bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3371: PRMT blockade induces defective DNA replication stress response via ATR suppression and synergizes with PARP inhibition
Authors: Bisht Deepa , Li Yang , Dobrolecki Lacey E. , Sallas Christina , Zhang Xudong , Kerr Travis D. , Wang Yalong , Awasthi Sharad , Kaundal Babita , Wu Siqi , Peng Weiyi , Mendillo Marc L. , Lu Yiling , Jeter Collene R. , Peng Guang , Liu Jinsong , Westin Shannon N. , Sood Anil K. , Lewis Michael T. , Das Jishnu , Yi S. Stephen , Bedford Mark T. , McGrail Daniel J. , Sahni Nidhi 
Published: March 2024

Abstract
Aberrant protein arginine methylation has been observed in multiple cancer types, making it an attractive drug target. Proteins can undergo asymmetric arginine methylation by type I protein arginine methyltransferases (PRMTs), predominately by PRMT1 and to a lesser extent PRMT4, or symmetric arginine methylation by type II PRMTs, predominately PRMT5. Here, we performed targeted proteomics following inhibition of PRMT1, PRMT4, and PRMT5 across cancer cell lines. We found that inhibition of both type I and type II PRMTs suppressed levels of total and phosphorylated ATR protein in cancer cell lines, and down-regulated expression of the ATR gene. Loss of ATR from PRMT inhibition resulted in defective DNA replication stress response activation in following exogenous replication stress. Since PARP inhibitors are known to induce replication stress, we next combined PRMT inhibition with PARP inhibition and found inhibition of PRMT1 or PRMT5 greatly exacerbated PARP inhibitor induced DNA damage. Based on this observation, we assessed the combination of PARP and PRMT inhibition in a panel of cell lines. While inhibition of both type I and type II PRMTs were synergistic with PARP inhibition in both cells with intact and deficient homologous recombination, type I PRMT inhibition resulted in higher toxicity in non-malignant cells. Therefore, we validated the synergy of combined PARP/PRMT5 inhibition in primary patient-derived organoids. Finally, we demonstrate that the combination of PARP and PRMT5 inhibition improves overall survival in both BRCA-mutant and wild-type patient-derived xenograft models without any detectable hematological toxicities typically associated with PARPi combination therapies. Taken together, these results demonstrate that PRMT5 inhibition may be a well-tolerated approach to improve tumor sensitivity to PARP inhibition.
Citation Format: Deepa Bisht, Yang Li, Lacey E. Dobrolecki, Christina Sallas, Xudong Zhang, Travis D. Kerr, Yalong Wang, Sharad Awasthi, Babita Kaundal, Siqi Wu, Weiyi Peng, Marc L. Mendillo, Yiling Lu, Collene R. Jeter, Guang Peng, Jinsong Liu, Shannon N. Westin, Anil K. Sood, Michael T. Lewis, Jishnu Das, S. Stephen Yi, Mark T. Bedford, Daniel J. McGrail, Nidhi Sahni. PRMT blockade induces defective DNA replication stress response via ATR suppression and synergizes with PARP inhibition [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 3371.
Abstract 3401: Uncovering virus induced dysregulated processes in cancer and their impact on outcomes
Authors: moghadam Mohadeseh Soleimanpour , Khosh Azad , Ebrahimi Diako 
Published: March 2024

Abstract
The National Cancer Institute has designated several viruses such as EBV, HBV, HCV, HIV, HPV, and HTLV as agents that either cause cancer or increase the risk of developing cancer. However, extensive analyses of tumor genome and transcriptome datasets have identified numerous additional virus types, the functional implications of which remain largely unknown. Viral infection often dysregulates unique molecular processes within tumor cells and alters the composition of immune cells in the tumor microenvironment. For instance, HPV-positive tumors have been shown to exhibit a significantly elevated expression of the DNA editing enzyme APOBEC3B compared to HPV-negative tumors. Furthermore, HPV positive tumors display and increased number of C-to-T mutations induced by this protein. The genome and transcriptome of tumor tissue biopsies contain a wealth of information about these virus-associated signatures. However, advanced signal processing approaches are needed to extract these viral signatures from complex tumor datasets, and elucidate their specific roles in cancer. Here, we developed a quantitative approach to investigate the link between viral infection and dysregulation of a seven-membered A3 enzyme family (A3A/B/C/D/F/G/H). The primary role of these enzymes is to restrict viral infections by inducing C-to-U mutations in viral genomes. However, at least three members of this enzyme family (A3A/B/H) can also induce mutations in cellular DNA, and drive tumor formation and evolution. We used NMF (Nonnegative Matrix Factorization) to deconvolute the expression profiles of A3 enzymes in &gt;10,000 bulk RNAseq datasets from diverse TCGA tumors. This analysis revealed the expression profiles of A3 enzymes within tumor and tumor microenvironment cells including various immune cells. Next, we conducted an association analysis to identify the link between the presence of viral infection and the proportion of each of these tumor and tumor microenvironment expression profiles. As expected, our analyses revealed strong associations between tumor-specific A3 expression profiles and infections by oncolytic viruses such as HPV. Notably, and somewhat unexpectedly, our analyses also revealed associations with viruses about which little is known in the field of cancer. For example, in certain tumors, we identified a robust association between bacteriophages and a tumor-specific A3 expression profile characterized by A3B upregulation. Taken together, our analyses provide evidence for the link between A3 dysregulation and infection by viruses including bacteriophages.
Citation Format: Mohadeseh Soleimanpour moghadam, Azad Khosh, Diako Ebrahimi. Uncovering virus induced dysregulated processes in cancer and their impact on outcomes [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 3401.
Abstract 3431: Genetically determined circulating lactase/phlorizin hydrolase concentrations and risk of colorectal cancer: A two-sample mendelian randomization study
Authors: Han Sihao , Yao Jiemin , Yamazaki Hajime , Streicher Samantha , Rao Jianyu , Nianogo Roch , Zhang Zuo-Feng , Huang Brian 
Published: March 2024

Abstract
Background: Colorectal cancer (CRC) ranks as the third most common cancer worldwide. Despite its established connection with genetic, dietary, and lifestyle factors, gaps remain in the understanding of its etiology. Lactase-phlorizin hydrolase (LPH) plays a critical role in milk digestion and influences crucial nutrient absorption and gut microbiota composition. A direct relationship of CRC risk with LPH level remains unexplored. Our study aims to elucidate the potential causal link between genetically determined LPH levels and CRC risk.
Methods: We applied a two-sample Mendelian Randomization (MR) strategy to investigate the causal link between elevated LPH levels and CRC risks. Genetic instruments for LPH (one cis-variant and three trans-variants) were derived from the Fenland Study, and CRC-associated summary statistics for these instruments were extracted from the FinnGen Study, PLCO Atlas Project, and Pan-UK Biobank. Primary MR analyses focused on a cis-variant (rs4988235) for LPH levels, with results integrated via meta-analysis. MR analyses using all variants were also undertaken. This analytical approach was further extended to assess CRC subtypes, specifically colon and rectal cancer.
Results: Meta-analysis across the three datasets illustrated an inverse association between genetically predicted LPH level and CRC risk (OR: 0.92 [95% CI, 0.89-0.95]). Subtype analyses revealed associations of genetically predicted elevated LPH levels with reduced risks for both colon cancer (OR: 0.92 [95% CI, 0.89-0.96]) and rectal cancer (OR: 0.92 [95% CI, 0.87, 0.98]). Consistency was observed across varied analytical methods and different datasets.
Conclusions: Our study suggests an inverse relationship between genetically determined LPH level and CRC risk. Further exploration is warranted to unveil the underlying mechanisms and validate LPH’s potential role in CRC prevention.
Citation Format: Sihao Han, Jiemin Yao, Hajime Yamazaki, Samantha Streicher, Jianyu Rao, Roch Nianogo, Zuo-Feng Zhang, Brian Huang. Genetically determined circulating lactase/phlorizin hydrolase concentrations and risk of colorectal cancer: A two-sample mendelian randomization study [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 3431.
Abstract 3466: Prognostic implications of lymph node micrometastasis in patients with gastric cancer
Authors: Yamamoto Atsushi , Okamoto Hirotaka 
Published: March 2024

Abstract
Purpose: The clinical significance of lymph node micrometastasis (LNMM) remains controversial in gastric cancer (GC). In this study, we investigated the prognostic impact of patients with LNMM GC.Methods: A total of 624 patients with pathologically lymph node metastasis negative (pN0) and N1 status (pN1) who underwent gastrectomy between 2004 and 2018 were enrolled in this retrospective study. The diameter of tumor cell clusters in metastatic lymph nodes was measured in 120 patients with pN1 GC. Results: Patients with lymph node tumors of diameter &lt; 1500 μm (LNMM) had significantly better prognosis than those with tumors of diameter ≥ 1500 μm (p = 0.012; log-rank test). Cox’s proportional hazards model revealed that LNMM (p = 0.016), several dissected lymph nodes (p = 0.049), and the provision of adjuvant chemotherapy (p = 0.002) were independent prognostic factors for overall survival of patients with pN1 GC. There was no significant difference in overall survival between patients with LNMM who received chemotherapy and those who did not (p = 0.332). Conclusions: LNMM is associated with favorable prognosis and could be an independent prognostic marker in patients with pN1 GC. LNMM in GC may be considered as one of the factors preventing adjuvant chemotherapy.
Citation Format: Atsushi Yamamoto, Hirotaka Okamoto. Prognostic implications of lymph node micrometastasis in patients with gastric cancer [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 3466.
Abstract 3490: Unveiling sex differences in lung adenocarcinoma through multi-omics integrative protein signaling networks
Authors: Chen Chen , Saha Enakshi , DeMeo Dawn L. , Quackenbush John , Lopes-Ramos Camila M. 
Published: March 2024

Abstract
Sex differences in lung adenocarcinoma (LUAD) are evident in incidence rates, prognostic outcomes, and therapy responses, yet the underlying molecular mechanisms driving these disparities remain underexplored. In this study, we conducted a comprehensive proteogenomic analysis encompassing 38 females and 73 males with LUAD from the Clinical Proteomic Tumor Analysis Consortium (CPTAC) dataset. Employing Transcription Inference using Gene Expression and Regulatory data (TIGER), we inferred sex-differentially activated transcription factors (TFs) from The Cancer Genome Atlas (TCGA) LUAD gene expression data and identified sex-differentially activated kinases using CPTAC protein phosphorylation data. We further constructed a comprehensive kinase-TF signaling network by integrating these sex-differentially activated kinases with TFs, identifying all paths shorter than 3 in the protein interaction networks to highlight druggable pathways. Our analyses revealed that many proteins exhibit not only sex-biased abundance but also sex-biased phosphorylation and acetylation. Furthermore, these sex-biased proteins were associated with critical biological pathways including cell proliferation, immune response, and metabolism. Using kinase-TF signaling networks, we found substantial sex bias in the activities of clinically actionable TFs and kinases, including the glucocorticoid receptor (NR3C1), AR, AURKA, CDK6, and MAPK14. Leveraging the PRISM cancer cell line screening database, we identified several small-molecule drugs, such as glucocorticoid receptor agonists and aurora kinase inhibitors, potentially exhibiting sex-specific efficacy as LUAD therapeutics. Our findings showed that the activity of some clinically relevant TFs and kinases differ by sex in LUAD, underscoring the need to consider sex as a biological variable and the utility of multi-omics integrative protein signaling networks in advancing our understanding of cancer biology and the development of sex-aware therapeutics.
Citation Format: Chen Chen, Enakshi Saha, Dawn L. DeMeo, John Quackenbush, Camila M. Lopes-Ramos. Unveiling sex differences in lung adenocarcinoma through multi-omics integrative protein signaling networks [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 3490.
Abstract 3497: Glioma Immune Microenvironment Composition Calculator (GIMiCC): A method of estimating the proportions of eighteen key cell types from human brain tissue assayed using Illumina DNA methylation microarray technology
Authors: Pike Steven C. , Wiencke John K. , Zhang Ze , Molinaro Annette M. , Koestler Devin C. , Christensen Brock C. , Kelsey Karl T. , Salas Lucas A. 
Published: March 2024

Abstract
Precise detection of both tumor subclass and immune composition is critical in the pursuit of personalized immunotherapeutic treatment strategies for glioma. DNA methylation (DNAm) biomarkers are promising on both fronts. DNAm-based biomarkers for molecular classification have been developed and integrated into World Health Organization (WHO) diagnostic criteria. However, prediction of the tumor microenvironment is not as well defined. To fill this gap, we present GIMiCC, an approach for cellular deconvolution of DNAm microarray data for four WHO 2021 tumor subclasses: glioblastoma, oligodendroglioma, grade 2/3 astrocytoma and grade 4 astrocytoma. Using data from 17 isolated cell types, we describe the derivation of the deconvolution libraries and test the method on independent datasets from the Cancer Genome Atlas (TCGA) and the DKFZ molecular neuropathology classifier (PMID: 29539639). We utilize GIMiCC to illustrate that DNAm-based glioma classification is unlikely to be biased by compositional variation. In addition, we utilize GIMiCC to identify composition independent DNAm alterations that are associated with high immune infiltration. Our future work aims to optimize GIMiCC and advance the clinical evaluation of glioma with this new tool.
Citation Format: Steven C. Pike, John K. Wiencke, Ze Zhang, Annette M. Molinaro, Devin C. Koestler, Brock C. Christensen, Karl T. Kelsey, Lucas A. Salas. Glioma Immune Microenvironment Composition Calculator (GIMiCC): A method of estimating the proportions of eighteen key cell types from human brain tissue assayed using Illumina DNA methylation microarray technology [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 3497.
Abstract 350: Targeting prohibitins by fluorizoline leads to the activation of ISR and apoptosis through DELE1 and HRI by an impairment of the mitochondrial protein import machinery
Authors: Sánchez-Vera Ismael , Maritorena-Hualde Nekane , Schuler Max-Hinderk , Cosialls Ana M- , Lavilla Rodolfo , Pons Gabriel , Jae Lucas T , Iglesias-Serret Daniel , Gil Joan 
Published: March 2024

Abstract
Prohibitins are ubiquitously expressed within the cell, but they are mainly located at the inner mitochondrial membrane. These proteins are closely associated with tumour progression, invasion, and apoptotic resistance, being overexpressed in various primary tumours such as lymphoma and endometrial cancer. Notably, we have developed a novel synthetic molecule, fluorizoline, which induces apoptosis by selectively targeting PHBs in different cancer cell lines and primary samples from various haematological neoplasias. We have previously described that fluorizoline-induced apoptosis is mediated through the activation of the pro-apoptotic branch of the integrated stress response (ISR) pathway in HeLa and HAP1 cells, concretely, by the ATF4-CHOP-NOXA axis. In a recent study, we identified compensatory mechanisms for four ISR-related kinases. Importantly, HRI emerged as the primary kinase responsible for activating this pathway and promoting apoptosis, suggesting that mitochondrial stress could lead to this activation of the ISR.Here, we investigate the OMA1-DELE1-HRI molecular pathway responsible for sensing mitochondrial stress and activating the ISR cancer cell lines. Firstly, we demonstrate that fluorizoline treatment triggers the cleavage of large DELE1 (L-DELE1) to its cleaved form (S-DELE1) through western blot analysis, and its subsequent sorting to the cytosol as confirmed by confocal analysis. Using DELE1 KO lines generated by CRISPR/Cas9 technology, we demonstrate that DELE1 is involved in the activation of the ISR and apoptosis induced by fluorizoline. However, although we cannot rule out OMA1 involvement, fluorizoline-induced ISR activation does not strongly depend on OMA1. Interestingly, our data suggests that targeting PHBs, either by fluorizoline or by their downregulation, could result in mitochondrial protein import machinery impairment. This impairment may potentially be the cause of DELE1 accumulation in the cytosol, leading to the subsequent activation of the ISR by HRI upon fluorizoline treatment.
Citation Format: Ismael Sánchez-Vera, Nekane Maritorena-Hualde, Max-Hinderk Schuler, Ana M- Cosialls, Rodolfo Lavilla, Gabriel Pons, Lucas T Jae, Daniel Iglesias-Serret, Joan Gil. Targeting prohibitins by fluorizoline leads to the activation of ISR and apoptosis through DELE1 and HRI by an impairment of the mitochondrial protein import machinery [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 350.
Abstract 3502: Multi-omics approach to cholangiocarcinoma-related biology and development of precision medicine
Authors: Kwon Woo Young , Kang Incheon , Lee Sung Hwan 
Published: March 2024

Abstract
Introduction: Cholangiocarcinoma is a diverse tumor entity characterized by distinct tumor biology and clinical phenotypes, which are influenced by the unique tumor microenvironment (TME) and anatomical location—whether intrahepatic, peri-hilar, or distal extrahepatic. Consequently, there is a clear need for a precision strategy that relies on cancer-specific, multi-omic features, moving away from traditional molecular subtypes derived from bulk RNA sequencing.
Methods: We conducted thorough multi-omic analyses utilizing data from the Cancer Dependency Map (DepMap) project. This encompassed cancer-specific molecular characterization through various omics data, genome-wide loss-of-function screening employing the CRISPR-Cas9 system, and drug sensitivity assessments via compound screening. These efforts aimed to reveal cancer-specific molecular subtypes with clinical relevance. The identified cancer-specific molecular signatures were subsequently validated in independent translational cohorts.
Results: Through integrative profiling of the transcriptome in bile duct cancer cell lines (n=39) obtained from the Cancer Cell Line Encyclopedia (CCLE), we unveiled cancer-specific molecular subtypes exhibiting distinct tumor biology across all omics layers, coupled with clinical relevance and prognostic significance. The major molecular features of each subtype demonstrated reproducibility in validation cohorts. Additionally, subtype-specific molecular biomarkers, encompassing mutational signatures and metabolites, were identified. Finally, we analyzed target drugs with subtype-specific genetic dependencies to formulate a precision strategy tailored to the distinct molecular characterizations of each subtype.
Conclusions: A thorough analysis utilizing a multi-omics dataset uncovered precision strategies founded on cancer-specific molecular subtypes of cholangiocarcinoma, both in terms of tumor classification and discriminative therapeutic opportunities. It is imperative to conduct prospective translational studies in conjunction with clinical trials, all centered around the cancer-specific molecular subtypes, to establish a precision strategy for effectively managing cholangiocarcinoma.
Citation Format: Woo Young Kwon, Incheon Kang, Sung Hwan Lee. Multi-omics approach to cholangiocarcinoma-related biology and development of precision medicine [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 3502.
Abstract 3504: ARS2 and paraspeckle interactions: A nexus for lncRNA mediated drug resistance and cancer progression in hepatocellular carcinoma
Authors: Thillainadesan Gobi , Leong Hon Sing , Alawamry Omar 
Published: March 2024

Abstract
Paraspeckles, elaborate sub-nuclear assemblies composed of the lncRNA NEAT1-2 and a cohort of RNA-binding proteins, have a noted association with cancer progression and drug resistance. The specific mechanisms, however, have remained obscure. Our investigation into Hepatocellular Carcinoma (HCC) reveals a critical interaction: the sequestration of ARS2—an RNA-binding protein vital for the suppression of mRNA transcripts and the maturation of miRNAs—within paraspeckles. This sequestration leads to increased levels of NEAT1-2, derails miRNA processing, and diminishes the gene-silencing function of ARS2, thereby enhancing the expression of oncogenic genes. This discovery positions the ARS2-paraspeckle axis as a pivotal factor in cancer biology and a promising target for future treatments.
Citation Format: Gobi Thillainadesan, Hon Sing Leong, Omar Alawamry. ARS2 and paraspeckle interactions: A nexus for lncRNA mediated drug resistance and cancer progression 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 3504.