bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB191: Downregulation of Stem-loop binding protein by nicotine and its role in nicotine-induced cell transformation in human lung epithelial cells
Authors: Sun Qi , Chen Danqi , Jin Chunyuan 
Published: July 2021

Abstract
The use of electronic-cigarettes has increased substantially in recent years among the younger population in particular. The liquid nicotine is the main component of the e-cigarette. Mice exposed to e-cigarette smoke (ECS) generated by heating the liquid nicotine developed lung adenocarcinoma and bladder hyperplasia. This implicated a potential role for ECS/nicotine in cancer development, while the underlying mechanisms remain unclear. Here we report that nicotine reduces the protein level of Stem-loop binding protein (SLBP), a critical factor for the stability, processing and translation of canonical histone pre-mRNAs, in human lung epithelial BEAS-2B cells. It has been known that canonical histone mRNAs typically do not end in a poly(A) tail and that depletion of SLBP results in polyadenylation of canonical histone mRNAs that appeared to be carcinogenic. Indeed, nicotine exposure induced polyadenylation of mRNAs for histones H2A, H2B, H3.1, H3.2, and H4. Interestingly, the inhibitor for nAChRs (nicotinic acetylcholine receptors) reversed nicotine-induced SLBP depletion. Moreover, the depletion of SLBP was attenuated not only by both the inhibitors and siRNAs specific for CDK1/2 and CK2, but also by inhibition of AKT signal pathway. Importantly, nicotine-induced anchorage-independent cell growth was rescued by overexpression of SLBP. These results suggest that activation of nAChR and a series of signal transduction pathways are involved in nicotine-mediated SLBP reduction and they may play an important role in nicotine-induced cell transformation and carcinogenesis.Keywords: Nicotine, Stem-loop binding protein, Cell transformation, nAChR
Citation Format: Qi Sun, Danqi Chen, Chunyuan Jin. Downregulation of Stem-loop binding protein by nicotine and its role in nicotine-induced cell transformation in human lung epithelial cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB191.
Abstract LB192: Sulforaphane suppression of Prmt5 and Mep50 function suppresses the mesothelioma cancer stem cell phenotype
Authors: Ezeka Geraldine C. , Adhikary Gautam , Kandasamy Sivaveera , Friedberg Joseph , Eckert Richard 
Published: July 2021

Abstract
Mesothelioma is an aggressive and fatal cancer of the mesothelial lining which is caused by asbestos exposure. The current treatment strategy is surgical resection followed by chemotherapy, but this is marginally successful and leads to drug resistant and recurrent disease. Mesothelioma cancer stem cells (MCS cells) comprise an important subpopulation of highly aggressive mesothelioma tumor cells that maintain tumor formation and mediate drug resistance. Our goal is to identify proteins that maintain the MCS cell and non-stem cancer cell survival as therapy targets. Protein arginine methyltransferase 5 (PRMT5) functions with the MEP50 cofactor to catalyze symmetric dimethylation of specific arginine resides in histones 3 and 4 to silence tumor suppressor gene expression and enhance cancer cell survival. Our studies show that loss of PRMT5 or MEP50 reduces H4R3me2s formation in MCS cells and that this is associated with a reduction in MCS cell spheroid formation, invasion and migration. Additionally, treatment with sulforaphane (SFN), a promising diet-derived cancer prevention and therapy agent, reduces PRMT5/MEP50 level and H4R3me2s formation, and suppresses the MCS cell phenotype. Moreover, forced expression of PRMT5/MEP50 antagonizes SFN suppression of the MCS cell phenotype, suggesting that loss of PRMT5/MEP50 is required for SFN action. SFN treatment also markedly reduces tumor formation and this is associated with reduced PRMT5/MEP50 expression and H4R3me2s formation. These findings suggest that SFN suppresses PRMT5/MEP50 function to attenuate the MCS cell phenotype and reduce tumor formation, and that SFN may be a useful mesothelioma prevention and therapy agent.
Citation Format: Geraldine C. Ezeka, Gautam Adhikary, Sivaveera Kandasamy, Joseph Friedberg, Richard Eckert. Sulforaphane suppression of Prmt5 and Mep50 function suppresses the mesothelioma cancer stem cell phenotype [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB192.
Abstract LB205: The IRF8-MEF2D transcription factor circuit regulated by a druggable multiple post-translational modification (PTM) reader ZMYND8 in acute myeloid leukemia
Authors: Cao Zhendong , Budinich Krista A. , Huang Hua , Lu Bin , Zhang Zhen , Ren Diqiu , Zhou Yeqiao , Huang Yuhan , Pingul Bianca , Kingsley Molly C. , Lenard Alexandra K. , Qi Jun , Carroll Martin P. , Blobel Gerd A. , Faryabi Robert B. , Bernt Kathrin M. , Berger Shelley L. , Shi Junwei 
Published: July 2021

Abstract
The transformed state in acute leukemia requires gene regulatory programs involving transcription factors (TFs) and chromatin modulators. Here, we uncover an IRF8-MEF2D TF regulatory circuit as an acute myeloid leukemia (AML)-specific dependency. We discover and characterize the mechanism by which the chromatin ‘reader' ZMYND8 directly activates IRF8 in parallel with the MYC proto-oncogene through their AML-specific enhancers. ZMYND8 is essential for AML proliferation in vitro and in vivo and associates with MYC and IRF8 enhancer elements that we define in cell lines and in patient samples. ZMYND8 occupancy at IRF8 and MYC enhancers requires BRD4, a transcriptional coactivator essential for AML proliferation. We show that ZMYND8 binds to the ET domain of BRD4 via its chromatin reader cassette, which in turn is required for proper chromatin occupancy and maintenance of leukemic growth in vivo. Our results rationalize ZMYND8 as a potential selective therapeutic target for modulating essential transcriptional programs in AML.
Citation Format: Zhendong Cao, Krista A. Budinich, Hua Huang, Bin Lu, Zhen Zhang, Diqiu Ren, Yeqiao Zhou, Yuhan Huang, Bianca Pingul, Molly C. Kingsley, Alexandra K. Lenard, Jun Qi, Martin P. Carroll, Gerd A. Blobel, Robert B. Faryabi, Kathrin M. Bernt, Shelley L. Berger, Junwei Shi. The IRF8-MEF2D transcription factor circuit regulated by a druggable multiple post-translational modification (PTM) reader ZMYND8 in acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB205.
Abstract LB212: The VGLL4 tumor suppressor inhibits transglutaminase-2 dependent YAP1-TEAD signaling to attenuate the cancer phenotype
Authors: Mickle McKayla B. , Adhikary Gautam , Xu Wen , Shrestha Suruchi , Eckert Richard L. 
Published: July 2021

Abstract
Epidermal squamous cell carcinoma (SCC) is among the most common and aggressive forms of cancer. We previously showed that the pro-cancer transcription factor, YAP1, drives an aggressive SCC cancer phenotype by binding to nuclear TEAD transcription factors to activate pro-cancer gene expression. Vestigial-like protein 4 (VGLL4) is a tumor suppressor that is downregulated in epithelial cancers. It binds to TEAD factors to displace YAP1 binding to reduce YAP1-dependent transcription and target gene expression. The present study shows that VGLL4 overexpression reduces SCC cell TEAD-dependent transcription to reduce expression of mRNA and protein encoding YAP1-target genes (CTGF, CYR61, CCND1), and pro-cancer collagen genes (COL1A2, COL3A1) leading to reduced cell proliferation, spheroid formation, invasion and migration. Identical results were observed in response to transient and stable VGLL4 overexpression. Similarly, VGLL4 expression reduces YAP1 activity in tumors leading to reduced YAP1 target and pro-cancer collagen gene expression and reduced and EMT marker proteins levels which is associated with reduced tumor formation. Loss of YAP1 responsive gene expression appears to be essential for VGLL4 attenuation of the aggressive phenotype, as forced overexpression of CCND1 or COL1A2 antagonizes VGLL4 action. These findings suggest VGLL4 functions as a tumor suppressor in SCC by repressing YAP1/TEAD signaling and consequently attenuating the SCC phenotype.
Citation Format: McKayla B. Mickle, Gautam Adhikary, Wen Xu, Suruchi Shrestha, Richard L. Eckert. The VGLL4 tumor suppressor inhibits transglutaminase-2 dependent YAP1-TEAD signaling to attenuate the cancer phenotype [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB212.
Abstract LB241: Genomic and molecular features of metachronous metastasis in clear cell renal cell carcinoma
Authors: Naeini Marjan Mojtabavi , Rohatgi Neha , Ghoshdastider Umesh , Hakimi Ari A. , Skanderup Anders Jacobsen 
Published: July 2021

Abstract
Molecular features associated with risk of metachronous metastases (MM) in clear cell renal cell carcinoma (ccRCC) are poorly defined. Here, we performed systematic genomic and molecular analysis of 192 ccRCC primary tumors with extended clinical follow-up for development of MM. Whole-exome sequencing analysis revealed no association between somatic mutations and development of MM. However, chromosomal deletions at 1p33 were more prevalent in tumors that later progressed with MM. We inferred immune cell infiltrates and found that depletion of regulatory T cells and M1 macrophages were associated with development of MM. Next, we used bulk tumor transcriptome deconvolution to estimate cancer (malignant) and stromal (non-malignant) cell gene expression differences between MM and indolent primary tumors. Downregulation of the Crumbs complex component PATJ (1p31) in cancer cells of MM tumors suggested loss of apicobasal cell polarity as a risk factor in metastatic progression. We also identified downregulation of fatty acid degradation in cancer cells of MM tumors. Overall, our results nominate novel genomic and molecular features underpinning metachronous metastasis in ccRCC.
Citation Format: Marjan Mojtabavi Naeini, Neha Rohatgi, Umesh Ghoshdastider, Ari A. Hakimi, Anders Jacobsen Skanderup. Genomic and molecular features of metachronous metastasis in clear cell renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB241.
Abstract LB244: The role of stromal Per2 in regulation of tumorigenesis
Authors: Mayer Shimrit , Shaashua Lee , Lior Chen , Lavon Hagar , Novoselsky Alexander , Scherz-Shouval Ruth 
Published: July 2021

Abstract
The tumor microenvironment (TME) comprised of multiple proteins, extracellular matrix(ECM) and various cell types that together promote tumor initiation, progression andhomeostasis in a cell-cell communication manner. In this study, we set to understand howthe stromal circadian clock supports the cancer cells, specifically the contribution of thecore clock gene Per2 to tumor initiation and progression. The circadian clock is anendogenous, evolutionally conserved and ubiquitously expressed pacemaker, consisting ofcell autonomous clocks and a central pacemaker located in the hypothalamussuperchiasmatic nucleus (SCN). Together these clocks synchronize numerous biologicalprocesses between the organism and its environment. Amongst these processes are DNAdamage repair, metabolism, and cell cycle. Several studies showed that disruption ofcircadian rhythms has been associated with various forms of cancer in humans and mice.While Per2 was previously suggested to be a tumor suppressor, in this study we found thatthe core clock gene Per2 in the TME is essential for tumor initiation and metastaticcolonization. Another core gene, Per1, is dispensable. We further showed that lossof Per2 in the TME leads to transcriptional rewiring at early stages of metastasesformation, and suppresses subsequent metastatic tumor progression. Thus, our resultsunravel an unexpected protumorigenic role for the core clock gene Per2 in the TME. Thesefindings may imply a non-circadian role for Per2, differentiating it from Per1 withpotential implications for therapeutic dosing strategies and treatment regimens.
Citation Format: Shimrit Mayer, Lee Shaashua, Chen Lior, Hagar Lavon, Alexander Novoselsky, Ruth Scherz-Shouval. The role of stromal Per2 in regulation of tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB244.
Abstract LB248: Implantation factors assist in the growth of gynecologic tissues in ectopic locations
Authors: Sunde Jan , O'Neil Derek , Katz Tiffany , Wasickanin Morgan 
Published: July 2021

Abstract
OBJECTIVE: Develop a model of endosalpingiosis and endometriosis to investigate the mechanisms which facilitate implantation of exfoliated cells in the peritoneum.
BACKGROUND: Endosalpingiosis (ES) and endometriosis (EM) are the growth of tubal and endometrial epithelium respectively, outside of their site of origin and have been associated with ovarian cancer. Why this growth happens has not been elucidated since Sampson first proposed the concept of retrograde menstruation nearly 100 years ago. We hypothesized there is retrograde flow of uterine implantation factors which drive ectopic growth. To test this hypothesis, we developed a transgenic fluorescent murine model of ES and EM that successfully demonstrated peritoneal implantation in mice. Using the model, we explored possible influences on implantation.
METHODS: tdTomato (tdT) transgenic fluorescent mice were used as donors to allow for visualization of tissues in recipient mice. A progesterone knockout (PKO) of the tdT mouse that blocks implantation factors was created by giving 0.1 mg/kg progesterone on postnatal days 2-10. Metestrus endometrium was induced hormonally in donor tdT and wild-type (WT) female C57BL/6J mice. The tdT oviductal cells and endometrium were then harvested for intraperitoneal injection into synchronized recipient WT mice, receiving minced endometrium alone, minced oviduct alone, or a combination of minced oviduct and WT endometrial tissue (for implantation factors) from non-treated or PKO tdT donors. Ectopic lesions were identified using fluorescence in-vivo imaging and UV light.
RESULTS: PKO tdT oviduct had significantly reduced implantation (4 lesions/6 mice, p&lt;0.02) compared to tdT oviduct without treatment (28 lesions/8 mice). Additionally, PKO tdT oviduct implantation (10 lesions/3 mice) may be restored when implanted with WT endometrium (p=0.07). Chi square was used to evaluate for statistical significance.
ConclusionImplantation factors required for blastocyst implantation are crucial to initiate ectopic tissue growth. We have developed a novel mouse model of ectopic growth of gynecologic tissues which demonstrates that the removal of implantation factors from endometrium and oviduct reduces ectopic lesions. This model allows us to study the initial step of implantation of these lesions that could give rise to malignancies which will ultimately allow for the development of new prevention and treatment modalities.
Citation Format: Jan Sunde, Derek O'Neil, Tiffany Katz, Morgan Wasickanin. Implantation factors assist in the growth of gynecologic tissues in ectopic locations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB248.
Abstract NG02: Identification of high priority genes for basic and translational pancreatic cancer research
Authors: Nwosu Zeribe Chike , Giza Heather C. , Charlestin Verodia , Nassif Maya , Kim Daeho , Kemp Samantha , Steele Nina G. , Lyssiotis Costas A. , Pasca di Magliano Marina 
Published: July 2021

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is highly metastatic and drug resistant and is one of the most lethal solid malignancies. Genomic profiling studies have defined the molecular subtypes and mutational landscape of PDAC and extensive gene expression profiling dataset have been accumulated to date. However, there is a knowledge gap on the consistency of gene expression across profiled PDAC samples and this limits the prospects of clinical translation. To facilitate novel drug target prioritization and biomarker discovery, we have extensively analyzed over 20 publicly accessible datasets. We report the most consistently expressed genes in PDAC tissues compared to non-tumors. Specifically, we identified 3,938 consistent genes, including 2,010 consistently upregulated genes, topmost of which included LAMC2, TMPRSS4, S100P, SLC6A14, COL10A1, CTSE, LAMB3, CEACAM5/6, and glucose transporter SLC2A1, and 1,928 consistently downregulated genes top among which include AOX1, IAPP, albumin (ALB), SERPINI2, PDK4 and PNLIPRP1/2 (adjusted P&lt;0.05). Over 50% of the genes are unknown. In addition, these genes largely reflected the same expression pattern in bulk and single cell RNA sequencing analysis, showed tumors-specificity, and correlated with several cancer indices including proliferation, metastasis, mutation and tumor grade. Pathway enrichment analyses revealed ‘pathways in cancer', ‘focal adhesion', ‘p53', ‘cell cycle', ‘transcription factor binding', “glycolysis” among upregulated processes. These pathway alterations were accompanied by profound metabolic alterations and signatures of disrupted pancreatic homeostasis. Interactome and disease ontology analyses further linked the consistent genes with precancerous conditions, PDAC, and malignancy. We found that ~41% of the genes predicted patients' overall survival in at least two datasets while clustering analyses and receiver operating characteristic analysis uncovered highly probable biomarkers. Subsequent analysis of gene silencing datasets identified 185 ‘high-priority' genes (notably candidates in cell cycle and glycolysis) whose knockdown suppress PDAC viability. Our multi-dimensional analysis is an important milestone in the quest for mechanisms, drug targets and biomarkers in PDAC, and outlines an adaptable analytical approach that can aid biomarker or therapeutic target discovery in other cancers.
Citation Format: Zeribe Chike Nwosu, Heather C. Giza, Verodia Charlestin, Maya Nassif, Daeho Kim, Samantha Kemp, Nina G. Steele, Costas A. Lyssiotis, Marina Pasca di Magliano. Identification of high priority genes for basic and translational pancreatic cancer research [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr NG02.
Abstract PL01-04: Epigenetic mechanisms of malignant clonal dominance and immune evasion
Authors: Dawson Mark A. 
Published: July 2021

Abstract
All cancers emerge following a period of clonal selection and subsequent clonal expansion. Whilst the evolutionary trajectories and clonal fitness imparted by genetic intra-tumour heterogeneity (ITH) are becoming increasingly clear, little is known about the non-genetic mechanisms that contribute to ITH and malignant clonal fitness. In this presentation I will discuss some of our recent work addressing the significance of transcriptional processes that facilitate malignant clonal dominance in isogenic cancer cells. I will also highlight emerging evidence showing the importance of manipulating transcriptional regulators to facilitate anti-cancer immune surveillance in a broad range of cancers.
Citation Format: Mark A. Dawson. Epigenetic mechanisms of malignant clonal dominance and immune evasion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr PL01-04.
Abstract PL03-02: (Re)emerging principles of cancer therapy
Authors: Kaelin William George 
Published: July 2021

Abstract
It is likely that some of the mutations that occur late during evolution, whether passenger mutations or passenger mutations, are likely only tolerated (let alone advantageous to the cancer cell) because of the mutations that preceded them. If so, targeting mutations that occur early during tumor evolution should selectively kill cancer cells by unmasking the otherwise deleterious effects of subsequent mutations. There are now many precision cancer drugs that target such early mutations, including EGFR inhibitors for lung cancer, c-Kit mutations for GI stromal tumors, and B-Raf inhibitors for B-Raf mutant melanomas. Inactivation of the von Hippel-Lindau tumor suppressor protein (pVHL) is an early event in kidney cancer. Inactivated proteins can sometimes be tackled by exploiting epistatic relationships or synthetic lethality. For example, pVHL suppresses the HIF2 transcription factor, which in turn regulates VEGF. VEGF inhibitors are now mainstays of kidney cancer treatment. HIF2 was viewed as “undruggable”, but undruggable proteins can sometimes be targeted by allosteric modulators or degraders. A first-in-class allosteric HIF2 inhibitor has advanced to phase 3 trials based on promising early data. Most cancer drugs work better in the frontline setting, and a recent study of previously untreated von Hippel-Lindau disease patients strongly suggests this will be true for the HIF2 inhibitor. Combination therapy will be required to cure most cancer. It is tempting to combine drugs that have interdependent actions in an attempt to achieve synergy, but this increases the risk of cross-resistance. The classical way to prevent resistance is to combine drugs that have distinct mechanisms of action (to minimize toxicity and cross-resistance). In this regard, immunotherapy has emerged as a powerful modality to treat cancer cells, and complements therapies aimed at inducing cancer cell death. Both kidney cancer and melanomas are highly immunogenic and can respond to immune checkpoint blockade, yet kidney cancer has a much lower mutational burden than melanoma. Recent work suggests that kidney cancers promiscuously express endogenous retroviruses, which might serve as a source of neoantigens. If true, it might be possible to pharmacologically enhance ERV expression to augment immunotherapy.
Citation Format: William George Kaelin. (Re)emerging principles of cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr PL03-02.