bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3752: The role of miR-200 in anaplastic thyroid cancer aggressiveness
Authors: Huth Hugo , Fuziwara César , Kimura Edna 
Published: April 2023

Abstract
Anaplastic Thyroid Cancer (ATC) is the most aggressive and lethal of all thyroid cancer histotypes, characterized by undifferentiated, highly proliferative and invasive cells, which are intrinsically resistant to conventional treatment. Deregulation of microRNAs (miRNAs), a group of small non-coding RNAs that post-transcriptionally regulates protein expression, has been linked with cancer development. Specifically, the miR-200 family has been postulated to control the balance between epithelial and mesenchymal cell states through Epithelial-Mesenchymal Transition (EMT), a critical process for tumor metastasis. Previous results showed that miR-200c, a member of miR-200 family, is downregulated in ATC, but the biological effect of its deregulation remains unclear. Therefore, this study aims to evaluate the antitumor effect of miR-200c on ATC cell aggressiveness. Using plasmid overexpression, we induced miR-200c upregulation in KTC2 (KTC2-200c) and SW1736 (SW-200c) cells to analyze its role in cell differentiation, proliferation, migration, and EMT markers expression. Light microscope images showed that KTC-200c and SW-200c cells presented an epithelial morphology in contrast with the control group which displayed mesenchymal morphology. Analysis by qPCR and western blot of KTC-200c and SW-200c cells showed that upregulation of miR-200c expression enhanced mRNA and protein expressions of the epithelial marker E-cadherin, while diminished the mRNAs and protein levels of the mesenchymal markers N-cadherin and ZEB1/2. Additionally, KTC2-200c and SW-200c presented reduced cell colony formation and cell proliferation, and reduced cell migration visualized by wound healing assay and transwell assay. In conclusion, this study evidences the tumor suppressor role of miR-200 in controlling ATC cell aggressiveness. Grants from FAPESP (2021/12284-0, 2019/17282-5, 2019/25116-8) and CNPq (311210/2021-0).
Citation Format: Hugo Huth, César Fuziwara, Edna Kimura. The role of miR-200 in anaplastic thyroid cancer aggressiveness. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3752.
Abstract 3754: The cell- and non-cell autonomous actions of UCA1 dysregulation in hypopharyngeal cancer
Authors: Wu Li-Wha 
Published: April 2023

Abstract
Long non-coding RNAs (lncRNAs), encoding noncoding transcripts greater than 200 nucleotides, are multifunctional regulator of gene expression and play vital roles in various biological processes. Urothelial cancer-associated 1 (UCA1) is one such molecule and found to be dysregulated in the development of several cancer types, including those in bladder, colon, stomach, lung and breast. One previous study showed that an upregulation of UCA1 expression profile in hypopharyngeal cancer tissues relative to their adjacent normal counterparts significantly negated overall survival among these cancer patients. However, the molecular mechanism whereby UCA1 played any role in HPC, a subtype of head and neck cancer and often detected in advanced stages, remains elusive. In this report, we showed that ectopic UCA1 expression promoted cell migration and invasion while reducing cell proliferation. The increase of migration and invasion was accompanied by partial epithelial mesenchymal transition. By contrast, UCA1 depletion had the opposite effect. In addition to the presence of UCA1 in the culture medium (CM) and a stimulatory effect of CM derived from UCA1-OE cells on cell migration and invasion, we found a predominant nuclear localization of UCA1 in HPC cells. PTBP3, a RNA-binding protein, was identified as a novel interacting partner of UCA1 by RNA pulldown and mass spectrometry. PTBP3 silencing significantly reduced UCA1 mRNA expression, suggesting a regulatory role in UCA1 stability. While mapping the interacting domains between UCA1 and PTBP3, we are also in the process of identifying the involvement of UCA1-PTBP3 axis in hypopharyngeal carcinogenesis. We hope to validate if UCA1 can serve as a novel therapeutic target against or diagnostic marker for hypopharyngeal cancer.
Citation Format: Li-Wha Wu. The cell- and non-cell autonomous actions of UCA1 dysregulation in hypopharyngeal cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3754.
Abstract 3762: A novel lncRNA, GTF2A1-AS1, is required for cell cycle progression and cell proliferation
Authors: Goldstein Yael , Nizri-Megnaji Tali , Ginsberg Doron 
Published: April 2023

Abstract
Long noncoding RNAs (lncRNAs) are major regulators of many cellular processes including cell cycle progression, cell proliferation and tumorigenesis. In this study, we identify a novel lncRNA, GTF2A1-AS1, and reveal its effects on cell cycle progression and cancer growth. Inhibition of GTF2A1-AS1 expression alters cell cycle distribution, leading to a decrease in the number of G1 cells and a concomitant increase in all other stages of the cell cycle, and in particular S phase, suggesting its involvement in the regulation of G1/S transition. Accordingly, knock down of GTF2A1-AS1 enhances G1 phase exit upon release from a late G1 block. In agreement with its suggested role in G1/S transition, prolonged silencing of GTF2A1-AS1 enhances proliferation of human cancer cells. GTF2A1-AS1 RNA is mostly nuclear and its gene is localized upstream to the protein-coding gene GTF2A1. GTF2A1-AS1 functions in trans to repress the expression of EIF5A2 and HOXA13. Knockdown of either EIF5A2 or HOXA13 rescues the effects of GTF2A1-AS1 silencing on cell proliferation, indicating that it functions mainly by modulating the levels of these two proteins. In agreement with the effect of GTF2A1-AS1 silencing on cell cycle progression and cell proliferation, low levels of GTF2A1-AS1 are associated with reduced survival in brain cancer patients. In conclusions, our data identify GTF2A1-AS1 as a novel lncRNA that regulates cell-cycle progression and cell proliferation and has a potential role in human cancer.
Citation Format: Yael Goldstein, Tali Nizri-Megnaji, Doron Ginsberg. A novel lncRNA, GTF2A1-AS1, is required for cell cycle progression and cell proliferation. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3762.
Abstract 3773: DeMixMir: deconvolution of microRNA sequencing data from heterogeneous tumor samples
Authors: Montierth Matthew , Nemeth Kinga , Tao Xinghua , Calin George , Wang Wenyi 
Published: April 2023

Abstract
Measuring tumor heterogeneity is a key issue in modern clinical oncology, with relevance to understanding cancer progression, resistance to therapy, and recurrence. Studies of the transcriptomic landscape in cancer have rapidly advanced in scale, enabled by novel methods and advancing technologies. One such novel method is TmS, a computational estimate of tumor-specific total messenger RNA content from heterogeneous tumor samples, which is calculated by combining genomic and transcriptomic deconvolutions. We have previously shown TmS as a promising pan-cancer biomarker for patient prognosis. Given the fruitful study of tumor cell total messenger RNA content, a logical extension is to investigate the utility of estimating tumor cell content of other RNA species. MicroRNAs (miRNAs) are small noncoding RNAs that regulate mRNA expression, and their dysregulation is a hallmark feature observed across cancers. A computational method to derive tumor cell total miRNA content from bulk sequencing data is especially needed since miRNAs cannot yet be reliably profiled at single cell resolution. Here we develop and benchmark DeMixMir, a new expansion of our reference-free transcriptomic deconvolutional model DeMixT, in order to recover tumor-specific miRNA proportions from mixed samples. For benchmarking, we generated an artificially mixed dataset of small RNA sequencing consisting of a total of 30 samples that were made by mixing HS-5 fibroblast cells with either wildtype or Dicer1 knockout HCT116 colorectal cancer cells. The tumor and fibroblast cell lines were mixed at 5 different proportions, to simulate a broad spectrum of tumor/nontumor cell mixing scenarios, with three independent replicates generated at each mixing ratio. DeMixMir demonstrated high accuracy in estimating the tumor-specific miRNA proportions in both the wildtype and the Dicer1 knockout mixtures. We further calculated tumor cell total miRNA content using DeMixMir output. Our proof-of-concept study suggests estimating tumor cell total miRNA content across tumor tissues at scale is feasible and likely valuable for advancing understanding of the complex roles miRNAs play in the cancer ecosystem.
Citation Format: Matthew Montierth, Kinga Nemeth, Xinghua Tao, George Calin, Wenyi Wang. DeMixMir: deconvolution of microRNA sequencing data from heterogeneous tumor samples. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3773.
Abstract 3781: NF-κB classical and alternative signaling differentially regulate miRNA expression in ovarian cancer
Authors: Kamdar Rahul D. , Harrington Brittney S. , Korrapati Soumya , Attar Emma , Wong Nathan , House Carrie D. , Annunziata Christina M. 
Published: April 2023

Abstract
The NF-κB signaling pathway has been shown to contribute to epithelial ovarian cancer (EOC) through its classical and alternative pathways, characterized by the RelA and RelB transcription factors respectively. Previous studies have highlighted the role of RelA in sustaining the proliferative cancer cell population, while RelB aids in promoting the survival of chemoresistant, stem-like tumor-initiating cells (TICs) that promote disease relapse. In further characterizing the downstream effects of NF-κB signaling on EOC, we hypothesize NF-κB signaling differentially regulates the expression of several microRNAs (miRNAs) to promote TIC survival and proliferation through its classical and alternative pathways. miRNAs comprise a subset of small, noncoding RNAs that regulate gene expression, making them amenable for therapeutic targeting. Inducible shRNA stably expressed in OV90 EOC cells to knockdown RelA or RelB were analyzed by miR-seq to identify the differential expression of miRNAs in cells grown in TIC vs adherent (adh) conditions. Several miRNAs were differentially expressed in these conditions with RelA or RelB knockdown; we identified and validated the expression of two candidate miRNAs: hsa-miR-452-5p and hsa-miR-335-5p. We observed the decreased expression of hsa-miR-452-5p when either RelA or RelB is knocked down, while also observing the increased expression of hsa-miR-335-5p when RelA is knocked down. By inhibiting miR-452-5p in conjunction with disrupting NF-κB activity, we found changes in cell viability, sphere formation, and expression of the stem cell marker ALDH. Understanding the role of miRNA signaling in the context of NF-κB will better define the transcriptional roles of RelA and RelB in EOC. Ongoing work will further characterize the downstream targets of these miRNAs as potential therapeutic targets.
Citation Format: Rahul D. Kamdar, Brittney S. Harrington, Soumya Korrapati, Emma Attar, Nathan Wong, Carrie D. House, Christina M. Annunziata. NF-κB classical and alternative signaling differentially regulate miRNA expression in ovarian cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3781.
Abstract 3824: Remodeling of anaplastic thyroid cancer cell signaling and immune landscape by natural alkaloid berberine
Authors: Jarboe Tara , Kopec Kaci , DeSouza Nicole R. , Geliebter Jan , Tiwari Raj K. , Li Xiu-Min 
Published: April 2023

Abstract
Anaplastic thyroid cancer (ATC) is universally diagnosed as Stage IV with a five-year-survival of 4%, illuminating its dreadful prognosis. ATC is undifferentiated, has an inflammatory tumor microenvironment (TME), and metabolic dysregulation. As it is refractory to all established therapies, we propose a novel therapeutic - Berberine (BBR), a natural plant alkaloid, with numerous cellular targets that can potentially reprogram ATC’s aggressive phenotype. This research comprehensively examines the multitarget efficacy of BBR. Following initial dose response studies, all assays used 100µM concentration of BBR or DMSO vehicle control for 24-hour exposure. To model the ATC tumor microenvironment, monocyte cell line U937 cells were activated and polarized into a proinflammatory macrophage phenotype. In the presence of berberine at the activation and polarization stages, 33 soluble inflammatory mediators were downregulated in the conditioned media compared to controls. Targeting the aggressiveness of anaplastic disease, berberine slowed proliferation by 50% selectively in ATC cells from 48 to 72 hours, while sparing the immortalized normal thyroid cells. BBR also delayed wound healing by 30% in ATC cells after 24, 48, and 72 hours. These observations were substantiated by Western blot analysis of ATC and immortalized normal cells where BBR decreased phosphorylation of MEK, ERK, and ribosomal protein S6, crucial downstream regulators of the pro-proliferative and pro-survival pathways and increased phosphorylation of AMPKα, activating its anti-tumor and regulatory effects. Validation of in vitro findings via RNA-Seq was conducted by Genewiz from Azenta Life Sciences and Qiagen’s Ingenuity Pathway Analysis was used for in silico modeling. Greater than 400 significantly differentially expressed genes were identified suggesting that BBR regulates mitochondrial metabolism, cholesterol biosynthesis, glycometabolism, apoptosis, inflammation, and proliferation. BBR’s ability to alleviate inflammatory mediators in the TME, depress overactive cell signaling, and regulate metabolism to make it a more targetable cancer reveals it as an interesting candidate to prime ATC for combination therapy.
Citation Format: Tara Jarboe, Kaci Kopec, Nicole R. DeSouza, Jan Geliebter, Raj K. Tiwari, Xiu-Min Li. Remodeling of anaplastic thyroid cancer cell signaling and immune landscape by natural alkaloid berberine. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3824.
Abstract 3923: Identification of membrane-expressed CAPRIN-1 as a novel and universal cancer target and generation of a therapeutic anti-CAPRIN-1 antibody TRK-950
Authors: Okano Fumiyoshi , Saito Takanori , Minamida Yoshitaka , Kobayashi Shinichi , Ido Takayoshi , Miyauchi Yasushi , Wasai Ukei , Ke Jiang , Aicher Alexandra , Heeschen Christopher , Yonehara Tetsu 
Published: April 2023

Abstract
Specific targets for cancer treatment are highly desirable, but still remain to be discovered. While previous reports suggested that CAPRIN-1 localizes in the cytoplasm, here we now show that part of this molecule is strongly expressed on the cell membrane surface in most solid cancers, but not normal tissues. Notably, the membrane expression of CAPRIN-1 extended to the subset of highly tumorigenic cancer stem cells and EMT induced metastatic cancer cells. In addition, we revealed that cancer cells with particularly high CAPRIN-1 surface expression exhibited enhanced tumorigenicity. We generated a therapeutic humanized anti-CAPRIN-1 antibody (TRK-950), which strongly and specifically binds to various cancer cells and shows anti-tumor effects via engagement of immune cells. TRK-950 was further developed as a new cancer drug and a series of pre-clinical studies demonstrates its therapeutic potency in a tumor bearing mouse model and safety in a relevant cynomolgus monkey model. Together our data demonstrate that CAPRIN-1 is a novel and universal target for cancer therapies. A phase I clinical study of TRK-950 (NCT02990481) has been completed and a phase Ib study (combination with approved drugs) is currently underway (NCT03872947).
Citation Format: Fumiyoshi Okano, Takanori Saito, Yoshitaka Minamida, Shinichi Kobayashi, Takayoshi Ido, Yasushi Miyauchi, Ukei Wasai, Jiang Ke, Alexandra Aicher, Christopher Heeschen, Tetsu Yonehara. Identification of membrane-expressed CAPRIN-1 as a novel and universal cancer target and generation of a therapeutic anti-CAPRIN-1 antibody TRK-950. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3923.
Abstract 3927: Genome-wide screening and validation of molecular targets and biomarkers for lung cancer
Authors: Daigo Yataro , Takano Atsushi , Nakamura Yusuke 
Published: April 2023

Abstract
The number of lung cancer patients who respond well to currently available standard therapies is still small, new molecular targeted therapies with companion diagnostics are eagerly needed. We have been developing new molecular therapies targeting oncoproteins with their cancer biomarkers as follows, i) To identify strongly expressed genes in 120 lung cancers by genome-wide gene expression profile analysis, ii) To verify the candidate genes for their scarce expression in 23 normal organs, iii) To validate the clinicopathological significance of their protein expression by tissue microarray covering about 400 lung cancers (non-small cell lung cancers (NSCLCs) and SCLCs), iv) To examine their importance in the growth and/or invasion of cancer cells by siRNA, small molecule inhibitor, cell permeable peptides targeting their function and/or antibody assays, and v) To analyze the oncogenic function of the target molecules. By this system, we identified 50 oncoproteins and selected a LSERT (lung cancer-specific receptor tyrosine kinase) as a candidate. Immunocytochemical and immunohistochemical analyses confirmed that LSERT protein was expressed in cytoplasm and cytoplasmic membrane of lung cancer cells, but it was hardly expressed in normal lung cells. Strong LSERT expression was associated with poorer prognosis for surgically-treated NSCLC patients, and it was an independent prognostic factor. Exogenous expression of LSERT increased the cell growth and invasion probably through its elevated kinase activity and subsequent phosphorylation of downstream proteins. Inhibition of LSERT expression by siRNAs or treatment with anti-LSERT antibody suppressed the growth of lung cancer cells. Our genome-wide screening might be a useful approach to identify target molecules for developing new therapeutics and diagnostics. LSERT could be a candidate cancer biomarker and therapeutic target for lung cancer.
Citation Format: Yataro Daigo, Atsushi Takano, Yusuke Nakamura. Genome-wide screening and validation of molecular targets and biomarkers for lung cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3927.
Abstract 3974: Discovery and validation of therapeutic targets in immune cells by mass spectrometry-based proteomics
Authors: Au Yu-Wah , Satijn David , Mehnert Martin , Lachaud Amaury , Feng Yuehan , Vowinckel Jakob , Bon Hélène 
Published: April 2023

Abstract
Immuno-oncology (IO) has substantially improved the survival of cancer patients over the past several years encouraging the discovery of novel IO targets which are typically proteins expressed on the surface of immune cells. Sensitive quantification of proteins in complex biological samples is routinely achieved by immunoassays that use antibodies specific to target proteins. Such approaches can be a limitation in IO drug discovery and development as de novo development of antibodies is associated with long lead times, high costs, and high failure rates.
Protein quantification using mass spectrometry (MS) is agnostic to species and matrices and removes the barriers of availability or specificity of antibody-based assay. Further, MS proteomics workflows can support both large scale discovery studies but also represent an attractive alternative to targeted quantitative studies.
The main purpose of this work is to assess the performance of the TrueDiscovery™ and TrueSignature™ MS-proteomics platforms for the deep proteome and surfaceome profiling of human primary and immortalized immune cells compared to flow cytometry solutions. We assess the number of quantified proteins and specifically the coverage of immune cell marker proteins in primary human immune cells across cell count groups from 2 million down to 2500 immune cells. In addition, we compared the quantification of a multiplexed surface antigens panel using TrueSignature™ and QIFI® flow cytometry platforms.
We found that the applied MS-based proteomics workflows achieve high sensitivity and robustness in detection and quantification of immune cell markers down to 2500 primary immune cells. Additionally, we observed a strong correlation of the quantitative data derived from our MS-based proteomics workflows with flow cytometry supporting the substitution of immunoassays by MS-based proteomics workflows in target discovery and validation.
Citation Format: Yu-Wah Au, David Satijn, Martin Mehnert, Amaury Lachaud, Yuehan Feng, Jakob Vowinckel, Hélène Bon. Discovery and validation of therapeutic targets in immune cells by mass spectrometry-based proteomics. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3974.