bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-353: Spatiotemporal quantification of tumor-associated tertiary lymphoid structures in murine lung adenocarcinoma
Authors: Nader Mursal , Joshi Nikhil S. 
Published: August 2018

Abstract
In many human cancer types (i.e., lung, breast, melanoma), infiltrating immune cells are found in complex, lymph node (LN)-like structures known as the tumor-associated tertiary lymphoid structures (TA-TLSs). TA-TLSs are associated with longer patient survival and perform critical functions of LNs such as facilitating recruitment of T cells into the tumor microenvironment, mediating interactions between T cells and tumor-antigen presenting dendritic cells (DCs), and enabling local activation of T cells. Furthermore, using a genetically engineered mouse model (GEMM) of lung adenocarcinoma, we have previously shown that TA-TLSs form as tumors develop and that therapeutically depleting regulatory T cells (Tregs) from TA-TLSs elicits the anti-tumor immune response and results in tumor destruction. Hence, a powerful anti-tumor immune response can be both stimulated and suppressed in TA-TLSs, suggesting that therapeutically targeting the formation and maintenance of TA-TLSs would result in strong anti-tumor outcomes. Understanding how TLS formation is altered by experimental manipulation requires quantitative spatial and temporal analysis of the location, number, and size of TLSs in the tumor-bearing lung. Visualizing the presence of TA-TLSs throughout a tumor-bearing lung lobe presents several technical challenges, thus we have developed a high throughput immunofluorescence (IF) analysis pipeline for visualization and quantification of TA-TLSs in our model. This streamlined process requires 1-2 weeks per lung lobe. We are analyzing tertiary lymphoid structures in influenza-infected mice as a comparison to tumor-associated TLSs. Here, we hypothesize that there are key differences in the location and composition of influenza associated TLSs and TA-TLSs, which will provide substantial mechanistic insight into the biology and formation of TLSs. Using this spatiotemporal quantification technique, detailed interrogation of TLSs in lung adenocarcinoma will provide cellular and molecular targets for therapeutic modulation of TA-TLSs. Furthermore, this method can be expanded and adapted for the study of TA-TLSs in other disease models.
Citation Format: Mursal Nader, Nikhil S. Joshi. Spatiotemporal quantification of tumor-associated tertiary lymphoid structures in murine lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-353.
Abstract LB-355: Loss of keratinocyte desmoglein 1 occurs during melanoma development and alters crosstalk between keratinocytes and melanocytes
Authors: Arnette Christopher , Johnson Jodi L. , Burks Hope E. , Koetsier Jennifer L. , Green Kathleen J. 
Published: August 2018

Abstract
Ultraviolet (UV)-induced mutations in melanocytes are a well-established cause of melanoma. However, histologically normal “fields” of altered keratinocytes present in sun-exposed epidermis could also drive initiation and progression of melanoma. We previously demonstrated that UV radiation reduced expression of the keratinocyte desmosomal cadherin, desmoglein 1 (Dsg1), and that loss-of-function mutations in Dsg1 increased keratinocyte cytokine production in Severe dermatitis, multiple Allergies, and Metabolic wasting (SAM) syndrome. Based on these observations we hypothesized that loss of Dsg1 alters the microenvironment through increased cytokine signaling. Here, we show that Dsg1 expression is progressively reduced in regions surrounding human dysplastic nevi, melanoma in situ, and stage I/II melanomas. In contrast, keratinocyte E-cadherin was not significantly altered in early tumors. Dsg1 knockdown in keratinocytes in vitro increased phospho-EGFR, phospho-Stat3, and nuclear NFκB, while increasing keratinocyte mRNAs encoding IL-1α, IL-1β, IL-6 and IL-8 pro-inflammatory cytokines. Re-expressing silencing-resistant Dsg1 returned cytokine levels to control levels. To determine whether Dsg1 loss in keratinocytes elicits paracrine-mediated changes in melanocyte behavior, we treated normal primary melanocytes with conditioned media from Dsg1-silenced keratinocytes. Short-term (overnight) exposure to Dsg1-deficient conditioned media resulted in significantly increased melanocyte dendrite length, similar to morphology changes induced by UV exposure; however, long-term (7 day) exposure resulted in significantly shorter dendrites. Melanocytes exposed to Dsg1-deficient media increased melanin secretion and decreased melanin retention, a phenomenon associated with the process of transformation. Melanocytes incorporated into Dsg1-deficient 3D human skin equivalents exhibited aberrant behavior, including increased numbers and mis-localization to suprabasal layers. Based on these observations, we propose that under homeostatic conditions Dsg1 functions to maintain baseline levels of cytokine signaling, but that Dsg1 loss due to environmental stress disrupts keratinocyte:melanocyte communication through altered paracrine signaling to promote melanoma initiation.
Citation Format: Christopher Arnette, Jodi L. Johnson, Hope E. Burks, Jennifer L. Koetsier, Kathleen J. Green. Loss of keratinocyte desmoglein 1 occurs during melanoma development and alters crosstalk between keratinocytes and melanocytes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-355.
Abstract LB-356: Maintenance of breast cancer stem-like cells by cancer associated fibroblast-derived soluble factors
Authors: Murayama Takahiko , Nishimura Tatsunori , Tojo Arinobu , Gotoh Noriko 
Published: August 2018

Abstract
Accumulating evidence indicates the presence of cancer stem cells (CSCs) or tumor initiating cells in many types of tumors, which would be the leading cause of poor prognosis of tumor patients. They are defined as cell populations which have self-renewal ability and multi-differentiation capacity, and have been thought to greatly contribute to tumor initiation, recurrence and metastasis. CSCs are also known to be highly resistant to conventional therapies. Therefore, developing CSC targeting therapy is in urgent need to eradicate cancer cells efficiently. Stem cell properties of CSCs are thought to be maintained by the interaction with the tumor microenvironment, suggesting that it is important to identify factors which mediate such an interaction between cancer cells and the microenvironment. In this study, we focused on cancer-associated fibroblasts (CAFs) that forms the great part of breast tumor microenvironment and investigated how CAFs influence the functions of CSCs. By sphere forming assay, we found that some soluble factors secreted by CAFs induced growth of CSC-like populations. Then, to identify which factors are upregulated when fibroblasts get CAF-like properties, we compared transcriptomes of fibroblasts which were cultured with or without clinical sample-derived breast cancer cells by RNA-seq analysis. We found two genes in the same gene family were highly upregulated in co-cultured cells and they could induce sphere forming ability of CSCs. We are advancing our research based on a hypothesis that these two factors contribute to maintenance of stem cell functions of CSCs. Here, we will introduce results obtained by recent experiments.
Citation Format: Takahiko Murayama, Tatsunori Nishimura, Arinobu Tojo, Noriko Gotoh. Maintenance of breast cancer stem-like cells by cancer associated fibroblast-derived soluble factors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-356.
Abstract LB-373: Comprehensive analysis of cancer stemness
Authors: Malta Tathiane M. , Sokolov Artem , Gentles Andrew J. , Burzykowski Tomasz , Poisson Laila , Weinstein John , Kamińska Bożena , Huelsken Joerg , Omberg Larsson , Gevaert Olivier , Colaprico Antonio , Czerwińska Patrycja , Mazurek Sylwia , Mishra Lopa , Heyn Holger , Krasnitz Alex , Godwin Andrew K. , Lazar Alexander J. , Network The Cancer Genome Atlas Research , Stuart Joshua M. , Hoadley Katherine , Laird Peter W. , Noushmehr Houtan , Wiznerowicz Maciej 
Published: August 2018

Abstract
Cancer progression involves the gradual loss of a differentiated phenotype and acquisition of progenitor and stem cell-like features. Here, we provide new stemness indices for assessing the degree of oncogenic dedifferentiation. We took advantage of an innovative one-class logistic regression machine learning algorithm (OCLR) to extract transcriptomic and epigenetic feature sets derived from non-transformed pluripotent stem cells and their differentiated progenies. Using OCLR, we were able to sort TCGA tumor samples by stemness phenotype and identify previously undiscovered biological mechanisms associated with the dedifferentiated oncogenic state. Analyses of tumor microenvironment revealed the correlation of cancer stemness with immune checkpoint expression and infiltrating immune system cells not previously anticipated. We have shown the de-differentiated oncogenic phenotype increased in the metastatic tumor that further justify their more aggressive phenotype. Application of our stemness indices reveals features of intra-tumor heterogeneity in molecular profiles obtained from the single-cell analyses. Finally, the machine learning-based indices allowed for the identification of chemical compounds and novel targets for the cancer therapies aiming at tumor differentiation. Our findings provide new prognostic signatures that enable cancer biologists and oncologists to quantify the impact of tumor stemness on outcome across cancer types and may help to pave the way for progress in treatment strategies for cancer patients.
Citation Format: Tathiane M. Malta, Artem Sokolov, Andrew J. Gentles, Tomasz Burzykowski, Laila Poisson, John Weinstein, Bożena Kamińska, Joerg Huelsken, Larsson Omberg, Olivier Gevaert, Antonio Colaprico, Patrycja Czerwińska, Sylwia Mazurek, Lopa Mishra, Holger Heyn, Alex Krasnitz, Andrew K. Godwin, Alexander J. Lazar, The Cancer Genome Atlas Research Network, Joshua M. Stuart, Katherine Hoadley, Peter W. Laird, Houtan Noushmehr, Maciej Wiznerowicz. Comprehensive analysis of cancer stemness [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-373.
Abstract LB-384: A-to-I miR-378a-3p editing prevents melanoma progression via regulation ofPARVA expression
Authors: Shoshan Einav , Velazquez-Torres Guermarie , Fuentes-Mattei Enrique , Ivan Cristina , Bar-Eli Menashe 
Published: August 2018

Abstract
Although recent studies have shown that adenosine-to-inosine (A-to-I) RNA editing occurs in microRNAs (miRNAs), the effects of A-to-I miRNAs editing on melanoma growth and metastasis are yet to be determined. Previously we have reported that metastatic melanoma cell lines and tumor specimens have reduced expression of ADAR1 and consequently are impaired in their ability to perform A-to-I microRNA (miRNA) editing. Here we report that miR-378a-3p is undergoing A-to-I editing only in the non-metastatic but not in metastatic melanoma cells. The function of the edited form is different from its wild-type counterpart. The edited form of miR-378a-3p preferentially binds to the 3'UTR of the PARVA oncogene and inhibits its expression, thus preventing the progression of melanoma towards the malignant phenotype. Indeed, edited miR- 378a-3p but not its WT form inhibits melanoma metastasis in vivo. These results further emphasize the role of RNA editing in melanoma progression.
Citation Format: Einav Shoshan, Guermarie Velazquez-Torres, Enrique Fuentes-Mattei, Cristina Ivan, Menashe Bar-Eli. A-to-I miR-378a-3p editing prevents melanoma progression via regulation ofPARVA expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-384.
Abstract LB-385: miR-3140 suppresses tumor cell growth by targeting BRD4 via its coding sequence and downregulates the BRD4-NUT fusion oncoprotein
Authors: Muramatsu Tomoki , Tonouchi Erina , Gen Yasuyuki , Hiramoto Hidekazu , Tanimoto Kousuke , Inoue Jun , Inazawa Johji 
Published: August 2018

Abstract
Bromodomain Containing 4 (BRD4) mediates transcriptional elongation of the oncogene MYC by binding to acetylated histones. BRD4 has been shown to play a critical role in tumorigenesis in several cancers, and the BRD4-NUT fusion gene is a driver of NUT midline carcinoma (NMC), a rare but highly lethal cancer. microRNAs (miRNAs) are endogenous small non-coding RNAs that suppress target gene expression by binding to complementary mRNA sequences. Here, we show that miR-3140, which was identified as a novel tumor suppressive miRNA by function-based screening of a library containing 1090 miRNA mimics, directly suppressed BRD4 by binding to its coding sequence (CDS). miR-3140 concurrently downregulated BRD3 by bind to its CDS as well as CDK2 and EGFR by binding to their 3' untranslated regions. miR-3140 inhibited tumor cell growth in vitro in various cancer cell lines, including EGFR tyrosine kinase inhibitor-resistant cells. Interestingly, we found that miR-3140 downregulated the BRD4-NUT fusion protein and suppressed in vitro tumor cell growth in a NMC cell line, Ty-82 cells. Furthermore, administration of miR-3140 suppressed in vivo tumor growth in a xenograft mouse model. Our results suggest that miR-3140 is a candidate for the development of miRNA-based cancer therapeutics.
Citation Format: Tomoki Muramatsu, Erina Tonouchi, Yasuyuki Gen, Hidekazu Hiramoto, Kousuke Tanimoto, Jun Inoue, Johji Inazawa. miR-3140 suppresses tumor cell growth by targeting BRD4 via its coding sequence and downregulates the BRD4-NUT fusion oncoprotein [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-385.
Abstract LB-388: New clinical diagnostic approach for miRNA quantification using the Chlorella virus DNA ligase
Authors: Hynstova Iveta , Mrackova Tereza , Adamcova Michaela , Dvorakova Barbora , Stastna Zlata , Slaby Ondrej , Bartos Milan , Ruzicka Viktor 
Published: August 2018

Abstract
miRNAs have an immense potential to serve as diagnostic, prognostic and prediction biomarkers in the whole field of oncology. Their utilization in liquid biopsy as a non-invasive diagnostic tool is very promising as well. However, to our knowledge, no miRNA-based diagnostics is currently used in clinical laboratories. We believe the reason is simple - the lack of easy, fast, sensitive and reproducible measurement technology, which would have passed the strict clinical validation criteria. On this count we have optimized a very promising miRNA detection technique, utilizing the enzyme Chlorella virus DNA ligase (SplintR® ligase, New England Biolabs), for clinical use. This two-step method involves ligation of two adjacent DNA oligonucleotides hybridized to a miRNA target, followed by TaqMan probe real-time quantitative PCR (qPCR). We managed to reduce the total procedure time from previous 5 hours to 2 hours and 15 minutes maintaining the high sensitivity (1 amol/µl in original clinical sample) and large dynamic range (7 logs). Moreover, we enabled the use of two PCR detection chemistries - more cost-effective SYBR green or more specific TaqMan probe. Based on this optimized method we developed an assay for detection of miR-142-5p, potential marker of colorectal cancer. We measured miR-142-5p profiles in the real samples of whole blood, plasma and serum of healthy donors. The results showed an excellent correlation with the TaqMan qPCR assay and miREIA® immuno-based technology for absolute quantification of miRNA. We conclude, that using SplintR® ligase for miRNA detection is potentially useful for clinical diagnostics.
This work was funded by the Ministry of Industry and Trade of Czech Republic, project No. CZ.01.1.02/0.0/0.0/16_084/0008832.
Citation Format: Iveta Hynstova, Tereza Mrackova, Michaela Adamcova, Barbora Dvorakova, Zlata Stastna, Ondrej Slaby, Milan Bartos, Viktor Ruzicka. New clinical diagnostic approach for miRNA quantification using the Chlorella virus DNA ligase [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-388.
Abstract SY14-01: Determinants of neoantigen immunogenicity
Authors: Delamarre Lelia 
Published: August 2018

Abstract
Genetic instability is a hallmark of cancer, and can lead to accumulation of hundreds of somatic mutations. These mutations, which are unique to each patient, have the potential to be immunogenic if presented on major histocompatibility complex (MHC) molecules and recognized as “non-self” neoantigens by the immune system. There is now compelling evidence that neoantigens have an important role in driving antitumor immunity. Mutational load correlates with clinical response to immune checkpoint blockade therapy in cancer patients. In addition, neoantigen-directed tumor-infiltrating lymphocyte therapy was shown to lead to regression of metastatic lesions in patients. The recent advent of next-generation sequencing technologies has enabled rapid and comprehensive discovery of cancer mutations in individual patients and provides the opportunity to develop novel approaches to selectively target neoantigens. A major challenge, however, is that only a small fraction of the mutations generate T-cell responses. Currently, MHCI binding prediction is used as the major criterion for prioritizing neoantigens. Although this approach enriches for immunogenic neoantigens, a high frequency of false positive remains. For a mutant peptide to be immunogenic, the source protein has to be processed, the resulting mutant peptide needs to bind MHCI, and finally T cells must recognize the MHCI/peptide complex. To investigate the determinants of neoantigen immunogenicity, we performed profiling of the immunopeptidome by mass spectrometry and generated a dataset of immunogenic and nonimmunogenic mutant peptides identified in mouse tumor models by vaccination.
Citation Format: Lelia Delamarre. Determinants of neoantigen immunogenicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr SY14-01.
Abstract SY14-02: Personalized therapies: Neoantigen discovery and vaccination
Authors: Bhardwaj Nina 
Published: August 2018

Abstract
Tumor antigens derived from somatic mutations, or indels, are referred to as mutation-derived tumor antigens (MTAs) but are also known as neoantigens,or tumor-specific antigens. Evidence suggests that MTAs play a significant role in the endogenous adaptive immune response to tumors, and in the induced response following treatment with checkpoint inhibitors such as anti-CTLA-4 or anti-PD-1. This session will cover the concept of shared neoantigens in cancer and vaccine approaches to elicit adaptive antitumor immunity.
Citation Format: Nina Bhardwaj. Personalized therapies: Neoantigen discovery and vaccination [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr SY14-02.
Abstract SY17-01: Metabolic impact on immune cell subsets in the tumor microenvironment and its therapeutic relevance
Authors: Zou Weiping 
Published: August 2018

Abstract
We have studied the crosstalk among immune cell subsets (Tregs, Th17, Th22, CD8+ T cells, and APCs) and tumor (stem) cells in the tumor microenvironment, and its impact on tumor immunity and therapy. Over the past few years, our team has achieved important insights into cancer immunopathogenesis. Our research efforts demonstrate that the tumor microenvironment comprises immune cells that have been reprogrammed by active tumor-mediated processes to defeat tumor immunity and promote tumor progression in a highly effective manner. These studies have helped define the nature of immune responses in the cancer microenvironment, form the concept of immunosuppressive networks in the cancer microenvironment, and provide significant insights into designing current immune therapies including inhibitory B7 checkpoint blockade (PD-L1, B7-H1) to treat cancer patients. In this talk, we focus on how glycolysis and oxidative stress affect naïve T cells, effector T cells, and Tregs in the tumor microenvironment. We have demonstrated that tumor-associated glycolysis affects naïve T-cell phenotype via the FIP200-associated autophagy pathway and controls effector T-cell poly-functionality via EZH2-H3K27me3 mediated-epigenetic regulatory mechanism. Furthermore, we have found that tumor Tregs sustain and amplify their suppressor capacity by inadvertent death via oxidative stress. This process is highly regulated through energy metabolism. The work highlights the metabolic pathways controlling T-cell subset functional behavior and affecting cancer immune checkpoint therapy.
Citation Format: Weiping Zou. Metabolic impact on immune cell subsets in the tumor microenvironment and its therapeutic relevance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr SY17-01.
Abstract SY18-02: The relationship between Batf3-DC and antitumor T-cell responses
Authors: Spranger Stefani 
Published: August 2018

Abstract
Cancer immunotherapy has attracted enormous attention and investment, stimulated by successes of immune checkpoint blockade drugs, such as anti-CTLA4 and anti-PD-1. Despite the potential of immunotherapy to eradicate even metastatic cancer, only a minority of cancer patients respond to checkpoint blockade agents. Clinical and preclinical data provide evidence that the presence of tumor-specific CD8 T cells within the tumor microenvironment (TME) is critical for the response to checkpoint blockade. Another major component of tumor-infiltrating immune systems is the mononuclear phagocytic cell compartment, which provides both pro- and antitumoral properties, depending on its composition. A rare subset of conventional dendritic cells, marked by CD103 and the transcription factor Batf3, is required for the uptake, transport, and presentation of tumor-derived antigens to CD8 T cells in the tumor-draining lymph node. Tumors lacking CD103+ dendritic cells do not mount spontaneous antitumor immune responses and fail to respond to checkpoint blockade therapy. Moreover, we observed that absence of this subset of DC is mediating resistance to adoptive T-cell transfer. Analysis of tumor-residing CD103+ dendritic cells revealed that this small subset of cells provides the predominant source of effector T-cell recruiting chemokines (CXCL9 and 10) and is a critical component of the TME. This observation imposes a more detailed and refined analysis of the contribution of tumor-residing dendritic cells to the local antitumor immune response.
Citation Format: Stefani Spranger. The relationship between Batf3-DC and antitumor T-cell responses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr SY18-02.