and cancer cells acquire dysregulated gene expression programs through mutational and non-mutational processes. Neuroblastoma, a high-risk tumor, is associated with transcriptionally regulated heterogeneity, and different cohorts of master transcription factors contribute to the distinct cellular populations and differential sensitivity to treatment. Recent studies have identified opportunities to control the cellular response to treatment by manipulating transcriptional programs defining cell states.
CELL REPORTS MEDICINE
(2022)
Article
Oncology
Daniel P. Bondeson, Brenton R. Paolella, Adhana Asfaw, Michael Rothberg, Thomas A. Skipper, Carly Langan, Gabriel Mesa, Alfredo Gonzalez, Lauren E. Surface, Kentaro Ito, Mariya Kazachkova, William N. Colgan, Allison Warren, Joshua M. Dempster, John M. Krill-Burger, Maria Ericsson, Andrew A. Tang, Iris Fung, Emily S. Chambers, Mai Abdusamad, Nancy Dumont, John G. Doench, Federica Piccioni, David E. Root, Jesse Boehm, William C. Hahn, Michael Mannstadt, James M. McFarland, Francisca Vazquez, Todd R. Golub
Summary: Despite advances in precision medicine, the clinical prospects for patients with ovarian and uterine cancers remain bleak. In this study, the authors identified a correlation between overexpression of the phosphate importer SLC34A2 and sensitivity to the phosphate exporter XPR1 in cancer cell lines. They also observed this correlation in patient-derived tumor samples. Inhibition of phosphate efflux led to intracellular phosphate accumulation and reduced tumor cell viability.