bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 7016: Plastic epigenome in youth: Insights from open chromatin in stem cells
Authors: Liu Yu-Yu , Takeuchi Chihiro , Yamashita Satoshi , Ushijima Toshikazu 
Published: March 2024

Abstract
The presence of plasticity in the epigenomes of young individuals is suggested by the aggressive phenotypes observed in cancers among adolescent and young adults (AYAs), including gastric cancers. To demonstrate the presence of this plasticity and identify the underlying epigenomic characteristics in gastric stem cells during youth, we examined organoids established from murine stomach tissue and conducted single-cell RNA-seq and ATAC-seq using murine antrum-pyloric tissues at ages of 3 weeks and 50 weeks, corresponding to human infancy and middle-age adult, respectively.
Organoids established from infant mice showed higher dependence to niche factors, and stronger response to cytokine signals. Ligand-receptor analysis using single-cell RNA-seq data of tissues showed that infant epithelial stem cells and stromal cells had stronger interactions. Both supported the plastic nature of infant gastric epithelial cells.
Single-cell ATAC-seq enabled us to identify epithelial stem cell population in infant and middle-aged mice, and 71 and 118 chromatin peaks were specific to infant and adult stem cells, respectively. Motif enrichment analysis showed an enrichment of binding sites for bZIP family transcription factors in infants, and an enrichment of binding sites of a chromatin remodeling factor and a family of transcription factors in adults. Additionally, comparison between differentiated epithelial cells, marked by the pit cell marker Muc5ac, and stem cells, marked by Lgr5, showed more pronounced differences: 46,772 peaks specific to pit cells and 39,076 peaks specific to stem cells. Interestingly, regions specific to pit cells were enriched in binding sites of the chromatin remodeling factor and the family of transcription factors, identical to the open regions specific to adult stem cells. This suggested that the chromatin accessibility profile of aged stem cells approaches to that of differentiated cells, leading to a loss of stemness. The single-cell RNA-seq data also revealed an increase in interactions between differentiated epithelial cells and fibroblasts in aged mice, as opposed to infant, suggesting the emergence of aberrant interactions in aged stomach tissue.
Collectively, our data suggested that chromatin accessibility of gastric stem cells undergo an epigenomic shift during aging, approaching to the profiles of differentiated cells and losing their plasticity, and that a specific chromatin remodeling factor and a family of transcription factors could be involved in the process.
Citation Format: Yu-Yu Liu, Chihiro Takeuchi, Satoshi Yamashita, Toshikazu Ushijima. Plastic epigenome in youth: Insights from open chromatin in stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7016.
Abstract 7024: Development of quality control methods for reliable NGS measurement of methylation in cfDNA
Authors: Willey James C. , Crawford Erin L. , Craig Daniel J. , Morrison Thomas M. , He Hua-Jun , Herman James G. 
Published: March 2024

Abstract
Background and Purpose: Reliable measurement of circulating free genomic DNA (cfDNA) methylation patterns promises a means for cancer early detection as well as treatment response. Use of Next Generation Sequencing (NGS) methods to measure the cfDNA methylome across a large number of potentially methylated CpG sites may enable earlier detection by overcoming stochastic sampling associated with the small specimens obtainable by a blood draw. Wide-spread adoption of these methods for clinical diagnostic applications will be facilitated through improved quality controls that increase reliability. The goal of this study is to assess the performance of the SNAQ-SEQ™ method as a means to establish a limit of detection (LOD) for measurement of methylation at each targeted CpG site. For this purpose, we used test materials that were developed by the National Institute for Standards and Technology (NIST) to mimic methylated cfDNA.
Methods: NIST test materials were formulated by physically shearing cell line gDNA then subjecting it to size separation to mimic a size distribution similar to that observed in cfDNA, then mixing sheared DNA in its “native” state of methylation with sheared DNA that was in vitro methylated. Non-sheared NIST test materials also were assessed in these studies. Synthetic spike-in internal standards (IS) were combined with NIST test materials and the combined samples were bisulfite converted, then subjected to PCR-amplicon library preparation. Libraries were sequenced on an Illumina MiSeq instrument and bioinformatic analysis was conducted using the Qiagen CLC Workbench.
Results and Conclusions: In initial testing of an off-the-shelf IS for a region of the SOX2 gene, average methylation (preserved C) across 14 targeted CpG sites was 16.4% (0.5%-50%) in the “native” NIST non-sheared sample. This was consistent with the 11.6% methylation across all of SOX2 measured by the NIST. In contrast, in IS corresponding to the targeted SOX2 region the average preserved C was 0.32% (0.03%-0.5%). Use of synthetic internal standards enabled determination of LOD for each individual methylated site, controlling for all known sources of technical error, including inefficient bisulfite conversion, nucleotide substitution error, and alignment error. Studies are now underway that use the NIST test materials to measure methylation at five targets known to be altered in cfDNA from lung cancer subjects, SOX2, CDO1, TAC1, SOX17, and HOXA7.
Citation Format: James C. Willey, Erin L. Crawford, Daniel J. Craig, Thomas M. Morrison, Hua-Jun He, James G. Herman. Development of quality control methods for reliable NGS measurement of methylation in cfDNA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7024.
Abstract 7058: NSD2 overexpression drives multiple myeloma dependence on adenylate kinase 2 by diverting one-carbon metabolism to the epigenome
Authors: Sobh Amin , Encinas Elena , Patel Alisha , Surapaneni Greeshma , Kaestner Charlotte , Poullard Janai , Clerio Monica , Vasan Karthik , Freeman Tzipporah , Lv Dongwen , Dupere-Richer Daphne , Riva Alberto , Barwick Benjamin , Zhou Daohong , Boise Lawrence , Mitsiades Constantine , Kim Baek , Bennett Richard , Chandel Navdeep , Licht Jonathan 
Published: March 2024

Abstract
Chromosomal translocation (4;14), an adverse prognostic factor in multiple myeloma (MM), drives overexpression of the oncogenic histone methyltransferase NSD2. Genome-wide CRISPR screens in isogenic MM cells with high and low NSD2 expression identified adenylate kinase 2 (AK2), an enzyme critical for transport of ATP from the mitochondria, as an NSD2-driven vulnerability. AK2 suppression in t(4;14) MM cells decreased NADP(H) critical for conversion of ribonucleotides to deoxyribonucleosides by the enzyme ribonucleotide reductase (RNR). Consequently, metabolomic studies revealed depletion of deoxynucleotide triphosphates (dNTPs) in AK2-deficient t(4;14) MM cells, which resulted in replication stress, DNA damage and apoptosis. Exogenous supplementation with deoxynucleosides rescued AK2 depleted MM cells confirming the role of AK2 in dNTP homeostasis. In addition, NSD2 overexpression drives a large genome-wide increase in chromatin methylation, which depletes the methyl donor S-adenosylmethionine (SAM). Accordingly, we found that high NSD2 expression in MM cells disrupts creatine biosynthesis, a process dependent on SAM. The creatine/phosphocreatine system represents an alternative means of transporting high energy phosphate from the mitochondria. Hence, creatine supplementation restored NADP(H) levels and rescued AK2-deficient t(4;14) MM cells indicating that the hypersensitivity of these cells to AK2 depletion is driven by creatine deficiency due to NSD2 overexpression. Furthermore, AK2 inhibition impaired ATP-dependent protein folding increasing sensitivity of t(4;14) MM cells to proteasome inhibition. These findings delineate a novel mechanism in which aberrant transfer of carbon to the epigenome creates a metabolic vulnerability, with direct therapeutic implications for t(4;14) MM.
Citation Format: Amin Sobh, Elena Encinas, Alisha Patel, Greeshma Surapaneni, Charlotte Kaestner, Janai Poullard, Monica Clerio, Karthik Vasan, Tzipporah Freeman, Dongwen Lv, Daphne Dupere-Richer, Alberto Riva, Benjamin Barwick, Daohong Zhou, Lawrence Boise, Constantine Mitsiades, Baek Kim, Richard Bennett, Navdeep Chandel, Jonathan Licht. NSD2 overexpression drives multiple myeloma dependence on adenylate kinase 2 by diverting one-carbon metabolism to the epigenome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7058.
Abstract 7065: AMBRA1 coordinates mitochondrial function to regulate cancer stemness and tumorigenesis in hepatocellular carcinoma
Authors: Liu Yan , Xie Yunong , He Yimiao , Ma Stephanie , Tong Man 
Published: March 2024

Abstract
Hepatocellular carcinoma (HCC) is a prevalent and aggressive cancer, with emerging evidence highlighting the role of cancer stem cells (CSCs) in its progression. AMBRA1 has been implicated to exert both tumor-promoting and tumor-suppressive roles through regulating cell cycle and mitophagy in various solid tumors. However, the functional roles of AMBRA1 in modulating cancer stemness and tumorigenesis in HCC remain elusive. Initial analysis of The Cancer Genome Atlas data revealed a significant inverse correlation between AMBRA1 expression and stemness indices (TSS) in HCC patients, with low AMBRA1 levels associated with an upregulated oxidative phosphorylation (OXPHOS) gene signature. To elucidate the functional consequences of AMBRA1 modulation in liver tumor development and stemness maintenance, we exploited both hydrodynamic mouse models and human HCC cell lines. Our findings indicate that hepatic AMBRA1 deletion enhances cancer stemness and tumorigenesis both in vivo and in vitro. Moreover, HCC cells with reduced AMBRA1 expression demonstrated heightened mitochondrial activity, characterized by increased oxygen consumption, respiration, mitochondrial membrane potential, and intracellular ATP levels. Apart from OXPHOS, we also observed a concomitant up-regulation and enrichment of MYC targets in TSS-high and AMBRA1-low HCC patients, pointing towards a deregulated c-MYC signaling to promote cancer stemness under AMBRA1 regulation in HCC. Collectively, our results demonstrate that AMBRA1 loss enhances mitochondrial function to support hepatic tumorigenesis in HCC.
Citation Format: Yan Liu, Yunong Xie, Yimiao He, Stephanie Ma, Man Tong. AMBRA1 coordinates mitochondrial function to regulate cancer stemness and tumorigenesis in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7065.
Abstract 7069: NEK2 is frequently upregulated in esophageal adenocarcinoma associating with poor prognosis
Authors: Chen Lei , Lu Heng , Ballout Farah , Hu Tianling , Chen Zheng , Peng Dunfa 
Published: March 2024

Abstract
Esophageal adenocarcinoma (EAC) has become a significant clinical challenge due to rapid increase in the incidence during the past four decades in the USA and Western countries. However, the prognosis of EAC patients is still poor with 5-year overall survival rate about 20%. There is an urgent need to identify novel therapeutic targets associated with EAC biology. NEK2 is the first identified human NEK (Never in mitosis A (NIMA) related kinase) gene among the 11 serine/threonine kinases family. Aberrant NEK2 expression is reported in a variety of human cancers and plays important roles in tumorigenesis, progression, and drug-resistance. However, the expression of the NEK2 in EAC and its precancerous condition (Barrett’s esophagus, BE) has not been investigated. Using bioinformatic approaches, we first analyzed the TCGA and 9 GEO databases (a total of 10 databases in which eight contain EAC and 6 contain BE) and found that NEK2 was significantly upregulated in EAC as compared to normal esophagus in 7 of the 8 databases. Meanwhile, genomic alterations of NEK2 are only found in 1.2% of EAC. We validated the overexpression of NEK2 using qRT-PCR, western blotting, immunohistochemistry in EAC cell lines and in primary EAC tissues. Functionally, we demonstrated that overexpression of NEK2 in EAC cells promoted tumor cell growth. Targeting NEK2 in EAC cells significantly inhibited EAC tumor growth. Our data suggests that frequent overexpression of NEK2 plays an important role in EAC.
Citation Format: Lei Chen, Heng Lu, Farah Ballout, Tianling Hu, Zheng Chen, Dunfa Peng. NEK2 is frequently upregulated in esophageal adenocarcinoma associating with poor prognosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7069.
Abstract 7071: Pharmacological targeting of SUMOylation leads to cBAF complex stabilization and disruption of the synovial sarcoma signature
Authors: Floros Konstantinos V. , Li Jinxiu , Roberts Jane L. , Kurupi Richard , Fairchild Carter K. , Hu Bin , Xing Yanli , Dalton Krista M. , Boikos Sosipatros A. , Stamatouli Angeliki M. , Dozmorov Mikhail G. , Koblinski Jennifer E. , Jones Kevin B. , Radhakrishnan Senthil K. , Faber Anthony C. 
Published: March 2024

Abstract
Synovial Sarcoma (SS) is driven by the SS18-SSX translocation event and occurs often in people under 30. In general, SS is refractory to chemotherapy and other therapeutic approaches. SS18-SSX does not directly bind to DNA but instead alters BAF complexes away from a wild-type SS18-containing cBAF complex towards a SS18-SSX- containing ncBAF complex to drive a SS-specific transcription program. Small molecule targeted therapies are expanding beyond the kinome, providing additional tools to treat cancers that are not yet amenable to targeted therapies. Here we demonstrate that SS18-SSX activates the SUMOylation program and SS are sensitive to the small molecule SAE1/2 inhibitor, subasumstat (TAK-981). Mechanistically, we demonstrate TAK-981 de-SUMOylates the cBAF/PBAF complex member, SMARCE1, leading to stabilization and restoration of cBAF complexes. This phenotypic shift leads to a DNA damage and cell death response, resulting in tumor inhibition across mouse models of SS. As such, TAK-981 combined with standard-of-care chemotherapy enhances SOC-induced DNA damage, leading to tumor regressions. Targeting the SUMOylation pathway in SS restores cBAF complexes, positioning it as a clinical candidate to treat this refractory cancer.
Citation Format: Konstantinos V. Floros, Jinxiu Li, Jane L. Roberts, Richard Kurupi, Carter K. Fairchild, Bin Hu, Yanli Xing, Krista M. Dalton, Sosipatros A. Boikos, Angeliki M. Stamatouli, Mikhail G. Dozmorov, Jennifer E. Koblinski, Kevin B. Jones, Senthil K. Radhakrishnan, Anthony C. Faber. Pharmacological targeting of SUMOylation leads to cBAF complex stabilization and disruption of the synovial sarcoma signature [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7071.
Abstract 7075: Global epitranscriptomic and transcriptomic footprint revealed upregulation of methylated single minded 2-small variant (meSIM2-SV) in colorectal cancer (CRC) by NTMT1(METTL11A) via m6A-YTHDF1-dependent manner
Authors: Rai Sudhir Kumar , Gong Ting , Gao Zitong , Qin Yujia , Huo Matthew , Nakastu Ken , Yang Hua , Fu Yuanyuan , Wu Lang , Jijiwa Mayumi , Nasu Masaki , Chen Shaoqiu , Huang Gang , Fei Peiwen , Deng Youping 
Published: March 2024

Abstract
Establishing global footprint of altered m6A mRNA is a unique method to identify the new prognostics biomarkers. Altered N6-methyladenosine(m6A) RNA methylation regulates cancer progression with uncharacterized mechanism. Here, we present novel link between m6A modification on 5’-UTR SIM2-SV contribution in colorectal cancer progression. MeRIP and RNA-seq data from 68 fresh frozen CRC samples revealed 13,843 altered m6A methylated peaks and found highest in chromosomes 1, 2, and 3. Analysis uncovered 119 overlapping genes and clusters into 32 up-regulated genes with 56 up-hyper peaks, 8 up-regulated genes with 9 up-hypo peaks, 12 down-regulated genes with 14 down-hyper peaks, and 28 down-regulated genes with 40 down-hypo peaks. A significant increase in the SIM2 m6A and RNA level led us to perform correlation analysis between the SIM2SV and m6A RNA regulators. SIM2SV was significantly correlated with YTHDF1 m6A-readers and m6A-NTMT1 writer, suggesting important roles of SIM2SV in CRC oncogenicity. m6A-sequencing identified m6A enrichment in 5’-UTR of SIM2SV gene which further verified. siNTMT1 and siYTHDF1 manipulation in HCT116 and RKO cell lines verified a decrease in SIM2SV gene/protein expression, and m6A level. Knockdown effects also showed decrease in cell proliferation, clonogenicity and induced cell cycle arrest in the G2/M phase for NTMT1 and YTHDF1 versus SIM2 Knockdown showed cell cycle arrest in S/G2 phase. Our investigation revealed the role of new writer NTMT1 for methylated SIM2SV gene expression in colorectal cancer proliferation via m6A-YTHDF1(as “decoder”) dependent manner. Further investigation on m6A modification specifically on SIM2 mRNA revealed the essential roles of its writer NTMT1 and its reader YTHDF1 in CRC development, evidently supporting the importance of the unique landscape of m6A epigenetic modification in colorectal neoplasm, which not only advance our understanding of CRC pathobiology but also provides a new set of molecular targets for building up effective tools to fight CRC.
Citation Format: Sudhir Kumar Rai, Ting Gong, Zitong Gao, Yujia Qin, Matthew Huo, Ken Nakastu, Hua Yang, Yuanyuan Fu, Lang Wu, Mayumi Jijiwa, Masaki Nasu, Shaoqiu Chen, Gang Huang, Peiwen Fei, Youping Deng. Global epitranscriptomic and transcriptomic footprint revealed upregulation of methylated single minded 2-small variant (meSIM2-SV) in colorectal cancer (CRC) by NTMT1(METTL11A) via m6A-YTHDF1-dependent manner [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7075.
Abstract 7102: The central dogma of hepatocellular carcinoma: Genomic, transcriptomic, and proteomic changes
Authors: MA Hoi Tang , YU Chun Yin , NG Lau Yan 
Published: March 2024

Abstract
Cancer is a disease condition characterized by remarkable heterogeneity, wherein numerous molecular features display considerable disparities even with the same patient cohorts, leading to varied treatment outcomes. The primary factor contributing to the substantial differences observed across cancers stems from unique combinations of genetic mutations. Epigenetic alterations further contribute to differential gene expression and splicing, thereby enhancing transcriptomic diversity. The protein products originating from the cancer transcriptome constitute the specific intracellular and extracellular environment, consequently exerting supplementary effects on epigenetic, transcriptomic, and proteomic changes. The complex interplay and mutual influence between genetic aberrations, transcriptomes, and proteomes significantly contribute to shaping the extensive spectrum of molecular characteristics observed in cancer. With label-free mass spectrometry, RNA-sequencing, and low-pass whole genome sequencing, the quantification of the proteome, transcriptome, and genetic abbreviation of the cancer can be evaluated. With the mouse hydrodynamic tail vein injection (HDVI) models of hepatocellular carcinoma (HCC), different subtypes of HCC derived from different genetic abbreviations can be generated. With the proteome, transcriptome, and genetic abbreviation data of the better-defined HCC from HDVI models and HCC patients, the patient-derived HCC can be classified according to the origin of the genetic abbreviation used in the generation of the HDVI-derived HCC. Furthermore, the proteome of patient-derived plasma will be analyzed, and the signature change unique to HCC classified by different origins of genetic abbreviation will provide an abstract of the proteome, transcriptome, and genetic abbreviation of the HCC tissue. The transcriptomics and proteomics data of HDVI mice produced from five distinct sets of genetic abbreviations have been measured. The proteome and transcriptome of tissue, as well as the proteome of plasma, from a small cohort of HCC patients were studied and classified using this resource to illuminate the fundamental landscape of HCC. The final results will be presented and discussed at the meeting.
Citation Format: Hoi Tang MA, Chun Yin YU, Lau Yan NG. The central dogma of hepatocellular carcinoma: Genomic, transcriptomic, and proteomic changes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7102.
Abstract 7112: Preclinical profile of novel and potent small molecule inhibitors of PARG
Authors: Patra Sukanya , Pothuganti Manoj , Kummari Githavani , Sankeshi Venu , Kapaka Jyothipriya , Karche Navnath , Mekala Ramamohan , Viswanadha Srikant 
Published: March 2024

Abstract
Poly(ADP-ribose) glycohydrolase (PARG) is primary enzyme involved in the dePARylation process of DNA repair, specifically in the single strand break repair (SSBRs). PARG is a macrodomain protein with exo- and endo-glycohydrolase activity that liberates free ADP-ribose and PAR chains, respectively. It interacts with various Poly(ADP-ribose) polymerase (PARP) proteins to facilitate appropriate and timely DNA repair. The balance between PARP and PARG activity is essential for efficient DDR. Inhibition of PARG lead to altered DNA repair in cancer cells. We have identified highly potent PARG inhibitors with picomolar IC50 in. PARG is the primary enzyme for dePARylation and accounts for 90% of dePARylation activity. Treatment of HCC-1806 cells with PARG inhibitors showed dose dependent increase of PARylation signature, with sub micromolar IC50. Compounds also demonstrate significant functional, anti-proliferative activity in ovarian and breast cancer cell lines besides a favourable ADME profile. Further pharmacokinetic and pharmacodynamic characterization of the identified hits is currently in progress.
Citation Format: Sukanya Patra, Manoj Pothuganti, Githavani Kummari, Venu Sankeshi, Jyothipriya Kapaka, Navnath Karche, Ramamohan Mekala, Srikant Viswanadha. Preclinical profile of novel and potent small molecule inhibitors of PARG [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7112.