bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A011: Epigenetic vulnerabilities in patient-derived colorectal cancer organoids
Authors: Tran Loan , Tezerji Raheleh Sheibani , Malla Carlos Uziel Perez , Malzer Anna , Logo Ajna , Misura Katarina , Mair Theresia , Dillinger Thomas , Kuroll Madeleine , Atanasova Velina , Kabiljo Julijan , Schachner Helga , Wöran Katharina , Stift Judith , Dolznig Helmut , Pulverer Walter , Bergmann Michael , Egger Gerda 
Published: December 2022

Abstract
Colorectal cancer (CRC) is a major cause of cancer-related deaths worldwide. Here, we established human patient-derived colorectal cancer organoid cultures (PDOs) to decipher the patient-specific DNA methylation profile and drug sensitivity towards 5-aza-2’-deoxycytidine, a DNA methyltransferase inhibitor. Organoid lines (n=15) were generated from adjacent normal mucosa and tumor tissue located in different anatomical sites of the colon and rectum. The derived PDOs were characterized on a histopathological level and reproduced the grade and differentiation capacity of their parental tumors. Additional genotypic profiling of PDOs showed a high degree of similarity to the original patient tumors. However, the stability of the DNA methylation landscape of human cancer organoids remains largely unknown. In genome-wide methylation analysis of long-term organoid cultures (up to 6 months in culture), we observed surprisingly stable methylation signatures that recapitulates the patient’s profile whilst demonstrating the vast intertumoral heterogeneity among patients. Strikingly, we identified a tumor-specific methylation signature that consisted of 39 CpG sites, which were unmethylated in normal epithelial cells but highly (91-96%) methylated in all tumor cells analyzed. This signature allows for the estimation of the percentage of tumor content in resected tissues and might represent potent biomarkers for early CRC diagnostics. Notably, it has been demonstrated that PDOs have the potential to predict clinical outcome and response to chemo- and radiation therapy in patients. Herein, drug screening with 5-aza-2’-deoxycytidine revealed heterogeneous responses and a clustering into drug sensitive, median and resistant organoid lines. ATAC- and RNA-seq analyses identified pathways rendering drug sensitivity and resistance. Our findings highlight the utility of PDOs as an advanced model system to study the role of the epigenome, especially DNA methylation, and its impact on tumor burden and vulnerability towards epigenetic modifiers.
Citation Format: Loan Tran, Raheleh Sheibani Tezerji, Carlos Uziel Perez Malla, Anna Malzer, Ajna Logo, Katarina Misura, Theresia Mair, Thomas Dillinger, Madeleine Kuroll, Velina Atanasova, Julijan Kabiljo, Helga Schachner, Katharina Wöran, Judith Stift, Helmut Dolznig, Walter Pulverer, Michael Bergmann, Gerda Egger. Epigenetic vulnerabilities in patient-derived colorectal cancer organoids. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr A011.
Abstract A015: Cancer co-dependency mapping identifies a functional interplay between PRC2 and MLL-MEN1 complex in lymphoma
Authors: Chen Xiao , Li Yinglu , Lu Chao 
Published: December 2022

Abstract
Interplays between chromatin-associated complexes and modifications critically contribute to the partitioning of epigenome into stable and functionally distinct domains. Yet there is a lack of systematic identification of chromatin crosstalk mechanisms, limiting our understanding of the dynamic transition between chromatin states during development and disease. Here we perform co-dependency mapping of genes encoding nuclear proteins using CRISPR-Cas9-mediated fitness screens in pan-cancer cell lines to quantify gene-gene functional relationships. We identify 84 co-dependency modules and further define the molecular context underlying the essentiality of these modules by incorporating mutational, epigenome, gene expression and drug sensitivity profiles of cell lines. These analyses assign new protein complex functions and biochemical interactions, and predict new chromatin crosstalk, including an unexpected co-dependency between two transcriptionally counteracting chromatin complexes - polycomb repressive complex 2 (PRC2) and MLL-MEN1 complex. We show that PRC2-mediated H3K27 tri-methylation regulates the genome-wide distribution of MLL1 and MEN1. In lymphoma cells with EZH2 gain-of-function mutations, the re-localization of MLL-MEN1 complex drives oncogenic gene expression and results in a hypersensitivity to pharmacologic inhibition of MEN1. Together, our findings provide a resource for discovery of trans-regulatory interactions as mechanisms of chromatin regulation and potential targets of synthetic lethality.
Citation Format: Xiao Chen, Yinglu Li, Chao Lu. Cancer co-dependency mapping identifies a functional interplay between PRC2 and MLL-MEN1 complex in lymphoma. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr A015.
Abstract A032: MUC1-C regulates chromatin remodeling and drives the CSC state in human cancers
Authors: Bhattacharya trayee , Fushimi Atsushi , Yamashita Nami , Liu Tao , Liu Song , Kufe Donald W. 
Published: December 2022

Abstract
The oncogenic MUC1-C protein evolved in mammals to protect epithelial barrier tissues from the external environment. Chronic activation of MUC1-C promotes lineage plasticity, epigenetic reprogramming, and carcinogenesis. MUC1-C also induces the Yamanaka Pluripotency factors. Chromatin remodeling is critical for the cancer stem cell (CSC) state. Our studies have demonstrated that MUC1-C regulates chromatin remodeling by (i) activating the EZH2/PRC2 complex leading to H3K27 trimethylation, and (ii) the BMI1/PRC1 complex with H2A ubiquitylation. In addition, MUC1-C regulates global changes in chromatin accessibility that are mediated at least in part by JUN/AP-1 and ARID1A/BAF in association with driving the CSC state. We also found that silencing MUC1-C suppresses bulk H3K4 trimethylation and H3K27 acetylation levels in diverse human cancer cells. The COMPASS family of H3K4 methyl transferases (HMT) methylate histone H3K4 and the histone acetyl transferase (HAT) p300/CBP family catalyzes H3K27 acetylation. Involvement of MUC1-C in the regulation of COMPASS has not been previously reported. This study demonstrates that MUC1-C induces COMPASS SET1A and WDR5 gene expression by NF-kB p65-mediated transactivation. WDR5 is required for SET1A complex HMT activity. We found that MUC1-C and WDR5 are necessary for expression of FOS, ATF3 and other AP-1 family members. In a positive feedback loop, MUC1-C, WDR5 and AP-1 were shown to be responsible for induction of genes encoding effectors, including TRAF1 and RELB, in the chronic NF-kB inflammatory response. We also found that MUC1-C, NF-kB, WDR5 and AP-1 are necessary for induction of the (i) KLF4 master regulator of the pluripotency network, and (ii) NOTCH1 effector of stemness. Mechanistically, MUC1-C/NF-kB complexes recruit SET1A/WDR5 and AP-1 to enhancer-like signatures in these target genes, increase the deposition of H3K4me3 with the opening of chromatin, and activate their transcription. These findings demonstrate that MUC1-C activates the COMPASS SET1A/WDR5 complex in integrating the induction of genes that promote chronic inflammation, pluripotency, and the CSC state.
Citation Format: trayee Bhattacharya, Atsushi Fushimi, Nami Yamashita, Tao Liu, Song Liu, Donald W. Kufe. MUC1-C regulates chromatin remodeling and drives the CSC state in human cancers. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr A032.
Abstract B013: Suppression of TET1 expression down-regulates p16 and contributes to the resistance of SWI/SNF LOF tumors to PRC2 inhibition
Authors: Zhang Hailong 
Published: December 2022

Abstract
Polycomb repressive complex 2 (PRC2) drives the expansion of H3K27me3 epigenetic marker and suppress the expression of target genes including tumor suppressors. Activation mutations of EZH2, the catalytic subunit of the PRC2 complex, are thought to be the driver for certain malignancies such as diffused large B cell lymphoma (DLBCL). The SWI/SNF complex remodels nucleosomes to modulate transcription, they are generally considered as tumor suppressors and loss-of-function (LOF) mutations are frequently found across a wide variety of cancers. Many studies suggest that PRC2 is important for the proliferation of tumor cells with SWI/SNF LOF mutations, indeed, EZH2 inhibitor tazemetostat was approved by FDA for epithelioid sarcoma with SWI/SNF subunit SMARCB1 deletion. While not all SWI/SNF LOF tumors respond to PRC2 inhibition, we would like to know what subset of these tumors are sensitive to PRC2 inhibition. In this study, we have developed a potent and selective PRC2 inhibitor BR1763 which blocks the interaction of EED with tri-methylated histone H3 at Lys 27 (H3K27me3) and inhibits cellular H3K27me3 levels. By analyzing the gene expression patterns of BR1763 treated cells, we found that up-regulation of CDKN2A/p16 and down-regulation of E2F downstream gene are essential for cellular response to PRC2 inhibition. Further studies also confirmed that PRC2 inhibition caused P16 up-regulation and induced cell senescence for the sensitive cells. Importantly, suppression of TET1 expression contributes to the resistance to PRC2 inhibition in SWI/SNF LOF tumors, which may be caused by PcG hypermethylation on p16 promoters. TET1 expression, together with SWI/SNF LOF mutation status, can largely predict the sensitivity of tumor cells to PRC2 inhibition.
Citation Format: Hailong Zhang. Suppression of TET1 expression down-regulates p16 and contributes to the resistance of SWI/SNF LOF tumors to PRC2 inhibition. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr B013.
Abstract B015: Versatile biochemical and genomic platforms for drug discovery in chromatin remodeling research
Authors: Husby Natalia L. , Sun Lu , Willis Hannah , Marunde Matthew R. , Meiners Matt J. , Gillespie Zachary , Watson Rachel , Gopinath Saarang , Burg Jonathan M. , Cheek Marcus A. , Novitzky Katherine , Venters Bryan J. , Sun Zu-Wen , Keogh Michael-Christopher 
Published: December 2022

Abstract
Chromatin remodeling, driven by ATP-dependent remodeling enzymes, plays key roles in regulating gene expression, genome replication and repair. Aberrant nucleosome organization can severely disrupt these important processes, driving various cancers and developmental disorders. Remarkably, nearly 20% of all human cancers contain mutations in subunits from the SWI/SNF family of chromatin remodeling complexes, making them attractive therapeutic targets and interests of basic research. However, studies on the remodeling enzymes (and their multi-subunit complexes) in vitro are challenging partially due to the requirement for nucleosome-based substrates. We have created the EpiDyne® nucleosome remodeling substrate portfolio for use in biochemical assays to examine nucleosome immobilizing activities of chromatin remodelers. Here we present the development of multiple remodeling assays on the EpiDyne® platform (EpiDyne®-FRET, EpiDyne®-PicoGreenTM and EpiDyne®-TR-FRET). These nonradioactive plate-based assays are easy to use, ready for high-throughput inhibitor screening, and can be customized for various remodeling enzymes that exhibit distinct preferences in nucleosome compositions. Furthermore, genome-wide mapping of chromatin remodelers is fundamental for understanding their functions in diseases and responses to inhibitors in cells, but is often obscured by unreliable ChIP-seq approaches. To this end, we have optimized the CUTANA™ CUT&RUN approach to efficiently capture localizations of all major classes of chromatin remodelers with high signal to background. As a complementary research tool to the EpiDyne® platform, CUT&RUN facilitates the epigenomic research on chromatin remodelers for drug discoveries.
Citation Format: Natalia L. Husby, Lu Sun, Hannah Willis, Matthew R. Marunde, Matt J. Meiners, Zachary Gillespie, Rachel Watson, Saarang Gopinath, Jonathan M. Burg, Marcus A. Cheek, Katherine Novitzky, Bryan J. Venters, Zu-Wen Sun, Michael-Christopher Keogh. Versatile biochemical and genomic platforms for drug discovery in chromatin remodeling research. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr B015.
Abstract B028: CDK12/13 inhibition antagonizes resistance to KRASG12C inhibitors
Authors: Stern Yaakov E. , Ghosh Pompom , Walker-Mimms Hannah L. , Mosior John W. , Imbody Denis , Solanki Hitendra S. , Monastyrskyi Andrii , Duckett Derek R. , Haura Eric B. 
Published: December 2022

Abstract
Covalent inhibitors selectively targeting the KRASG12C mutation offer a promising new therapeutic opportunity for non-small cell lung cancer (NSCLC) patients, with partial or complete response observed in up to 40% of cancers harboring this lesion. As observed for other precision medicines targeting oncogenic drivers, resistance to these agents develops upon prolonged treatment. We have developed cell-based models of acquired resistance to the KRASG12C inhibitor sotorasib by serial passage of sotorasib-sensitive NSCLC cell lines in the presence of the drug. We have observed dynamic phosphorylation of the transcriptional elongation kinases CDK12 and CDK13 as well as hyperphosphorylation of a network of DNA damage response (DDR) proteins in sotorasib-resistant cell lines by phosphoproteomic profiling of resistant and sensitive cells. This is accompanied by elevated sensitivity to DDR pathway and CDK12/13 (e.g., SR-4835) inhibitors. Combined treatment of NSCLC cell lines with sotorasib and SR-4835 delays or prevents adaptation to sotorasib and the development of acquired resistance. Furthermore, gene expression profiling of SR-4835-treated cells reveals that CDK12/13 inhibition suppresses both DDR gene expression and metabolic pathways associated with resistance to sotorasib. This reflects synergy between SR-4835 and inhibitors targeting the DDR pathway in breast cancer cell lines and demonstrates that transcriptional elongation is a critical vulnerability for cells undergoing adaptation to KRASG12C inhibitors via DDR-dependent mechanisms.
Citation Format: Yaakov E. Stern, Pompom Ghosh, Hannah L. Walker-Mimms, John W. Mosior, Denis Imbody, Hitendra S. Solanki, Andrii Monastyrskyi, Derek R. Duckett, Eric B. Haura. CDK12/13 inhibition antagonizes resistance to KRASG12C inhibitors. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr B028.
Abstract IA002: Structural basis of chromatin transcription
Authors: Farnung Lucas 
Published: December 2022

Abstract
In eukaryotes, RNA polymerase (Pol) II transcribes chromatin and must move past nucleosomes, often resulting in nucleosome displacement. How Pol II unwraps the DNA from nucleosomes to allow transcription and how DNA rewraps to retain nucleosomes has been unclear. I will present the 3.0 Å cryo–electron microscopy structure of a mammalian Pol II-DSIF-SPT6-PAF1c-TFIIS-nucleosome complex stalled 54 base pairs within the nucleosome. The structure provides a mechanistic basis for nucleosome retention during transcription elongation where upstream DNA emerging from the Pol II cleft has rewrapped the proximal side of the nucleosome. The structure uncovers a direct role for Pol II and transcription elongation factors in nucleosome retention and explains how nucleosomes are retained to prevent the disruption of chromatin structure across actively transcribed genes. Importantly, the structure also provides the mechanistic basis for the survival of histone marks during transcription.
Citation Format: Lucas Farnung. Structural basis of chromatin transcription. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr IA002.
Abstract IA004: Novel inhibitors of histone H2B deubiquitinating enzymes
Authors: Wolberger Cynthia 
Published: December 2022

Abstract
Histone H2B-K120 is dynamically ubiquitinated and deubiquitinated during transcription and is a hallmark of actively transcribed genes. The Spt-Ada-Gcn5 acetyltransferase (SAGA) transcriptional coactivator contains a four-protein subcomplex called the deubiquitinating enzyme (DUB) module that removes ubiquitin from histone H2B-K120. The human DUB module contains the catalytic subunit ubiquitin-specific protease 22 (USP22), which is overexpressed in a number of cancers that are resistant to available therapies. We screened a massive combinatorial library of cyclic peptides and identified potent inhibitors of USP22. The top hit was highly specific for USP22 compared with a panel of 44 other human DUBs. Cells treated with peptide had increased levels of H2B monoubiquitination, demonstrating the ability of the cyclic peptides to enter human cells and inhibit H2B deubiquitination. These macrocycle inhibitors are, to our knowledge, the first reported inhibitors of USP22/SAGA DUB module and show promise for drug development.
Citation Format: Cynthia Wolberger. Novel inhibitors of histone H2B deubiquitinating enzymes. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr IA004.
Abstract IA007: Transforming chromatin: Oncohistone mutations in pediatric high-grade glioma
Authors: Budd Kaitlin , Kwon Chang-Hyuk , Kasper Lawryn H. , Roberts Christopher , Roach Jordan , Ocasio-Adorno Jennifer , Larson Jon D. , Baker Suzanne J. 
Published: December 2022

Abstract
Pediatric diffuse high-grade gliomas (HGGs) are a heterogeneous spectrum of disease with abysmal survival rates. Approximately half of diffuse high-grade gliomas in children arise in midline structures predominantly the brainstem, but also thalamus, cerebellum and spinal cord. Approximately 80% of these tumors harbor H3 K27M mutations, which result in dramatic depletion of the post-translational modification H3K27me3. Alternative mutations in diffuse midline gliomas can result in similar reduction of H3K27me3, leading to a redefined classification of this collection of tumors as diffuse midline glioma, H3 K27-altered. In contrast, distinct histone H3 mutations, H3.3 G34R/V, are found in approximately 30% of diffuse gliomas arising in the cerebral hemispheres of older adolescents and young adults, defining the tumor subgroup of diffuse hemispheric glioma, H3 G34-mutant. The striking spatiotemporal pattern of these histone mutations, termed oncohistones, indicates an intimate association between epigenetic dysregulation, brain development, and tumorigenesis. We will discuss use of genetically engineered and patient-derived models to investigate the contribution of oncohistone mutations to disrupted development, epigenetic dysregulation and gliomagenesis.
Citation Format: Kaitlin Budd, Chang-Hyuk Kwon, Lawryn H. Kasper, Christopher Roberts, Jordan Roach, Jennifer Ocasio-Adorno, Jon D. Larson, Suzanne J. Baker. Transforming chromatin: Oncohistone mutations in pediatric high-grade glioma. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr IA007.
Abstract IA020: Therapeutic targeting of MLL complexes in cancer
Authors: Armstrong Scott A. 
Published: December 2022

Abstract
Inappropriate expression of genes such as the homeotic (HOX) genes is found in up to 40% of cases of Acute Myelogenous Leukemia (AML). Two well-defined genetic subsets, those with MLL-rearrangements and those with NPM1 mutations, are known to possess high-level expression of HOX and MEIS1 genes and have been shown to be dependent on continued expression of these genes. Recent studies have defined the chromatin-bound protein complexes that maintain this aberrant gene expression. Furthermore, multiple groups including ours have now developed small molecule inhibitors of chromatin-associated complexes. Some of these small molecules, including those targeting DOT1L, EZH2, and Bromodomains are at various stages of clinical development. Another approach to target chromatin associated complexes is via disruption of protein-protein interactions. One such protein-protein interaction that is being targeted is the interaction between the histone methyltransferase MLL1 and Menin, an approach that has also been shown to reverse leukemogenic HOX/MEIS1 gene expression. We have developed novel, potent and orally bioavailable MLL1-Menin inhibitors and have brought one of these small molecules to clinical assessment. Inhibition of the MLL1-Menin interaction in MLL-rearranged and NPM1 mutant AML cells leads to loss of Menin from chromatin, destabilization of the Menin protein and specific changes in chromatin state that include loss of the MLL1 complex at select loci. This results in selective reversal of leukemogenic gene expression, changes in occupancy of multiple other chromatin complexes, rapid cellular differentiation and cell death. Also, we have recently found this interaction to be critical in subtypes of Sarcoma opening up novel potential therapeutic opportunities. These molecules have remarkable preclinical activity in human disease models including patient derived xenograft (PDX) models, show minimal toxicity and are now in phase I/II clinical trials. Inhibition of protein-protein interactions represents a potentially effective approach to destabilize chromatin associated complexes for cancer therapy.
Citation Format: Scott A. Armstrong. Therapeutic targeting of MLL complexes in cancer. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr IA020.