bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract IA18: Clock Control of HIF Activity and Muscle Tissue Regeneration
Authors: Peek Clara Bien 
Published: December 2020

Abstract
Circadian clocks generate rhythmic pulses of glucose metabolism and respiration to divide energy-producing and energy-consuming processes into separate periods in the light-dark cycle. At the cellular level, clocks direct the expression of thousands of genes involved in metabolism, tissue growth, and repair, yet our understanding of how clocks detect signals in the environment to coordinate transcription and metabolic flux at precise stages during development and in post-mitotic cells remains poorly understood. A breakthrough in understanding circadian mechanisms in metabolic plasticity came from our discovery that molecular clock transcription factors respond to changes in environmental oxygen. We uncovered a link between circadian clocks and the control of the oxygen- and mitochondrial stress-responsive hypoxia-inducible factor (HIF) pathway, which controls adaptation to low oxygen environments, such as during tumorigenesis and ischemic injury. Here, we demonstrate a role for the circadian clock in post-muscle injury myogenesis and tissue regeneration. Indeed, loss of Bmal1 in adult muscle stem cell populations leads to impaired regeneration after ischemic muscle injury in mice. Furthermore, we observe time-of-day differences in muscle regeneration rates, with more rapid tissue repair following injury during the dark (active) phase. In addition, myogenesis is reduced in primary Bmal1-/- myoblasts compared to controls, a phenotype that is exaggerated in hypoxic conditions. Finally, we observe that loss of Bmal1 in myoblasts leads to chromatin remodeling that alters transcription of genes involved in metabolic flux and myogenic gene expression. Together, our studies demonstrate that circadian clocks in muscle stem cells control metabolic and genomic reprogramming under hypoxia to regulate in vitro myogenesis and in vivo skeletal muscle regeneration.
Citation Format: Clara Bien Peek. Clock Control of HIF Activity and Muscle Tissue Regeneration [abstract]. In: Abstracts: AACR Special Virtual Conference on Epigenetics and Metabolism; October 15-16, 2020; 2020 Oct 15-16. Philadelphia (PA): AACR; Cancer Res 2020;80(23 Suppl):Abstract nr IA18.
Abstract PO-037: Leveraging polyamine metabolic stress to enhance sensitivity to epigenetic therapy for prostate cancer
Authors: Rowsam Aryn M. , Affronti Hayley C. , Rosario Spencer R. , Long Mark D. 
Published: December 2020

Abstract
While polyamines are required for proliferation in all cells, the prostate synthesizes and secretes high levels into its lumen, resulting in depletion of intracellular polyamines. To meet polyamine biosynthetic demands, which is enhanced in Prostate Cancer (CaP), there is high flux through one carbon metabolism to provide S’-Adenosylmethionine (SAM), which donates its aminopropyl group to polyamine synthesis. This flux is driven by Spermidine/ Spermine N1-Acetyltransferase (SSAT) which adds acetyl groups to spermidine and spermine, leading to their secretion. To deal with the stress, the methionine salvage pathway (MSP) recycles one carbon units lost during polyamine synthesis back to the methionine cycle for SAM replenishment, by methylthioadenine phosphorylase (MTAP). We have shown increased polyamine catabolism by SSAT stabilization and MTAP inhibition results in cell death in in vitro, in vivo, and ex vivo CaP models. We expect the CaP epigenome to be impacted by stressed acetyl-CoA and SAM pools, which are used by chromatin modifying enzymes, and that this stress will alter CaP sensitivity to epigenetic based drugs. While epigenetic therapies are currently being investigated in the clinic for targeting CaP, their success has been limited due to toxicity and non-specificity. We hypothesize that increased flux through polyamine metabolism and one carbon metabolism disrupts SAM and acetyl-CoA pool maintenance, making CaP cells sensitized to therapy targeting their utilization. Our findings suggest that certain histone modifications are affected by treatment with BENSpm in vitro. Additionally, we have found treatment of CaP cells with BENSpm and MTDIA induces significant broad DNA methylation changes. Furthermore, our preliminary data shows that the addition of metabolic therapies, BENSpm and MTDIA, to an epigenetic targeting drug, JQ1, further suppresses CaP growth in vitro. We expect that future studies combining our metabolic therapies with epigenetic drugs targeting acetyl-CoA and SAM usage will maintain anti-tumor efficacy with reduced systemic toxicity.
Citation Format: Aryn M. Rowsam, Hayley C. Affronti, Spencer R. Rosario, Mark D. Long. Leveraging polyamine metabolic stress to enhance sensitivity to epigenetic therapy for prostate cancer [abstract]. In: Abstracts: AACR Special Virtual Conference on Epigenetics and Metabolism; October 15-16, 2020; 2020 Oct 15-16. Philadelphia (PA): AACR; Cancer Res 2020;80(23 Suppl):Abstract nr PO-037.
Abstract PO-052: Combinatorial targeting of chromatin and metabolism for synergistic anti-cancer efficacy
Authors: Sheikh Tahir N. , Chen Xiao , Xu Xinjing , Patwardhan Parag P. , Schwartz Gary K. , Lu Chao 
Published: December 2020

Abstract
Altered cellular metabolic network and chromatin landscape represent two molecular hallmarks of cancer. Despite considerable interests, targeting metabolic or chromatin regulatory pathways as monotherapy was met with limited success in pre-clinical and clinical studies, in part due to the ability of cancer cells to rewire and adapt to the stress induced by therapeutic intervention. Therefore, there is a critical need to understand resistance programs and to identify strategies for more effective combinatorial therapies. We have previously uncovered that DNA and histone modifications are exquisitely sensitive to perturbations of the metabolic state. During tumor initiation, this metabolism-chromatin “crosstalk” is often hijacked by cancer cells to respond to fluctuations in signaling and nutrient abundance, but the role of such interplay in drug resistance has remained elusive. Here we demonstrated that cancer cells which developed resistance to inhibitor of glutamine catabolism (CB-839) displayed increased ratio of α-ketoglutarate to succinate that acts as a metabolic regulator of TET-family DNA hydroxylases and Jumonji-family histone demethylases. Accordingly, CB-839 resistant cancer cells showed global DNA hypomethylation and decreased levels of H3K9me3 and H3K27me3, which in turn resulted in increases in histone acetylation and a gene expression program that promoted metabolic adaptation to inhibition of glutaminolysis. Importantly, this altered chromatin landscape also represented a therapeutic vulnerability, as CB-839 resistant cells were selectively hyper-sensitive to small-molecule inhibitors of BET domain such as JQ1 and PLX51107. We are currently testing the possible synergistic effects of clinical stage glutaminase and BET inhibitors across various cancer types. Taken together, these results highlight the potential of exploring and therapeutically exploiting metabolic and chromatin interactions for developing rationally designed, precision combinatorial anti-cancer treatment strategies.
Citation Format: Tahir N. Sheikh, Xiao Chen, Xinjing Xu, Parag P. Patwardhan, Gary K. Schwartz, Chao Lu. Combinatorial targeting of chromatin and metabolism for synergistic anti-cancer efficacy [abstract]. In: Abstracts: AACR Special Virtual Conference on Epigenetics and Metabolism; October 15-16, 2020; 2020 Oct 15-16. Philadelphia (PA): AACR; Cancer Res 2020;80(23 Suppl):Abstract nr PO-052.
Abstract PO-055: Pan-cancer metabolic profiling of the tumor microenvironment
Authors: Rohatgi Neha , Ghoshdastider Umesh , Baruah Probhonjon , Skanderup Anders Jacobsen 
Published: December 2020

Abstract
Tumors are heterogeneous cellular environments with entwined metabolic dependencies. However, it is challenging to differentially profile metabolism in cancer and infiltrating non-malignant cells inside patient tumors. Here, we used a tumor transcriptome deconvolution approach to profile the metabolic states of cancer and non-cancer (stromal) cells in bulk tumors of 20 solid tumor types. This analysis highlighted metabolic genes and processes recurrently upregulated in cancer cells across tumor types, including the mitochondrial dicarboxylate carrier SLC25A10. Intriguingly, the tryptophan-degrading dioxygenase, IDO1, was highly recurrently overexpressed in stroma compared to cancer cells and normal tissue, suggesting that tryptophan-mediated suppression of antitumor immune response is predominantly constrained by the stroma. Oxidative phosphorylation was unexpectedly the most upregulated metabolic process in cancer cells compared to both stromal cells and a large atlas of cancer cell lines, suggesting that the warburg effect may be less pronounced in cancer cells in vivo. Overall, our analysis highlights fundamental differences in metabolic states of cancer and stromal cells inside tumors and establishes a pan-cancer resource to interrogate tumor metabolism.
Citation Format: Neha Rohatgi, Umesh Ghoshdastider, Probhonjon Baruah, Anders Jacobsen Skanderup. Pan-cancer metabolic profiling of the tumor microenvironment [abstract]. In: Abstracts: AACR Special Virtual Conference on Epigenetics and Metabolism; October 15-16, 2020; 2020 Oct 15-16. Philadelphia (PA): AACR; Cancer Res 2020;80(23 Suppl):Abstract nr PO-055.
Abstract PO-056: Role of the metabolite N-acetylaspartate in breast cancer progression
Authors: Balasubramanian Akhila , Zhang Weijie , Gu Franklin , Ambati Chandra , Putluri Nagireddy , Zhang Xiang , Namboodiri Aryan , Ambs Stefan , Sreekumar Arun 
Published: December 2020

Abstract
Breast cancer (BCa) is a disease that affects over a quarter million women in the US every year. Our laboratory studies reprogrammed energy metabolism in BCa, which is an essential hallmark of the disease. Specifically, we focus on the metabolic rewiring events that occur in BCa, intending to identify cancer-associated metabolic vulnerabilities to treat this aggressive disease. Using a global metabolic profiling approach, we have determined that the metabolite N-acetylaspartate (NAA) is highly accumulated in patients with BCa. Prior studies involving NAA in other cancer types have attributed its accumulation to the upregulation of the enzyme N-acetyl transferase (NAT8L), which synthesizes NAA. However, using matched gene expression data, we found that the accumulation of NAA in these BCa tumors rather coincides with the downregulation of aspartoacylase (ASPA), the enzyme that breaks down NAA. To determine the role of NAA in BCa progression, we generated multiple cell line models containing either NAT8L knockdown, ASPA overexpression, or a combination of the two in the cell line MDA-MB231 in a bid to deplete intracellular NAA. We used these models to test for metastasis by tail vein injection in immunocompromised mice. Consistent with our expectations and other reports, NAT8L knockdown resulted in reduced lung metastasis. Interestingly, however, NAA depletion via ASPA overexpression increased metastasis to the lung in vivo. Furthermore, the combination of ASPA overexpression with the knockdown of NAT8L led to a moderate phenotype between the two independent genetic modifications. Our findings of the metastasis-promoting effect of NAA depletion via ASPA overexpression leads to us believe that it is not just the accumulation of NAA but also its utilization that is important for breast cancer progression. Our future experiments are directed towards determining how NAA utilization causes a pro-tumorigenic phenotype. We would also like to study the current inconsistency between ASPA transcript levels in patient tumors and its observed tumor-promoting function in xenograft experiments. Completion of these studies will potentially define the importance of elevated NAA levels in the context of aggressive BCa. Since NAA is a metabolite that can be detected in serum, our study could also lead to the development of NAA as a non-invasive biomarker for early detection of aggressive BCa, thus providing a bigger window for therapeutic intervention.
Citation Format: Akhila Balasubramanian, Weijie Zhang, Franklin Gu, Chandra Ambati, Nagireddy Putluri, Xiang Zhang, Aryan Namboodiri, Stefan Ambs, Arun Sreekumar. Role of the metabolite N-acetylaspartate in breast cancer progression [abstract]. In: Abstracts: AACR Special Virtual Conference on Epigenetics and Metabolism; October 15-16, 2020; 2020 Oct 15-16. Philadelphia (PA): AACR; Cancer Res 2020;80(23 Suppl):Abstract nr PO-056.
Abstract PO-059: SOX2-mediated 5hmC dysregulation in GBM Stem Cells
Authors: Lopez-Bertoni Hernando 
Published: December 2020

Abstract
Primary brain tumors are among the most devastating forms of cancer and glioblastoma (GBM) represents the most aggressive and lethal form of the disease. We now know that GBM contain small subsets of cells that display tumor-propagating stem-like phenotypes (i.e. glioma stem cells or GSCs) that act as critical determinants of GBM resistance to current treatments and tumor recurrence for which there is no proven therapy. Altered patterns of DNA methylation are widely reported in human GBM. However, substantial knowledge gaps remain in our understanding of the molecular mechanisms responsible for this epigenetic dysregulation, its downstream consequences and role in the GBM tumor propagating phenotype. Understanding and ultimately targeting the epigenetic mechanisms that induce and maintain these tumor-propagating cell subsets is critical to improving GBM therapy and patient outcomes. DNA methylation generally occurs in cytosine-guanine (CpG) sequences and is established by DNMTs, which catalyze the conversion of cytosine to 5-methylcytosine (5mC). DNA methylation is a reversible process and is partially mediated by the ten-eleven translocation (TET) family of enzymes which function as deoxygenases to catalyze the conversion of 5mC to 5-hydroxymethylcytosine (5hmC). Levels of 5hmC closely track with the differentiation state of cells with terminally differentiated cells containing high levels of 5hmC and less differentiated cells having very low levels. Multiple studies found negative correlations between 5hmC levels and glioma grade and loss of 5hmC correlates with poor prognosis of GBM patients, strongly suggesting that these enzymes activate tumor suppressing mechanisms. Our preliminary data shows that exogenous SOX2 represses the TET2 demethylase and decreases 5hmC, the enzymatic product catalyzed by TET proteins, in GSCs. TET2 repression using 2 independent shRNA hairpins efficiently decreases 5hmc levels and significantly enhanced self-renewal capacity and tumor growth capacity of low-passage GSC isolates. We also show that SOX2 induces expression of miR-10b-5p, a known onco-miR predicted to target TET2, and inhibiting this miRNA partially rescues the reduction in 5hmC expression observed in GSCs expressing transgenic SOX2, thus implicating miR-10b-5p as a critical mediator of SOX2-induced onco-methylation, GSC induction and glioma malignancy. Our preliminary results support a mechanism in which SOX2 represses TET2 leading to 5hmC loss by directly activating miR-10b-5p transcription and predicts that targeting this novel mechanism of epigenetic dysregulation by inhibiting miR-10b-5p in vivo will can lead to pre-clinical GBM therapeutics.
Citation Format: Hernando Lopez-Bertoni. SOX2-mediated 5hmC dysregulation in GBM Stem Cells [abstract]. In: Abstracts: AACR Special Virtual Conference on Epigenetics and Metabolism; October 15-16, 2020; 2020 Oct 15-16. Philadelphia (PA): AACR; Cancer Res 2020;80(23 Suppl):Abstract nr PO-059.
Abstract B17: IKKα/STAT3 antagonistic signaling regulates fungi-bacteria endosymbiosis-associated carcinogenesis
Authors: Song Na-Young , Li Xin , Badger Jonathan H. , Brown Jami Willette , Sun Xhonghe , Shi Gongping , Zhu Feng , Jiang Chengfei , O'hUigin Colum , Wu Xiaolin , Trinchieri Giorgio , Hu Yinling 
Published: December 2020

Abstract
Clinically, oral fungating lesions frequently occur in cancer patients following radiation and chemotherapy. However, their role in carcinogenesis has not been fully understood. Our previous finding showed that defective IKKα-mediated autoreactive T cells promote fungal infection and esophageal malignancy, but whether IKKα-mediated altered epithelial properties regulate fungal colonization and carcinogenesis remains to be tested. To investigate whether IKKα-mediated altered epithelial properties regulate fungal colonization and carcinogenesis, we orally infected mice lacking Ikkα (IkkαΔSOE) or both Ikkα and Stat3 (IkkαΔSOEStat3ΔSOE) in the stem cells of the skin and mouth with fungi. We found that oral fungal infection enhanced Ikkα ablation-mediated skin and oral carcinogenesis in association with increased oral and skin bacteria counts and altered oral bacteria phylum from gram-positive to gram-negative. Enhanced oral fungal/bacterial infection increased inflammasome activities and systemic IL-17A/IL-1β signals. Surprisingly, Stat3 ablation rescued these phenotypes in IkkαΔSOEStat3ΔSOE mice. In addition, amoxicillin treatment inhibited skin carcinogenesis and oral/skin bacteria counts and reversed oral bacteria phyla in fungal-inoculated IkkαΔSOE mice. These findings highlight that cancer cell IKKα/STAT3 antagonizing pathways determine susceptibility to fungal and bacterial colonization, which impacts carcinogenesis. Human head and neck squamous cell carcinomas also share oncogenic pathways and bacteria sequences/counts with mice, suggesting that oral fungating/ulcerating lesions enhance local and distal tumorigenesis in humans.
Citation Format: Na-Young Song, Xin Li, Jonathan H. Badger, Jami Willette Brown, Xhonghe Sun, Gongping Shi, Feng Zhu, Chengfei Jiang, Colum O'hUigin, Xiaolin Wu, Giorgio Trinchieri, Yinling Hu. IKKα/STAT3 antagonistic signaling regulates fungi-bacteria endosymbiosis-associated carcinogenesis [abstract]. In: Proceedings of the AACR Special Conference on the Microbiome, Viruses, and Cancer; 2020 Feb 21-24; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2020;80(8 Suppl):Abstract nr B17.
Abstract B26: Comparative analysis of breast tumor microbiome in Black non-Hispanic (BNH) and White non-Hispanic (WNH) women
Authors: Thyagarajan Srikantha , Zhang Yan , Thapa Santosh , Allen Michael S. , Phillips Nicole , Vishwanatha Jamboor K. 
Published: December 2020

Abstract
African American women are approximately twice as likely to be diagnosed with highly aggressive estrogen receptor-negative (ER-) and TNBC subtypes of breast cancer than Caucasian women. Among biologic factors, microbiota has been implicated in the etiology of several kinds of cancer including breast cancer. Few recent studies have shown that the breast niche-specific microbiota may have a major influence on breast tumorigenesis as shown by a decreased abundance of bacterial species with known immunomodulatory and probiotic effect in paired tumor tissue as compared to normal tissue derived from healthy patients, including different microbiota profiles in different subtypes of breast cancer. To understand whether the breast tissue harbors microbiota profiles that are uniquely race-specific we have analyzed tumor and matched normal and tumor tissue using 16S rRNA targeted sequencing strategy. Two distinct breast tumor types derived from women were included in this study: triple-negative breast cancer (TNBC) and triple-positive breast cancer (TPBC) derived from BNH and WNH women. The data were analyzed for microbiota composition, abundance, and diversity parameters, alpha diversity and beta diversity. The preliminary microbiome analysis revealed specific differences in abundance both at the phylum and genus levels between WNH and BNH women breast tissues; the alpha diversity matric, Shannon index measuring both richness and evenness of microbiota diversity showed differences in microbial diversity between normal breast tumor tissue and the matched normal adjacent to tumor tissue. The microbiota richness was relatively lower in BNH TNBC tumor tissue as compared to its matched normal adjacent to tumor zone as defined by pathologic analysis. In contrast, the microbiota richness was higher in WNH TNBC tumor tissue as compared to its matched normal breast tissue. The multivariate analysis of beta diversity revealed a distinct clustering in BNH and WNH TNBC microbiota between both tumors as compared to normal tissue and BNH as compared to WNH racial groups. Research reported in this publication was supported by the National Institute on Minority Health and Health Disparities of the National Institutes of Health under Award Numbers S21MD012472 and U54MD006882.
Note: This abstract was not presented at the conference.
Citation Format: Srikantha Thyagarajan, Yan Zhang, Santosh Thapa, Michael S. Allen, Nicole Phillips, Jamboor K. Vishwanatha. Comparative analysis of breast tumor microbiome in Black non-Hispanic (BNH) and White non-Hispanic (WNH) women [abstract]. In: Proceedings of the AACR Special Conference on the Microbiome, Viruses, and Cancer; 2020 Feb 21-24; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2020;80(8 Suppl):Abstract nr B26.
Abstract B38: Virome assembly and annotation in brain tissue based on next-generation sequencing
Authors: Yuan Zihao , Ye Xiaohua , Zhang Ningyan , An Zhiqiang , Zheng Wenjin 
Published: December 2020

Abstract
Glioblastoma multiforme (GBM) is one of the most lethal brain tumors, and the virosphere in brain and its correlation with GBM triggering is controversy. The previous research in brain virosphere was mainly limited to the presence of human cytomegalovirus (HCMV); a comprehensive assessment of the brain virome based on the recently sequenced data and the understanding of the novel sequences that cannot be mapped to the known reference sequences are lacking. Here, we characterized the virome from 111 GBM samples and 57 normal brain samples from 8 projects in SRA database by known and novel viruses in a tested and comprehensive assembly approach. The annotation of those contigs showed most of the viral sequences belongs to the Retroviridae. A novel picornavirus, which was recently discovered from the invertebrate, can be detected in some GBM samples in full genome length. Furthermore, our analysis showed that the herpes virus fragments that are annotated as Epstein-Barr virus (EBV) only exist in the GBM with less than 1% of the EBV whole genome, supporting the absence of herpes virus in GBM. The further analysis showed that the contigs that have no annotations from the known databases may have the antibody properties and antibody epitopes to be the future drug targets. In this study, we characterized the virosphere in GBM and normal brain at a global level, to provide a basis for future GBM research and therapies.
Citation Format: Zihao Yuan, Xiaohua Ye, Ningyan Zhang, Zhiqiang An, Wenjin Zheng. Virome assembly and annotation in brain tissue based on next-generation sequencing [abstract]. In: Proceedings of the AACR Special Conference on the Microbiome, Viruses, and Cancer; 2020 Feb 21-24; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2020;80(8 Suppl):Abstract nr B38.