bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1697: Phase separation of BHLHE40 up-regulates SREBF1 and inhibits ferroptosis in pancreatic cancer cells
Authors: Cao Yizhi , Wang Xuelong , Liu Yang , Liu Pengyi , Qin Jiejie , Zhu Youwei , Zhai Shuyu , Shi Minmin , Wang Weishen , Deng Xiaxing , Peng Chenghong , Chen Hao , Ren Ruibao , Jiang Lingxi , Shen Baiyong 
Published: March 2024

Abstract
Pancreatic cancer (PCa) is one of the most lethal malignancies in human cancers. The enhanced infiltration of stromal tissue of PCa tumor microenvironment limits the identification of key tumor-specific transcription factors and epigenomic abnormalities in malignant epithelial cells. Integrated transcriptome and epigenetic multi-omics analysis of paired PCa organoids indicated that the basic helix-loop-helix transcription factor 40 (BHLHE40) was significantly upregulated in tumor samples. Increased chromatin accessibility at promoter region and enhanced mTOR pathway activity contribute to the elevated expression of BHLHE40. Integrated analysis of chromatin immunoprecipitation (ChIP)-seq, RNA-seq and high-through chromosome conformation capture (Hi-C) data together with chromosome conformation capture (3C) assay indicate that BHLHE40 not only regulates the sterol regulatory element-binding factor 1 (SREBF1) transcription as a classic transcription factor, but also links the enhancer and promoter regions of SREBF1 via forming liquid-liquid phase-separated droplets. Then, we find the BHLHE40-SREBF1-stearoyl-CoA desaturase (SCD1) axis protects PCa cells from ferroptosis, leading to the reduced accumulation of lipid peroxidation in cells. Moreover, SREBF1 inhibitor, Fatostatin, significantly suppresses the cell growth of PCa tumors with higher expression of BHLHE40. This study highlights the important roles of BHLHE40 mediated lipid peroxidation in inducing ferroptosis of PCa cells and provides a novel mechanism underlying the SREBF1 overexpression in PCa.
Citation Format: Yizhi Cao, Xuelong Wang, Yang Liu, Pengyi Liu, Jiejie Qin, Youwei Zhu, Shuyu Zhai, Minmin Shi, Weishen Wang, Xiaxing Deng, Chenghong Peng, Hao Chen, Ruibao Ren, Lingxi Jiang, Baiyong Shen. Phase separation of BHLHE40 up-regulates SREBF1 and inhibits ferroptosis in pancreatic cancer 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 1697.
Abstract 1701: ABI1 regulates prostate tumor plasticity through chromatin remodeling and transcriptional regulation
Authors: Kotula Leszek 
Published: March 2024

Abstract
Background: Prostate cancer remains a challenging issue affecting men worldwide. In contrast to localized disease, metastatic prostate cancer tumor is incurable. Progression to metastatic disease is characterized by tumor heterogeneity and plasticity regulated by epigenetic changes of tumor cells. While tumor heterogeneity is often associated with gene mutations, tumor plasticity is ascribed to transcriptional regulation and chromatin activity. The latter is modulated by treatment of prostate cancer leading to treatment resistance. Here, we identified a novel mechanism of epigenetic regulation in prostate cancer by an actin regulatory and signaling protein, Abelson Interactor 1 (ABI1).
Methods: To demonstrate the ABI1-DNA binding, we employed in vitro binding assays, NMR spectroscopy, and ChIP-seq. from cells expressing alternatively spliced isoforms of ABI1 that contain or lack the DNA binding HHR domain. To determine the ABI1 interactions with several transcriptional factors, we used immunoprecipitation and/or proximity ligation assay (PLA). We used ATAC sequencing to determine the chromatin accessibility in the presence or absence of ABI1 gene. RNA-seq established the activity of transcriptional factors and signaling pathways regulated by ABI1.
Results: Using NMR spectroscopy, we established that ABI1 demonstrated DNA binding dependent on the presence of alternatively spliced Exon 4. Exon 4 is located within the homeobox homology region (HHR). The DNA binding activity was confirmed using in vitro binding assays; the assay results confirmed the role of ABI1 HHR. Moreover, cells lacking ABI1 or expressing ABI1 lacking Exon 4 show low accessibility and activity of chromatin. In contrast, cells expressing ABI1 containing Exon 4 show active chromatin. RNA-seq analysis demonstrated that ABI1 regulated transcription in an Exon 4-dependent manner.
Conclusions: We uncovered a role of ABI1 in chromatin stability, that is dependent on the presence of the DNA binding region. Notably, ABI1's contribution to transcriptional activity occurs via a transient yet precisely defined interaction between its intrinsically disordered region and DNA. This regulatory control plays a pivotal role in managing tumor plasticity by establishing connections between the actin cytoskeleton, cellular signaling, and transcriptional regulation. Based on these findings, we propose that ABI1 functions as an epigenetic regulator, maintaining transcriptional homeostasis in prostate cancer.
Citation Format: Leszek Kotula. ABI1 regulates prostate tumor plasticity through chromatin remodeling and transcriptional regulation [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 1701.
Abstract 1717: RAS and PP2A co-regulated phosphosite on KDM1A dictates its substrate specificity & transcriptional outcome
Authors: Sharma Mukund , Aakula Anna , Kamila Jesse , Nätkin Reetta , Bonaldi Tiziana , Minucci Saverio , Nykter Matti , Westermarck Jukka 
Published: March 2024

Abstract
RAS-mediated human cell transformation requires simultaneous inhibition of tumor suppressor phosphatase PP2A; however, the target phosphosites co-regulated by RAS and PP2A are poorly characterized. In this study, we describe the phosphoregulation of an epigenetic regulator, KDM1A, by RAS and PP2A. KDM1A is a lysine-specific demethylase that can act as a transcriptional activator or inhibitor, depending on its specific activity toward various histone marks. However, the post-translational modifications regulating the substrate specificity of KDM1A are poorly addressed. We found that KDM1A physically interacts with PP2A through a conserved binding motif, and that mutating the motif residues decreased its interaction with PP2A. Additionally, PP2A activation or RAS inhibition led to increased chromatin recruitment of KDM1A. This enhanced chromatin recruitment of KDM1A was recapitulated upon CRISPR/CAS9-mediated substitution of the PP2A/RAS-targeted serine to alanine. Using histone proteomics, we further identified that the RAS/PP2A-regulated phosphosite determines the substrate specificity of KDM1A. This is evidenced by an increased demethylation of histone H3K9me2/3, a marker of gene activation. The differential gene expression profile of the phosphorylation mutants of KDM1A predominantly showed increased gene expression, further validating our findings. The gene expression profiles of KDM1A phosphomutant RAS mutant cells demonstrate gene level specificity indicating that this newly discovered KDM1A phosphoswitch has an important role in specifying KDM1A function in cancer. Collectively, our results demonstrate that RAS and PP2A activities converge on phosphoregulation of epigenetic machinery in cancer cells. This RAS and PP2A co-regulated phosphosite on KDM1A dictates both its histone mark specificity and transcriptional outcome.
Citation Format: Mukund Sharma, Anna Aakula, Jesse Kamila, Reetta Nätkin, Tiziana Bonaldi, Saverio Minucci, Matti Nykter, Jukka Westermarck. RAS and PP2A co-regulated phosphosite on KDM1A dictates its substrate specificity & transcriptional outcome [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 1717.
Abstract 1738: Precise detection of benign and malignant renal tumor via epigenetic characteristics of urinary cell-free DNA
Authors: Kong Wen , Dong Hang , Tang Haoran , Du Pan , Jia Shidong , Zhang Jin 
Published: March 2024

Abstract
Early detection of clear cell renal cell carcinoma (ccRCC) and accurate differentiation between malignant and benign lesions pose clinical challenges. Profiling the epigenetic pattern of patients through liquid biopsy offers a promising strategy for non-invasive cancer identification. This study utilizes the methylation characteristics of urinary cell-free DNA to enhance the precise diagnosis of ccRCC. In this study, 32 patients with malignant RCC, 20 patients with benign kidney lesions, and 28 age- and sex-matched healthy donors were enrolled. Urine samples were collected and applied by PredicineEPIC assay to analyze the whole genome methylation profiles. We assessed the methylation differences on cancer-specific altered regions and constructed a machine learning model for malignant and benign classification. Beta values were calculated for differentially methylated regions identified through literature mining and our current work. These features carry methylation signals that are recognized by gradient boosting machine and used for classification training. The leave-one-out cross-validation method compensated for the shotage of sample size. The sensitivity and specificity of the optimal model in the training set are both greater than 0.97, and it can achieve an accuracy of 0.95 on the validation set. This performance surpasses traditional diagnostic methods such as contrast-enhanced CT and MRI. This study demonstrated the technical feasibility of leveraging epigenetics profiles to discriminate malignant from benign lesions, suggesting a promising liquid biopsy-based approach for the precise detection of renal cell carcinoma.
Citation Format: Wen Kong, Hang Dong, Haoran Tang, Pan Du, Shidong Jia, Jin Zhang. Precise detection of benign and malignant renal tumor via epigenetic characteristics of urinary cell-free DNA [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 1738.
Abstract 1741: AlidaBio EpiPlex: A platform for multiplexed detection of RNA modifications in clinical samples
Authors: Price Andrew , Miles Zachary , Chevillet John , Purse Byron , Gregory Richard I. , Stengel Gudrun 
Published: March 2024

Abstract
It is becoming increasingly appreciated that RNA modifications are widespread in development and homeostasis, regulating RNA stability and translation, and that alterations to these modifications are associated with cancer development and progression. Although 170 different RNA modifications have been identified using mass spectrometry, there is a paucity of convenient, validated tools immediately available to cancer researchers to explore these modifications using relevant clinical samples in sufficient numbers, and accurately determine their suitability for use as diagnostic or drug targets. In addition, most existing methods concentrate only on m6A, the most prevalent modification in mRNA. Alida Bio has developed an end-to-end assay platform with an integrated bioinformatics solution that detects multiple modifications in the same reaction. This platform exploits targeted, multiplexed barcoding to reveal the quantitative abundance of modified transcripts, co-localization of multiple RNA modifications to the same gene, and gene expression profiles. Alida Bio's mission is to equip translational researchers with tools that will significantly improve their understanding of gene regulation through seamless measurement of RNA modifications.
Citation Format: Andrew Price, Zachary Miles, John Chevillet, Byron Purse, Richard I. Gregory, Gudrun Stengel. AlidaBio EpiPlex: A platform for multiplexed detection of RNA modifications in clinical samples [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 1741.
Abstract 1748: Dearth of smoking-induced mutations in oncogene-driven NSCLCs despite smoking exposure
Authors: Huang Chen-Yang , Jiang Nanhai , Shen Meixin , Lai Gillianne , Tan Aaron C. , Jain Amit , Saw Stephanie P. , Ang Mei-Kim , Ng Quan Sing , Lim Darren Wan-Teck , Kanesvaran Ravindran , Tan Eng-Huat , Tan Wan Ling , Ong Boon-Hean , Chua Kevin L. , Anantham Devanand , Takano Angela , Lim Tony KH , Tam Wai Leong , Sim Ngak Leng , Skanderup Anders J. , Tan Daniel S.W. , Rozen Steven G. 
Published: March 2024

Abstract
Non-small cell lung cancers (NSCLCs) in non-smokers are mostly driven by mutations in the oncogenes EGFR, ERBB2, and MET, and fusions involving ALK and RET. We term these “non-smoking-related oncogenes” (NSROs). NSRO-driven tumors account for approximately half of NSCLCs in East Asia, and, alarmingly, their age-adjusted incidence is increasing for unknown reasons. In addition to occurring in non-smokers, NSRO-driven tumors also occur in smokers. However, the clonal architecture and genomic landscape of these tumors remain largely unexplored. Here, we investigated genomic and transcriptomic alterations in 173 tumor sectors from 48 patients with NSRO-driven or typical-smoking NSCLCs. Overall, NSRO-driven NSCLCs in smokers and non-smokers had similar genomic landscapes and clonal architectures that were distinct from those in typical-smoking NSCLCs. Surprisingly, even in patients with prominent smoking histories, the mutational signature caused by tobacco smoking was essentially absent in NSRO-driven NSCLCs. We confirmed this unexpected finding in two large NSCLC data sets from other geographic regions. However, we observed differences in the tumor transcriptomes of NSRO-driven NSCLCs in smokers and non-smokers, with tumors in smokers displaying higher transcriptomic activities related to regulation of the cell cycle. This suggested that smoking does have an impact on tumor phenotype in NSCRO-driven NSCLC, likely through non-genetic mechanisms. We concluded that NSRO-driven NSCLCs, whether in non-smokers or smokers, constitute an important disease entity that is very different from typical-smoking NSCLC.
Citation Format: Chen-Yang Huang, Nanhai Jiang, Meixin Shen, Gillianne Lai, Aaron C. Tan, Amit Jain, Stephanie P. Saw, Mei-Kim Ang, Quan Sing Ng, Darren Wan-Teck Lim, Ravindran Kanesvaran, Eng-Huat Tan, Wan Ling Tan, Boon-Hean Ong, Kevin L. Chua, Devanand Anantham, Angela Takano, Tony KH Lim, Wai Leong Tam, Ngak Leng Sim, Anders J. Skanderup, Daniel S.W. Tan, Steven G. Rozen. Dearth of smoking-induced mutations in oncogene-driven NSCLCs despite smoking exposure [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 1748.
Abstract 1765: The genetic landscape of head and neck cancer using brush biopsy
Authors: John Evit , Lesluyes Tom , Baker Toby , Tarabichi Maxime , Van Loo Peter , Zhao Xiao 
Published: March 2024

Abstract
Oral premalignant lesions (OPLs) with genomic alterations have a heightened risk of evolving into oral squamous cell carcinoma (OSCC). Currently, genomic data are obtained through invasive tissue biopsy. Brush biopsy has been utilized for diagnosing dysplasia but its effectiveness in reflecting the complete genomic landscape of OPLs remains uncertain. This study investigates the potential of brush biopsy samples in accurately reconstructing the genomic profile of OPLs. The evolution and heterogeneity were assessed by assessing SNVs, copy number analysis, and subclonal architecture reconstruction of paired tissue-brush biopsy samples of oral epithelium, dysplastic lesion, and OSCC lesion. We found that brush biopsy accurately reflects the genomic landscape of oral lesions, mirroring about 90% of SNVs and comparable CNA profiles found in tissue biopsies. Genomic profiling with brush biopsy was tissue-specific, as SNVs identified in OPL or OSCC lesions were not found in adjacent normal mucosa. Shared SNVs and CNAs were observed between OPL and OSCC samples. This suggested a common ancestor giving rise to these lesions. Subclonal architecture reconstruction confirmed that both lesion types shared a common ancestor clone and then diverged evolutionarily. These findings underscore the potential of brush biopsies in accurately reconstructing the genomic profile of OPL and OSCC, highlighting their usefulness in understanding the biological processes involved in tumor evolution.
Citation Format: Evit John, Tom Lesluyes, Toby Baker, Maxime Tarabichi, Peter Van Loo, Xiao Zhao. The genetic landscape of head and neck cancer using brush biopsy [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 1765.
Abstract 1818: Novel efficient isolation and water-soluble prodrug preparation of anti-cancer natural product narciclasine
Authors: Kornienko Alexander , Rutledge Ryan 
Published: March 2024

Abstract
Narciclasine is a promising anti-cancer agent produced by plants of the family Amaryllidaceae. Narciclasine has been shown to be a potent anti-cancer agent against a variety of cancers carrying dismal outcomes, including glioblastoma, non-small cell lung cancer, and non-Hodgkin’s lymphoma. It is particularly effective in animal studies of brain cancer both primary, such as glioblastoma, metastatic tumors to the brain, such as melanoma and non-small cell lung cancer. Its isolation from plants has generally been accompanied with variable success as it depends on the plant species, their location and the time of plant collection. In this study, an optimized procedure for the extraction of narciclasine yielding 300 mg/kg of dried plant material. This represents a crucial step towards the development of optimized narciclasine derivatives, as the price of narciclasine from commercial sources ranges from $100-$500 per milligram. Additionally, clinical advancement of narciclasine and its derivatives has been severely thwarted, potentially owing to its sparing water-solubility. Insolubility in water makes administration at therapeutic dosages difficult and can lead to unfavorable pharmacokinetic and pharmacodynamic characteristics. To this effort, the synthesis of five prodrug esters of narciclasine is presented, with the target of a water-soluble narciclasine prodrug.
Citation Format: Alexander Kornienko, Ryan Rutledge. Novel efficient isolation and water-soluble prodrug preparation of anti-cancer natural product narciclasine [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 1818.
Abstract 1839: Proteomic and glycoproteomic differences associated with prostate cancer in urine
Authors: Shamsher Nikhiya , Garcia-Marques Fernando , Bermudez Abel , Flory Mark R. , Pitteri Sharon J. 
Published: March 2024

Abstract
Background and Aims: Prostate cancer is one of the most common cancers affecting men in the United States, with ~288,300 new cases and 34,700 deaths in 2023 alone. Prostate-specific antigen (PSA), the most widely used prostate cancer biomarker, lacks specificity and sensitivity, leading to unnecessary biopsies, overdiagnosis, and overtreatment. There is an urgent unmet clinical need to find new biomarkers that can distinguish patients with benign disease from those with prostate cancer. Urine is an attractive source for these biomarkers as prostate-derived proteins are more highly concentrated in urine than in blood. To better understand both global proteomic and glycoproteomic molecular signatures that could lead to improved diagnostics for prostate cancer, we analyzed urine samples from unaffected men, men with benign prostatic hyperplasia (BPH), and men with prostate cancer.
Methods: Urine samples (N = 58 total) were collected from unaffected men (N = 17), men with BPH (N = 24), and men with prostate cancer (N = 17). Samples were digested with trypsin and analyzed with high-resolution liquid chromatography-tandem mass spectrometry (LC-MS/MS) for shotgun proteomics analysis. Association with cancer was determined through supervised analysis using Pearson correlation. For glycoproteomics analysis, intact glycopeptides were enriched using strong anion exchange-electrostatic repulsion hydrophilic interaction chromatography, fractionated using high pH reversed-phase chromatography, and analyzed with LC-MS/MS. Association with the three conditions was determined through several rounds of supervised analysis using Pearson correlation.
Results: In total, 3542 human proteins were identified, and 78 proteins (p &lt; 0.01) were significantly associated with prostate cancer. The glycolysis pathway and lysosome pathway were enriched in samples from men with prostate cancer. In the glycoproteomics analysis, 36 proteins (p &lt; 0.05) had altered glycan diversity in one of the three conditions, and the complement and coagulation cascade pathway and the lysosome pathway were highly enriched. Six proteins (p &lt; 0.05) had significantly increased glycan diversity in the cancerous samples than in the BPH and normal samples.
Conclusions: This study identifies a set of interesting proteomic and glycoproteomic differences in urine from men with prostate cancer compared to BPH and non-cancer samples, which warrant further investigation in additional sample cohorts as potential novel biomarkers.
Citation Format: Nikhiya Shamsher, Fernando Garcia-Marques, Abel Bermudez, Mark R. Flory, Sharon J. Pitteri. Proteomic and glycoproteomic differences associated with prostate cancer in urine [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 1839.