bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB298: Simultaneous reprogramming of glioblastoma tumor cells and tumor-associated macrophages by tumor-suppressive microRNA
Authors: Nguyen Grace , Noh MinHye , Dai Yulin , Zhao Zhongming , Yoo Ji Young , Lee Tae Jin 
Published: April 2024

Abstract
Therapeutic outcomes in glioblastoma (GBM) patients remain dismal due to its resistance to conventional therapies. Tumor-supportive tumor microenvironment (TME) that is educated by tumor cells through immune editing is not properly primed for the treatment. Targeted reprogramming of both tumor cells and tumor-associated macrophages (TAMs) is expected to prime the tumor cells and the immunosuppressive TME. Tumor suppressive microRNAs (miRNAs) have been proposed as the most suitable therapeutic target to perform the tumor reprogramming role. We recently identified miR-138 as a putative tumor suppressive miRNA that can reprogram GBM tumor. However, achieving the simultaneous targeted reprogramming of two distinct cell types is a complex challenge, demanding a selective delivery system to minimize adverse side effects. Previously, we demonstrated that extracellular vesicles (EVs) can serve as carriers for the selective delivery of small noncoding therapeutic RNAs into cancer cells through the EV surface labeling with cancer-targeting ligands. Here, we report that the trypsin digestion of EV surface can enhance their surface labeling efficiency with cancer targeting ligands, such as folate, with favorable bio-distribution and pharmacokinetic profiles in GBM mice model. The folate-labeled trypsinized EVs demonstrated a potential to selectively target folate receptor (FR) positive GBM cells and TAMs both in vitro and in vivo. The selective targeting of folate-labeled trypsinized EVs led to the targeted delivery of miR-138 into both GBM tumor cells and TAMs, achieving anti-tumor efficacy. Mechanism of action studies revealed that the ectopically delivered miR-138 inhibits its previously identified known target genes to reprogram tumor cell proliferation and macrophage polarization. To our knowledge, this is the first preclinical study attempting to simultaneously modulate tumor cells and innate immunity by delivering tumor suppressive miR-138 using the trypsinized EV-based RNA delivery system for the GBM treatment. Our study results can be rapidly translated into human clinical trials in combination with current immunotherapies.
Citation Format: Grace Nguyen, MinHye Noh, Yulin Dai, Zhongming Zhao, Ji Young Yoo, Tae Jin Lee. Simultaneous reprogramming of glioblastoma tumor cells and tumor-associated macrophages by tumor-suppressive microRNA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB298.
Abstract LB299: Dihydrouridine synthase 2 sustains levels of tRNACys and prevents ferroptosis in lung cancer
Authors: Draycott Austin , Wang Matthew C. , Saucedo Diana Martínez , Escobar-Hoyos Luisa , Gilbert Wendy 
Published: April 2024

Abstract
Dihydrouridine is a universally conserved tRNA modification installed by enzymes that are important for human health. High expression of dihydrouridine synthase 2 (DUS2) predicts poor patient outcomes in lung adenocarcinoma (LUAD) for reasons that are not yet clear. Here, we show in human cells and mouse xenografts that DUS2 suppresses ferroptosis, a metal-dependent non-apoptotic form of cell death that is emerging as a therapeutic target in lung cancer. Elevated DUS2 correlates with resistance to ferroptosis inducers and loss of DUS2 causes increased sensitivity with concomitant accumulation of toxic lipid peroxides. Mechanistically, DUS2 is required to maintain tRNA CysGCA levels, supporting translation of cysteine-rich proteins including metallothioneins, key regulators of metal and redox homeostasis Notably, DUS2 KO cells cannot sustain normal levels of metallothioneins, a class of very cysteine rich proteins that serve as key regulators of both metal and redox homeostasis. Accordingly, DUS2 knockout cells are more susceptible to zinc intoxication and have lower levels of reduced glutathione, which partially explains their sensitivity to ferroptosis. Our findings demonstrate that DUS2 is required to support tRNACys levels and fend off ferroptosis in lung cancer cells. This highlights that individual tRNA substrates can play an outsized role in the biological functions of tRNA modifying enzymes, and demonstrates the therapeutic potential of targeting DUS2 in cancer.
Citation Format: Austin Draycott, Matthew C. Wang, Diana Martínez Saucedo, Luisa Escobar-Hoyos, Wendy Gilbert. Dihydrouridine synthase 2 sustains levels of tRNACys and prevents ferroptosis in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB299.
Abstract LB301: BRAFV600E drives WNT signalling in colorectal cancer via aberrant DNA methylation
Authors: Bouazzaoui Layla El , Bugter Jeroen M. , Küçükköse Emre , Verheem André , Post Jasmin B. , Fenderico Nicola , Rinkes Inne H. Borel , Snippert Hugo J. , Maurice Madelon M. , Kranenburg Onno 
Published: April 2024

Abstract
Objective: The BRAF V600E mutation drives the generation of an aggressive subtype of colorectal cancer (CRC). Although activation of WNT signalling is a generic hallmark of CRC, mutations in APC are uncommon in BRAF V600E-mutant CRC. Instead, mutations in RNF43 are the suspected WNT signalling driving event in these tumours. Here, we aimed to uncover how the WNT pathway is activated in BRAF V600E-mutant colon cancer.
Design: CRISPR-LbCpf1-corrected BRAF (V600E) and RNF43 (P441fs) organoids were analysed for their growth potential in the presence or absence of growth factors, for their ability to form tumours, and by immunoblotting, RNA sequencing, and DNA methylation assays.
Results: BRAF E600V organoids regained dependency on epidermal growth factor (EGF) receptor signalling for ERK pathway activation and proliferation, and completely lost tumorigenic potential. Correction of BRAF V600E, but not RNF43 P441fs, caused suppression of WNT target genes, while genes reflecting epithelial differentiation and negative regulators of WNT signalling were upregulated in BRAF E600V organoids. DNA methylation analysis revealed promoter hypermethylation of WNT antagonist genes in BRAF V600E organoids. Gene body hypermethylation, associated with transcriptional upregulation, was observed in key WNT-driven intestinal stem cell marker genes LGR5 and EPHB2, and in the WNT-effector TCF4. Treatment of BRAF V600E organoids with the DNA demethylating agent 5-aza-2′-deoxycytidine resulted in upregulation of WNT antagonist genes and a marked decrease in WNT target gene expression.
Conclusions: BRAFV600E, rather than mutant RNF43, is a prominent force behind WNT pathway activation, and is essential for maintaining tumorigenic capacity. BRAFV600E causes widespread dysregulation of DNA methylation leading to activation of WNT signalling.
Citation Format: Layla El Bouazzaoui, Jeroen M. Bugter, Emre Küçükköse, André Verheem, Jasmin B. Post, Nicola Fenderico, Inne H. Borel Rinkes, Hugo J. Snippert, Madelon M. Maurice, Onno Kranenburg. BRAFV600E drives WNT signalling in colorectal cancer via aberrant DNA methylation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB301.
Abstract LB302: circIPO7 dissociates caprin-1 from ribosomes and inhibits gastric cancer cell proliferation by suppressing EGFR and mTOR
Authors: Niu Liling , Liu Jing , Li Hui 
Published: April 2024

Abstract
circIPO7 dissociates caprin-1 from ribosomes and inhibits gastric cancer cell proliferation by suppressing EGFR and mTORLiling Niu, Jing Liu, Hui Li*Purpose: Circular RNAs (circRNAs) are vital participant of various pathophysiological processes through unique mechanisms. We previously reported that circIPO7 (circBase ID: hsa_-circ_0005092) was positively associated with postoperative recurrence of gastric cancer (GC). In the present study, we aimed to explore the biological function of circIPO7 in GC development. Methods: CCK-8, clone formation, Edu proliferation assay and xenograft model were used to analyze the effects of circIPO7 and caprin-1 on the cell proliferation and tumor growth in vivo and in vitro. Mass spectrometry, RNA pull down, RIP and RNA-FISH experiments were used to identify the co-localization and interaction between caprin-1 and circIPO7. RIP sequencing was used to analyze the mRNAs binding with caprin-1. Rescue experiment was conducted to evaluate the translational regulation of circIPO7 on caprin-1 downstream effector molecule.Results: circIPO7 was downregulated in GC tissues and cells compared to paracarcinoma tissues and normal epithelial cells. circIPO7 overexpression significantly suppressed GC cell proliferation in vitro and in vivo. Mechanistically, circIPO7 directly binds with caprin-1, an RNA-binding protein involved in mRNA translation, sharing overlapping binding sites with G3BP1. Thus, the complex containing overexpressed circIPO7 blocked the caprin-1-G3BP1 interaction and dissociated caprin-1 and its target mRNAs (EGFR and mTOR) from ribosomes, resulting in their translational inhibition, followed by PI3K/AKT/mTOR pathway inactivation.Conclusion: We demonstrate that circIPO7 serves as an RBP sponge for caprin-1, inhibits the translation of downstream proliferation-related mRNAs, and ultimately suppresses malignant cell proliferation. Taken together, these results suggest that circIPO7 may be a potential therapeutic target for GC treatment.
Citation Format: Liling Niu, Jing Liu, Hui Li. circIPO7 dissociates caprin-1 from ribosomes and inhibits gastric cancer cell proliferation by suppressing EGFR and mTOR [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB302.
Abstract LB306: PD-L1-targeted radioimmunethrapeutics combined with oncolytic virus for treatment of pancreatic cancer
Authors: Yoon Arum , Yun Chae-Ok , Kim Jin Su 
Published: April 2024

Abstract
Pancreatic cancer is difficult to treat, and the first line treatment provide only modest survival benefits to patients due to its highly desmoplastic and immune-desert phenotype. To overcome these hurdles, PD-L1-targeted radioimmunotherapy (RIT) using lutetium-177-labelled atezolizumab (177Lu-aPD-L1) combined with an oncolytic virus, named HY-oAd, that co-expresses three therapeutic genes (interleukin-12, granulocyte-macrophage colony-stimulating factor and relaxin) was investigated. HY-oAd treatment was shown to elevate PD-L1 expression level and promoted degradation of extracellular matrix (ECM) of pancreatic tumors, resulting in increased aPD-L1 or 64Cu-aPD-L1 accumulation in tumor tissues. Moreover, HY-oAd in combination with either aPD-L1 or 177Lu-aPD-L1 elicited more potent antitumor effect against the pancreatic tumors than respective monotherapy in pancreatic tumor models. The potent antitumor effect of HY-oAd+aPD-L1 combination therapy can lead to superior intratumoral infiltration and activation of dendritic cells and CD4+ or CD8+ T cells over the respective monotherapy. Collectively, our findings demonstrate that HY-oAd can potentiate PD-L1-targeted RIT through PD-L1 upregulation and ECM degradation, thus resulting in synergistic antitumor efficacy and antitumor immune response.
Citation Format: Arum Yoon, Chae-Ok Yun, Jin Su Kim. PD-L1-targeted radioimmunethrapeutics combined with oncolytic virus for treatment of pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB306.
Abstract LB313: Immunosuppressive effect of tumor-infiltrating IL-22 receptor-expressing myeloid cells in early-stage pancreatic ductal adenocarcinoma
Authors: Sung Yoolim , Kim Ji-Eun , Min Hyo-Jin , Chung Soo-Hyun , Kim Seong Who , Chang Eun-Ju 
Published: April 2024

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with a poor survival rate, largely due to the lack of diagnostic biomarker for early detection. Here, we found enriched IL-10R2+/IL-22R1+ myeloid cells in peripheral blood and specifically PDAC tissues respectively using xenograft/orthotropic PDAC mouse models. The subcutaneous injection of PDAC cell line in mouse showed a positive correlation of pancreatic tumor growth with increased IL-10R2+/IL-22R1+ myeloid cells by flow cytometry. We also verified that IL-10R2+CD45+ and IL-22R1+CD45+ myeloid cells were infiltrated in tumor tissues after 2 weeks and 3 weeks of injection in orthotropic murine PDAC model. Notably, the IL-10R2+IL-22R1+ cells were highly detected in tumor tissues after 7 days of injection, an earlier time point of PDAC progression. To define whether these cells have immunosuppressive functions to contribute further PDAC progression, IL-10R2+/IL-22R1+ myeloid cells were sorted from splenocytes after 3 days of tumor implantation and co-cultured with T cells in the presence of T cell receptor triggering. The proliferation and cytotoxicity of CD8+ T cells were alleviated by co-culture with IL-10R2+, IL-22R1+, or IL-10R2+IL-22R1+ myeloid cells, compared to that with IL-10R2-IL-22R1- cells. In addition, the population of regulatory T cells was increased when they were co-cultured with IL-22R1+ myeloid cells. Furthermore, the proliferation of human T cells in vitro was also inhibited by co-culture with IL-10R2+/IL-22R1+ myeloid cells from human peripheral blood, indicating the immunosuppressive function of IL-10R2+/IL-22R1+ cell population. Therefore, IL-10R2+/IL-22R1+ myeloid cell population could be a possible promising early detection marker for PDAC, contributing to the non-immunogenic features of tumor microenvironment during PDAC progression.
Citation Format: Yoolim Sung, Ji-Eun Kim, Hyo-Jin Min, Soo-Hyun Chung, Seong Who Kim, Eun-Ju Chang. Immunosuppressive effect of tumor-infiltrating IL-22 receptor-expressing myeloid cells in early-stage pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB313.
Abstract LB364: Generation and Application of a Robust Humanized Mouse Tumor Model System for Evaluation of NK-Targeting Therapeutics
Authors: Lu Feng , Ding Weiqun , Yang Guangliang , Jia Yaoqing , Wang Zhaoxiang , Yuan Xusheng , Yin Ming , Yang Zhijian , Yang WenQing 
Published: April 2024

Abstract
With the new waves of anti-tumor immunotherapy development, novel immunotherapies based on NK cells have emerged and advanced rapidly. Considering the inherent mechanisms of NK cells, various strategies are employed in tumor immunotherapy to maximize the efficacy of NK cells, including the following: 1) immune checkpoint inhibitors to relieve NK cell inhibition signals; 2) activation of NK cell activity; 3) targeted antibody therapy for tumor cell killing via antibody-dependent cellular cytotoxicity (ADCC), and 4) cell therapy, such as CAR-NK. Although numerous NK-targeting immune therapeutics or various NK-modulating modalities have been developed or advanced toward clinical trials, there is a lack of clinically relevant preclinical animal models that can be widely accepted for the evaluation of NK-modulating agents, particularly for models that involve functional human NK cells in the test system. This study generated a humanized mouse tumor model system which involves specific reconstitution of functional and durable human NK cells in a murine system, providing a clinically relevant tumor microenvironment. We first engineered a stable monoclonal feeder cell line in vitro to expand NK cells isolated from human peripheral blood mononuclear cells (hPBMCs) using magnetic bead separation. Using this approach, the human primary NK cells were robustly and consistently amplified (up to hundreds of fold) while maintaining their purity and functionality. When compared with primary NK cells using in vitro immune assays including ADCC and FACs, the expanded NK cells showed comparable results as the parental cells. In vivo experimental results indicated that a durable and functional NK reconstitution can be established in tumor-bearing severely immune deficient mice expressing hIL-15. Furthermore, this NK-humanized tumor model system was proven to respond to standard of care (SOC) NK-targeting drugs. In summary, this novel NK humanized in vivo model may represent an effective preclinical tool for assessing NK-modulating drugs, with the hope of facilitating the development process of novel immune therapeutics employing both adaptive and innate immunity.
Citation Format: Feng Lu, Weiqun Ding, Guangliang Yang, Yaoqing Jia, Zhaoxiang Wang, Xusheng Yuan, Ming Yin, Zhijian Yang, WenQing Yang. Generation and Application of a Robust Humanized Mouse Tumor Model System for Evaluation of NK-Targeting Therapeutics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB364.
Abstract LB367: Effects of modulation of ERAP1 activity in antigen processing and presentation
Authors: Mourid Shami Alvarez , James Edward , Guglietta Dario , Reeves Emma 
Published: April 2024

Abstract
ERAP1 is an enzyme that plays a key role in the antigen processing and presentation pathway as an editor of the peptide repertoire, allowing for the binding of neoantigens to MHC I. ERAP1 is polymorphic, with the different allelic variants showing various degrees of peptide trimming function expressed in humans. However, the trimming mechanism by which ERAP1 trims peptides is still not fully understood. The purpose of the study is to characterize the effect of the different ERAP1 variants and their inhibition on the peptide repertoire presented by tumor cells, enabling us to gain valuable insights into how this process works. This characterization will also enhance the pharmacological modulation of ERAP1, which has already been proven to promote T cell and NK-mediated anti-tumor cytotoxic response. By specifically targeting the activity levels of the ERAP1 variant expressed, we can adopt a personalized approach that maximizes the potential production of neoantigens, crucial for activating an anti-tumor immune response. We CRISPR knocked out the ERAP1 gene in the CT26 cell line and assessed the MHC I kinetics and stability by investigating the dissociation of pMHC complexes at the cell surface, using a Brefeldin-A decay assay and an acid-stripping test compared to wild-type. The assessment of MHC I assembly and cell surface expression kinetics showed higher MHC I in the ERAP1 KO cell line, highlighting that the lack of ERAP1 translated into a faster recovery time of peptide/MHC complexes at the cell surface. After assessing the kinetics, we re-expressed different human ERAP1 allotypes in CT26 ERAP1KO cell line through retroviral transduction and characterized MHC I expression levels through flow cytometry. Interestingly, MHC I expression levels varied across the transduced samples, with specific variants showing much higher expression levels indicating more peptide availability for loading onto the MHC molecules. Immunopeptidomic analysis comparing the WT, ERAP1 KO and the CT26 human ERAP1 transduced cell lines, showed distinct subsets of neoantigens presented in the KO cell line. ERAP1 plays a significant role in the assembly and recovery of peptide/MHC complexes. The reintroduction of different ERAP1 allelic variants greatly alters MHC I expression levels suggesting the formation of new peptide-MHC complexes responsible for the increase in MHC I expression. Modulation of ERAP1 activity significantly alters the presented peptide repertoire , uncovering neoantigens which are potentially immunogenic.
Citation Format: Shami Alvarez Mourid, Edward James, Dario Guglietta, Emma Reeves. Effects of modulation of ERAP1 activity in antigen processing and presentation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB367.
Abstract LB370: Exploring SLC35B family genes in colorectal carcinoma: Bioinformatics and functional insights into prognosis and therapy
Authors: Chang Yu-Jia , Yang Chang-Chun , Lee Cheng-Chin , Huang Chien-Yu 
Published: April 2024

Abstract
Colorectal carcinoma (CRC) poses a significant health challenge, with recent therapeutic advances yet to substantially improve long-term patient survival. Central to this study is the SLC35B gene family (SLC35B1-4), which encodes nucleotide sugar transporters essential to cellular membranes. Emerging research highlights a link between these transporters' dysfunction and the development and progression of tumors, yet the specific role of the SLC35B family in CRC remains unclear. Our investigation delves into the function of SLC35B genes in CRC, utilizing an integrated bioinformatics approach with databases like GENT2, TCGA, UALCAN, cBioportal, TIMER, and Kaplan-Meier plotter. Our analysis reveals a notable upregulation of SLC35B1/2/4 mRNA in CRC tissues compared to adjacent non-tumor tissues, with a concurrent downregulation of SLC35B3. Promoter methylation analysis shows increased methylation for SLC35B1/3/4, while SLC35B2 demonstrates decreased methylation. According to GEO and TCGA data, CRC patients exhibiting high SLC35B4 expression face lower survival rates. Multivariate Cox regression analysis confirms high SLC35B4 expression as an independent risk factor. Further, SLC35B4 expression correlates with increased infiltration of immune cells, particularly macrophages, and aligns positively with immune checkpoints such as CD274 and HAVCR2. In vitro assays link SLC35B4 to enhanced cancer cell proliferation, invasion, migration, and epithelial-mesenchymal transition (EMT). In vivo, SLC35B4 knockdown leads to reduced tumor growth in mouse xenograft models. RNA sequencing identifies 241 genes differentially expressed in SLC35B4 knockdown compared to control cells, with Gene Set Enrichment Analysis (GSEA) associating SLC35B4 with the PI3K-Akt signaling pathway. In summary, our research sheds light on the SLC35B gene family's role in CRC, especially SLC35B4, highlighting its potential as both a prognostic marker and a therapeutic target in CRC, particularly through its involvement in the PI3K-Akt signaling pathway.
Citation Format: Yu-Jia Chang, Chang-Chun Yang, Cheng-Chin Lee, Chien-Yu Huang. Exploring SLC35B family genes in colorectal carcinoma: Bioinformatics and functional insights into prognosis and therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB370.