bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB206: Simultaneous single cell profiling of open chromatin and gene expression in B cell lymphoma highlights tumor-specific regulatory networks
Authors: Maheshwari Shamoni , Wang Li , Gopalan Vijay , Shuga Joe , Chatterjee Sharmila , Belhocine Kamila 
Published: July 2021

Abstract
Profiling multiple analytes from a single cell enables additional dimensions to characterize tumor biology. Simultaneous measurement of epigenetic information and gene expression in single cells provides a clearer readout of the links between regulatory elements and target genes, allowing a more mechanistic interpretation of cell clusters and better cell type distinctions based on a cell's history and its future potential.
Here, we describe simultaneous measurement of gene expression and chromatin accessibility from thousands of single nuclei using the Chromium Single Cell Multiome ATAC + Gene Expression. We leverage a microfluidic platform to generate paired barcoded gene expression and ATAC-seq libraries, linking transcriptomic and open chromatin information at the single cell level. Using this method, we jointly profiled gene expression and chromatin accessibility from over 10,000 immune cells from healthy human PBMCs and over 14,000 cells from a human B cell lymphoma sample.
In healthy immune cells, we leveraged chromatin information to better parse distinct cell states within a gene expression-defined cell type, showing that the addition of ATAC profiling to gene expression improves resolution of cell type specification.
In B cell lymphoma, we used known markers of malignancy to segregate tumor B cells from normal B cells. We constructed regulatory networks in both cell states using the observed transcription factor motif enrichment in open chromatin regions combined with gene expression from the same cells. Comparing regulatory networks in healthy vs. tumor B cells highlighted the presence of unique regulatory networks in tumor B cells. Notably, the PAX5 tumor regulator was observed only in tumor B cells, and its impacts on the regulation of many downstream genes was characterized. Building this regulatory network analysis was only made possible through the joint profiling of open chromatin and gene expression at the single cell level. Our data demonstrate the power of simultaneous profiling of both epigenomic and transcriptomic data in characterizing cells in cancer state and extracting functional information from tumor samples.
Citation Format: Shamoni Maheshwari, Li Wang, Vijay Gopalan, Joe Shuga, Sharmila Chatterjee, Kamila Belhocine. Simultaneous single cell profiling of open chromatin and gene expression in B cell lymphoma highlights tumor-specific regulatory networks [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 LB206.
Abstract LB207: Glutamine transporter SLC38A3 promotes breast cancer migration via GSK3beta/beta-catenin/EMT pathway
Authors: Tan Zheqiong , Tressler Caitlin M. , Sonkar Kanchan , Glunde Kristine 
Published: July 2021

Abstract
Breast cancer is one of the most commonly diagnosed cancers and the leading cause of cancer-related death among women. Triple negative breast cancer (TNBC) is a subtype of breast cancer characterized by the absence of estrogen receptor, progesterone receptor and HER2 expression. TNBC shows a high capacity for early metastasis and leads to worse clinical outcomes than other breast cancer subtypes due to the lack of specific therapeutic targets. We are looking to develop cancer-specific therapeutic targets for TNBC. Many types of cancer cells including TNBC cells rely on glutamine as carbon and nitrogen source to fuel unchecked growth. We screened for key genes in regulating glutamine metabolism in a panel of breast cancer cell lines. This screen identified the mRNA and protein levels of solute carrier family 38 member 3 (SLC38A3), a glutamine transporter, to be upregulated in human breast cancer cell lines, especially in TNBC cell lines. The TCGA breast cancer patient database also showed that SLC38A3 mRNA is overexpressed in invasive ductal breast carcinoma tissues, and it is even higher in TNBC relative to other breast cancer subtypes. To test the biological role of SLC38A3 protein in TNBC cells, we performed loss-of-function experiments in multiple TNBC cell lines. Silencing of SLC38A3 decreased cellular glutamate, glutamine and alanine levels. Silencing of SLC38A3 also activated apoptosis, and suppressed cell viability, migration and invasion in several TNBC cell lines. Interestingly, silencing of SLC38A3 increased the activity of glycogen synthase kinase 3-β (GSK3β) which promoted the degradation of β-catenin, leading to the decrease of the mRNA levels of epithelial-to-mesenchymal-transition (EMT)-associated transcription factors in TNBC cell lines. In summary, we showed that SLC38A3 is overexpressed in TNBC and promotes breast cancer migration and invasion via GSK3β/β-catenin/EMT pathway, which could be a novel therapeutic target for breast cancer.
Citation Format: Zheqiong Tan, Caitlin M. Tressler, Kanchan Sonkar, Kristine Glunde. Glutamine transporter SLC38A3 promotes breast cancer migration via GSK3beta/beta-catenin/EMT pathway [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 LB207.
Abstract LB211: Epstein-Barr virus BART lncRNAs induce IKZF3/Aiolos to maintain EBV latency and promote tumorigenicity in nasopharyngeal carcinoma
Authors: HE Songtao , Liu Jiayan , Chen Honglin 
Published: July 2021

Abstract
Epstein-Barr virus (EBV) infection is one of the main causative factors of nasopharyngeal carcinoma (NPC), which is prevalent in southern China and some Southeast Asian countries. EBV infection in NPC cells is characteristically type II latency, where very few viral proteins (EBNA1, LMP1 and LMP2A) but high levels of noncoding RNAs (especially BARTs: BamHI-A rightward transcripts) are expressed. Our previous study found that BART lncRNAs modulate transcription of IKZF3, which encodes Aiolos, through epigenetic pathways in NPC cells. However, the biological significance functional mechanism of IKZF3/Aiolos are not yet clearly defined. We now further show that IKZF3/Aiolos expression levels are associated with copy numbers of EBV episomes in the EBV-harboring NPC cell line, NPC43, and specifically correlate to the level of lnc-BARTs, as demonstrated using CRISPR systems. Transcriptomic analysis of IKZF3-knockout C666-1 NPC cells revealed that 17 EBV-encoded microRNAs and 53 lytic genes were significantly downregulated or upregulated (FDR p value &lt;0.05 and posterior fold changes &gt;1.5). Immunoblot testing showed that the EBV lytic reactivator Zta and antigen BMRF1 are upregulated following knockout of IKZF3 in C666-1 cells, suggesting involvement of IKZF3/Aiolos in maintaining EBV latency in NPC. Gene ontology and KEGG (Kyoto Encyclopaedia of Genes and Genomes) analysis of IKZF3-knockout C666-1 cells found that most of the host genes with differential expression that are enriched in Epstein-Barr virus infection are associated with apoptosis, focal adhesion, cancer cell growth and mammary neoplasm (p value &lt;0.01). In addition, a soft agar assay demonstrated that oncogenic transformation of C666-1 cells was attenuated after knocking down expression of lnc-BARTs, knocking out IKZF3, or treatment with the IKZF3 inhibitor lenalidomide. Immunoprecipitation (IP) testing showed that Aiolos interacted with core elements (HDAC1 and MTA2) of the Mi-2/NuRD (nucleosome remodelling deacetylase) complex in NPC cells. Our findings suggest that Aiolos may recruit Mi-2/NuRD complexes for deacetylation of histone lysine residues bordering promoter regions of EBV lytic genes and host tumour suppressor genes, leading to inhibition of reactivation of EBV lytic infection, thereby preventing apoptosis of NPC cells.
Citation Format: Songtao HE, Jiayan Liu, Honglin Chen. Epstein-Barr virus BART lncRNAs induce IKZF3/Aiolos to maintain EBV latency and promote tumorigenicity in nasopharyngeal 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 LB211.
Abstract LB224: The potential effect of chronically increased endotoxin levels on breast carcinoma progression in obese patients.
Authors: Meirovitz Amichay , Nahmias Daniela , Hermano Esther , Maimon Ofra , Peretz Tamar , Elkin Michael 
Published: July 2021

Abstract
Obesity serves as a risk factor for estrogen-dependent postmenopausal breast cancer (BC). While the exact association occurring between these two disease states remains unknown, obesity-associated inflammation is thought to be the most likely contributing factor. In addition, obesity has been correlated to changes in gut microbiota composition and a subsequent chronic increase in bacterial endotoxin (lipopolysaccharide [LPS] - canonic ligand of toll-like receptor 4 [TLR4]) blood levels. It was recently shown that BC cells intrinsically express TLR4 and such expression has been associated with decreased patient survival as well as increased tumor growth. We hypothesized that obesity-associated endotoxemia may contribute to BC progression by utilizing TLR-dependent mechanisms and exerting cancer-promoting effects directly (on carcinoma cells) and indirectly (triggering abnormal activation of macrophages). Utilizing a chronic metabolic endotoxemia and breast cancer murine model as well as in vitro experimental systems, we found that continuous exposure to low concentrations of LPS not only promotes BC progression in vivo but stimulates BC cell growth in culture through the activation of key breast cancer-promoting signaling pathways (Stat3, Akt, ERK1/2). Obesity has reached epidemic proportions globally, where elucidation of the molecular mechanisms underlying breast tumor-promoting action of obesity has become of vital importance. Improving the understanding of such mechanisms has the potential to reveal improved efficacious therapy regimens and prevention strategies in a rapidly growing population of obese, breast cancer patients.
Citation Format: Amichay Meirovitz, Daniela Nahmias, Esther Hermano, Ofra Maimon, Tamar Peretz, Michael Elkin. The potential effect of chronically increased endotoxin levels on breast carcinoma progression in obese patients. [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 LB224.
Abstract LB230: Inactivation of the CFTR gene in duodena of mice exposed to hexavalent chromium (Cr(VI)) in drinking water supports its tumor-suppressor status and implies its role in Cr(VI)-induced carcinogenesis of the small intestines
Authors: Mezencev Roman , Auerbach Scott S. 
Published: July 2021

Abstract
Hexavalent chromium [Cr (VI)] compounds are used in metallurgical, chemical and refractory industries. Their carcinogenicity has been supported by a number of epidemiological and animal studies; however, their carcinogenic mode of action is still incompletely understood. To identify mechanisms involved in cancer development from toxicologically relevant exposures to Cr(VI), we analyzed gene expression data from duodena of mice exposed for 7 or 90 days to Cr(VI) in drinking water at concentrations 0.3-520 mg/L. This analysis included identification of upstream regulatory molecules that are likely responsible for the observed gene expression changes, and identification of annotated gene expression data from public repositories that correlate with gene expression changes in duodena of Cr(VI)-exposed mice. We identified the CFTR gene among top scoring upstream regulators, including at low exposure levels that, for the given timepoints, did not induce observable tissue damage. Furthermore, the expression data from duodena of Cr(VI)-exposed mice displayed a positive correlation with other datasets in public repositories associated with the inactive CFTR gene, of which the top scoring were datasets for ilea and duodena of Cftr-knockout mice. Our results support the tumor-suppressor role of the CFTR gene, which was previously suggested for intestinal carcinogenesis in humans and mice. Furthermore, our findings indicate, for the first time, the role of CFTR inactivation in chemical carcinogenesis and expand the range of plausible mechanisms that may be operative in Cr(VI)-mediated carcinogenesis of intestinal and possibly other tissues. Disclaimer: The views expressed are those of the authors and do not necessarily represent the views or policies of the US EPA.
Citation Format: Roman Mezencev, Scott S. Auerbach. Inactivation of the CFTR gene in duodena of mice exposed to hexavalent chromium (Cr(VI)) in drinking water supports its tumor-suppressor status and implies its role in Cr(VI)-induced carcinogenesis of the small intestines [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 LB230.
Abstract PL06-03: Exploiting genome instability for new cancer therapies: PARP inhibitors and beyond
Authors: Jackson Stephen P. 
Published: July 2021

Abstract
As DNA is frequently subject to a wide array of molecularly distinct forms of damage, life has evolved multiple DNA repair and associated processes, collectively termed the DNA-damage response (DDR). The importance of DNA repair and other DDR mechanisms is underlined by their deregulation or loss causing cancer and various human genetic disorders. Work in my laboratory aims to decipher DDR mechanisms, particularly those triggered by DNA double-strand breaks. In my talk, I will begin by briefly summarising past work by me and my collaborators that led to the world's first registered DDR enzyme inhibitor drug - the PARP inhibitor olaparib/Lynparza. I will then describe some of our recent work using CRISPR-Cas9 genetic screens to discover new DDR factors/regulators, identify potential new avenues for anti-cancer therapy, and help us understand how cancer cells can evolve resistance to DNA-damaging chemotherapies, PARP inhibitors or other DDR enzyme inhibitors.
Citation Format: Stephen P. Jackson. Exploiting genome instability for new cancer therapies: PARP inhibitors and beyond [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 PL06-03.
Abstract SY02-02: Understanding evolution of metastatic disease in renal cancer and melanoma
Authors: Turajlic Samra 
Published: July 2021

Abstract
While our knowledge of the evolutionary features of primary tumors has grown exponentially over the last few years our understanding of evolution of metastases is more limited and many open questions remain, regarding the timing of metastatic dissemination, the acquisition of metastatic competence and the underpinning of the variety of metastatic phenotypes observed in the clinic from latent metastases to solitary and oligo-metastases to widespread metastases. We have leveraged unique translational protocols that allow interrogation of tumor evolution from the earliest stages of diseases to death to address some of these questions. In the context of renal cell cancers we show that the mode of evolution at the primary tumor site determines the tempo and distribution of systemic metastases; that the features that distinguish metastasis-competent clones included genome instability and aneuploidy; and that metastatic competence often emerges in the centre of the primary tumor. In the context of melanoma we observe a wide spectrum of metastatic seeding that includes organ-specific metastatic clones, monophyletic and polyphyletic seeding and polyclonal mixing at metastatic sites. We observe progressive increase in aneuploidy and occurrence of whole genome doubling as melanoma metastases progress and resist treatment suggesting this as a a mechanism of immune-evasion and treatment resistance.
Citation Format: Samra Turajlic. Understanding evolution of metastatic disease in renal cancer and melanoma [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 SY02-02.
Abstract SY06-02: Optically activated nanomedicines: Photochemical activation as a priming and imaging tool in pancreatic cancer
Authors: Hasan Tayyaba 
Published: July 2021

Abstract
Optical activation of materials leads to thermal, photochemical and radiative processes which can be captured for response-based therapeutic design. The ability to use light as a reagent to provide free radical and activated oxygen-mediated cytotoxicity, combined with a control of conventional drug release, allows for the fabrication of light-controllable intelligent multiagent nanoconstructs that attack multiple pathways making nanomedicines more effective against cancer. This optically activated approach allows for a mechanistically diverse and spatiotemporally controlled strategy to tumor destruction. The molecules used for light activation have, in addition to therapeutic capabilities, finite fluorescence, creating an imaging handle and providing a built-in Theranostic process. Strategies for syntheses and applications of these nanoagents in biology and medicine will be discussed.
Citation Format: Tayyaba Hasan. Optically activated nanomedicines: Photochemical activation as a priming and imaging tool in pancreatic cancer [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 SY06-02.
Abstract SY24-01: Spatiotemporal definitions of immune archetypes across cancer types
Authors: Krummel Matthew F. 
Published: July 2021

Abstract
Cancers display significant heterogeneity with respect to tissue of origin, driver mutations and other features of the surrounding tissue. It is likely that persistent tumors differentially engage inherent patterns-here "Archetypes"-of the immune system, to both benefit from the tumor immune microenvironment (TIME) and to disengage tumor-targeting. To discover dominant immune system archetypes across diverse cancer types, we processed in an unbiased way 364 individual tumors across 12 cancer indications using standardized protocols. Computational clustering of flow cytometry and transcriptomic data obtained on cell sub compartments uncovered archetypes that exist across indications and are durable to increased granularity in higher dimensions. Immune composition-based archetypes differentiate tumors based upon the distribution of large unrelated collections of immune and tumor gene-expression patterns. Archetypes discovered this way also tie closely to well-established classifications of tumor biology. The resultant Immunoprofiler Initiative (IPI) resource provides a template for understanding cancer immunity as a collection of dominant patterns of immune infiltration and provides a rational path forward to study cancer immunity and learn how to modulate these patterns to improve therapy.
Citation Format: Matthew F. Krummel. Spatiotemporal definitions of immune archetypes across cancer types [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 SY24-01.
Abstract SY31-01: Remodeling of the cell surface proteome in cancer
Authors: Wells James A. 
Published: July 2021

Abstract
The cell surface proteome (surfaceome) is the primary hub for cells to communicate with the outside world, and are major targets for immunotherapy. Oncogenes are known to cause huge changes in cells (see Figure 1). Our group has applied state-of-the-art proteomics methods to quantitatively compare the surfaceomes of oncogene transformed (KRAS, HER2, EGFR, BRAF, MEK, AKT and MYC) versus isogenic controls (1-3). Oncogenes lead to large and bi-directional remodeling of the surfaceomes of isogenic cell lines that can be exploited for target ID. Each oncogene has a unique signature that depends on cell line, but broadly similar across cell lines. Differences among related oncogenes converge when viewed at functional level by Geneset analysis. Proliferative oncogenes (EGFR, HER2, KRAS, BRAF, MEK) remodel the surfaceome primarily through MAPK pathway. MYC is much more unique, especially in the large changes induced in solute carrier proteins. We have also recently developed a technology to identify proteolytic cut sites in membrane proteins (4) which also show bi-direction remodeling. We show proteolysis is an orthogonal remodeling event, and the union with expression data offers new neo-epitope markers for immunotherapy.
References
1. Martinko A.J., Truillet C., Julien O., Diaz J.E., Horlbeck, M.A., Whiteley G., Blonder J., Weissman J.S., Bandyopadhyay S., Evans M.J., Wells J.A. (2018) "Targeting RAS Driven Human Cancer Cells with Antibodies to Upregulated and Essential Cell-Surface Proteins." eLife. 2018;7:e31098
2. Leung, K. K., Wilson, G. M., Kirkemo, L. L., Riley, N. M., Coon, J. J., & Wells, J. A. (2020). Broad and thematic remodeling of the surfaceome and glycoproteome on isogenic cells transformed with driving proliferative oncogenes. PNAS 117 (14), 7764-7775.
3. Chen, W., Mou, K. Y., Solomon, P., Aggarwal, R., Leung, K. K., & Wells, J. A. (2021). Large remodeling of the Myc-induced cell surface proteome in B cells and prostate cells creates new opportunities for immunotherapy. PNAS, 118(4), 1-11.
4. Weeks, A. M., Byrnes, J. R., Lui, I., & Wells, J. A. (2021). Mapping proteolytic neo-N termini at the surface of living cells. PNAS, 2020.02.23.961904.
Citation Format: James A. Wells. Remodeling of the cell surface proteome in cancer [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 SY31-01.