bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1840: MYBBP1A AMPylated by SELO to influence its function
Authors: Li Wu 
Published: March 2024

Abstract
Introduction: MYBBP1A, named Myb-binding protein 1A, is a protein that mainly locates in nucleolar and shuttles between the nucleus and cytoplasm, nuclear import may be mediated by KPNA2, however export depend partially on XPO1/CRM1. It activates or represses transcription via interactions with sequence specific DNA-binding proteins. Repression may be mediated at least in part by histone deacetylase activity (HDAC activity). Acts as a corepressor and in concert with CRY1, represses the transcription of the core circadian clock component PER2. Preferentially binds to di-methylated histone H3 'Lys-9' (H3K9me2) on the PER2 promoter. MYBBP1A overexpressed in tumor than normal and have a significantly negative correlation with patient overall survival. We aim to explore the role of MYBBP1A in PDAC progression and underlying mechanism. In our research, we find and prove the novel AMPylating enzyme SELO-AMPylate MYBBP1A inhibits PDAC progression and modified site in S1353 and further influence downstream relative RNA, such as 18s rRNA, 28S rRNA.
Methods and Materials:
1. The function of MYBBP1A in tumorigenesis at the organismal and cellular levels.
MYBBP1A is widely expressed in different tissues. Firstly, we explored the correlation between MYBBP1A expression level and PDAC through TCGA database and Kaplan-Meier plotter. We then established MYBBP1A gene knockout mice mating with PDX/P53K172H/KRASG12C to induced a primary PDAC model to analyze the progression of pancreatic cancer. The effect of MYBBP1A on tumor cell growth and proliferation was explored through cell proliferation analysis and a nude mouse tumor xenograft model.
2. The MYBBP1A AMPylated by SELO influence MYBBP1A function in cell proliferation was investigated at the molecular and cellular levels.
AMPylation-specific antibodies were used to confirmed MYBBP1A AMPylated by SELO in both cell lysates and purified proteins through experiments such as CO-IP and WB. Stably expressed MYBBP1A WT/S1353A were constructed to verify the function in cell proliferation or migration by SELO. The signaling molecules were further explored through CO-IP and WB to identify the changed molecular by SELO-AMPylate-MYBBP1A, revealing the entire signaling pathways of AMPylation-mediated regulation of PDAC proliferation.
Conclusion: We have demonstrated the function of MYBBP1A in the formation of pancreatic cancer, and further revealed SELO-AMPylate-MYBBP1A importance in the process of reversing MYBBP1A’s role, which has played a certain significance for the treatment of pancreatic cancer and the exploration of related therapeutic targets.
Citation Format: Wu Li. MYBBP1A AMPylated by SELO to influence its function [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1840.
Abstract 1981: Profiling of protein interactome with cysteine-reactive libraries led to the discovery of EML4ALK dimerizers
Authors: Yang Diane , Harry Stefan , Codd Elizabeth , Kaluziak Stefan T. , Carlin Alexander D. , Zhang Edwin , Oppong-Holmes Zavontae , Yang Wenxin , Smith Abigail , Mitchell Dawn , Hara Mariko , Zhang Siwen , Onozato Maristela , Bar-Peled Liron , Iafrate Anthony J. 
Published: March 2024

Abstract
Cysteine covalent binders enable direct interactions with previously deemed undruggable protein targets, revolutionizing cancer therapeutics development. The primary focus has been on tailoring single-warhead compounds to target specific cysteine residues within the functional domains of target proteins. However, the biochemical properties including dimerization, induced conformational changes, and interactome disruption have been underexplored, presenting an ongoing limitation in current drug discovery approaches. In this study, we generated a library of 32 cysteine-reactive warhead compounds using various combinations of scaffolds and warheads to represent diverse reactivities. A combinatory assay approach, including cysteine druggability mapping (CDM) to discover reactive residues and SDS-PAGE fractionation assays to identify disrupted protein interaction events, was employed. Characterization of the library revealed distinct reactive cysteines and dimerization profiles among the 32 unique compounds. Compound 1C9, identified as a lead compound, demonstrated significant dimerization of EML4, a common fusion gene partner in lung cancer. Using the EML4ALK fusion gene as a proof of concept, we explored potential mechanisms underlying the compound-induced dimerization of EML4. Subsequent structure-activity relationship (SAR) studies and screening of 70 additional compounds were conducted to optimize ALK dimerization and minimize off-target effects. The enhanced compound disrupted the ALK cellular signaling pathways AKT and ERK upon dimerization of the EML4ALK fusion gene. Additionally, we discovered that covalent dimerization induced EML4ALK degradation without requiring a ubiquitin ligase like a PROTAC. In conclusion, our work has uncovered a novel class of cysteine covalent binders, which we believe are valuable tools to modulate protein-protein interactions in previously undruggable proteins in cancer. This discovery holds significant therapeutic potential for future drug development.
Citation Format: Diane Yang, Stefan Harry, Elizabeth Codd, Stefan T. Kaluziak, Alexander D. Carlin, Edwin Zhang, Zavontae Oppong-Holmes, Wenxin Yang, Abigail Smith, Dawn Mitchell, Mariko Hara, Siwen Zhang, Maristela Onozato, Liron Bar-Peled, Anthony J. Iafrate. Profiling of protein interactome with cysteine-reactive libraries led to the discovery of EML4ALK dimerizers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1981.
Abstract 201: Morphological changes to the vulvar squamous carcinoma cell line, A431, resulting from clobetasol-induced upregulation of vimentin
Authors: Lewis Jani E. , Haering Kia , Yokoyama Kazushige 
Published: March 2024

Abstract
Vimentin is recognized as an important marker in the epithelial-mesenchymal transition (EMT) of several cancer cell types. The overexpression of vimentin appears to coincide with increased tumor growth, migration, and poor prognosis. The vulvar cancer cell line, A431, is of squamous cell origin and displays hallmarks of a squamous cell including expression of cytokeratins 8 and 18 as well as E- and P-cadherin. We have found that treatment of A431 cells with the glucocorticoid, clobetasol, results in upregulation of vimentin which is accompanied by change to a more mesenchymal-like morphology. Despite this change in morphology, the cells continue to express cytokeratins 8 and 18. This suggests that the vimentin has a greater impact on cell morphology than does cytokeratins 8 and 18. However, we previously reported that the analogous glucocorticoid, dexamethasone, also downregulates E- and P-cadherin in these cells which may account for the observed change in morphology. Here we examine more closely the impact of vimentin on cellular morphology in the clobetasol treated A431 cells by both immunofluorescence microscopy and Raman imaging.
Citation Format: Jani E. Lewis, Kia Haering, Kazushige Yokoyama. Morphological changes to the vulvar squamous carcinoma cell line, A431, resulting from clobetasol-induced upregulation of vimentin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 201.
Abstract 2010: TRIM27 Interacts with KLF12 to regulate L1CAM expression, influencing cisplatin resistance and cancer metastasis in esophageal squamous cell carcinoma
Authors: Zhang Hao , Li Chunxiang , He Jie 
Published: March 2024

Abstract
Esophageal squamous cell carcinoma (ESCC) accounts for 85% of cases of esophageal cancer worldwide and is the predominant form of esophageal cancer in Asia. A significant number of patients with ESCC are diagnosed at an advanced stage, resulting in poor prognosis. Cisplatin resistance and cancer metastasis are the main clinical challenges in the treatment of advanced ESCC. KLF12 has been extensively characterized as a transcriptional repressor, and previous studies have unveiled its roles in angiogenesis, neural tube defect, and NK cell proliferation. However, the precise contribution of KLF12 to cancer treatment remains undefined. Here, we show that KLF12 is downregulated in various cancer types, and KLF12 downregulation promotes cisplatin resistance, cancer metastasis and recruitment of regulatory T cells (Tregs) in ESCC cell lines. Mechanistically, KLF12 binds to the promoters of L1CAM and represses its expression. Depletion of L1CAM abrogates cisplatin resistance, cancer metastasis, and Treg recruitment caused by KLF12 loss. Moreover, the E3 ubiquitin ligase TRIM27 binds to the N-terminal region of KLF12 and ubiquitinates KLF12 at K326 via K33-linked polyubiquitination. Notably, TRIM27 depletion enhances the transcriptional activity of KLF12 and consequently inhibits L1CAM expression. Overall, our study has firstly elucidated a novel regulatory mechanism involving TRIM27, KLF12 and L1CAM, which plays a substantial role in cisplatin resistance and cancer metastasis in ESCC, and targeting KLF12/L1CAM axis may be a promising approach for ESCC treatment.
Citation Format: Hao Zhang, Chunxiang Li, Jie He. TRIM27 Interacts with KLF12 to regulate L1CAM expression, influencing cisplatin resistance and cancer metastasis in esophageal squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2010.
Abstract 2036: Characterizing PARP inhibitor and next-generation anti-androgen therapy responses in advanced prostate cancer
Authors: Moore Love A. , Gonzalez Bryan Correa , Gao Allen C. , Lombard Alan P. 
Published: March 2024

Abstract
PARP inhibitors (PARPi) have been shown to be effective in prostate cancer patients with certain DNA repair defects, thus ushering in the era of precision medicine for this disease. Despite this advance, barriers remain which impede further progress including an incomplete understanding of therapeutic response. Our previous and on-going work shows that PARP inhibition leads to both cell death and a more cytostatic, senescence-like arrest. We hypothesize that persistent cells may later promote progression and treatment resistance. Recent clinical trials such as PROpel and TALAPRO-2 have demonstrated success in combining PARPi’s with next-generation anti-androgen therapies (NGAT) including abiraterone and enzalutamide. Whether NGAT’s are synthetic lethal and cell death promoting with PARP inhibition is poorly understood. Additionally, given the evolving clinical landscape for prostate cancer, it is important to test whether prior NGAT exposure may preclude response to combination therapy. In this study, we sought to characterize these combinations to better understand tumor cell response to treatment and the placement of treatment within the overall therapeutic paradigm. We’ve previously used the C4-2B metastatic castration-resistant prostate cancer cell line as a model which responds well to PARP inhibition. Here, we additionally utilize the C4-2B-derived enzalutamide and abiraterone resistant lines MDVR and AbiR, respectively. The combination of olaparib with abiraterone (recently approved from results of PROpel) was significantly more efficacious than either monotherapy in all three models. Additionally, combination of talazoparib and enzalutamide (approved from results of TALAPRO-2) was also more effective than monotherapy. These data suggest that prior development of NGAT resistance does not prevent benefit from NGAT and PARPi combinations. Although both combinations were found to cause significantly less cell growth, cells appeared more cytostatic rather than apoptotic, suggesting NGAT’s do not induce significant synthetic lethality with PARPi’s. Our work suggests that combining a PARPi with an NGAT promotes a persistent cytostasis which may give rise to eventual tumor progression and the development of resistance. Future studies are directed at further characterizing combinations with PARPi’s and the development of novel strategies to enhance their efficacy.
Citation Format: Love A. Moore, Bryan Correa Gonzalez, Allen C. Gao, Alan P. Lombard. Characterizing PARP inhibitor and next-generation anti-androgen therapy responses in advanced prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2036.
Abstract 2039: Cellular characterization of small molecule PD-L1 inhibitors reveal their novel mechanisms of action
Authors: Pan Weiling , Zhang Yongxian , Qi Fangfei , Xin Wenqun , Feng Zhigang , Chen Zhui , Ying Haiyan 
Published: March 2024

Abstract
Introductions: Immune checkpoint inhibitors, including PD-1/L1, are key regulators of immune response and promising targets in cancer immunotherapy. Like anti-PD-1/L1 antibodies, small molecule PD-L1 inhibitors that have been discovered by us and others could also efficiently block PD-1 and PD-L1 interaction and exhibit anti-tumor efficacy in preclinical and clinically settings. In this study, we explore the cellular mechanism of small molecule PD-L1 inhibitors, unveiling their novel mechanisms of action in the regulation of PD-L1 and its functions.
Materials and Methods: The cellular effects of the small molecule PD-L1 inhibitor on PD-L1 protein and RNA levels were assessed through Western blot and real-time qPCR experiments. HTRF assay and cellular luciferase reporter assay were used to evaluate the blockade of PD-1 and PD-L1 interaction in vitro and in cells. Flow cytometry and confocal microscopy were used to investigate the internalization of PD-L1 upon treatment with inhibitors. MSD assay was used to evaluate the alteration of soluble PD-L1 proteins.
Results: Small molecule PD-L1 inhibitors discovered by Abbisko Therapeutics potently blocked PD-1/PD-L1 interaction in vitro and in cellular system. It could also rapidly and strongly induce PD-L1 internalization in cells. Further profiling suggested that small molecule PD-L1 inhibitors specifically disrupt PD-L1 N-glycosylation, resulting in aberrant PD-L1 glycosylation. This, in turn, may hinder the proper translocation of newly synthesized PD-L1 to the cell surface, thereby abolishing its interaction with PD-1 and functions in immune regulation.
Conclusion: Taken together, these results for the first time revealed the distinctive mechanisms of our small molecule PD-L1 inhibitors. With their multi-layer inhibitory effects stemming from various mechanisms, small molecule PD-L1 inhibitors may offer potentially improved activities and an alternative therapeutic treatment for the cancer patients.
Citation Format: Weiling Pan, Yongxian Zhang, Fangfei Qi, Wenqun Xin, Zhigang Feng, Zhui Chen, Haiyan Ying. Cellular characterization of small molecule PD-L1 inhibitors reveal their novel mechanisms of action [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2039.
Abstract 2167: Microbial bile acid, 3-oxo-LCA, inhibits colorectal cancer progression
Authors: Sun Fei , Dong Xingchen , Qi Ming , Fu Ting 
Published: March 2024

Abstract
Colorectal cancer (CRC) affects a significant number of individuals each year, ranking as a leading cause of cancer-related deaths in the U.S. Bile acids (BAs), natural compounds crucial for digesting dietary fats, not only influence the gut microbiota but are also involved in gut health through their interaction with the Farnesoid X Receptor (FXR). Recent findings have highlighted certain microbiota-generated BAs like 3-oxo-lithocholic acid (LCA) and IsoLCA, modulate host immunity, hinder the expansion of intestinal pathogens, and potentially anti-aging. Despite the advancements in identifying the gut microbes behind these BAs, their precise impact on intestinal cells (IECs) and their role in disease progression are largely unexplored. Our pilot investigation unveiled 3oxoLCA as an FXR agonist, restoring FXR signaling in both cancer cells and APCmin/+ mice (a classic CRC mice model). As a result, 3-oxo-LCA inhibits the growth of both human and mouse CRC cells, such as MC38, CT26 and HCT116. Additionally, 3-oxo-LCA also restrained the intestinal stem cells (ISCs)’ proliferation in organoids from both wild-type and APCmin/+ mice, and patient-derived CRC organoids (PDCOs). Remarkably, treatment with 3-oxo-LCA decreased BAs levels, improved gut barrier function, reduced tumor load, and inhibited tumor progression in APCmin/+ mice. Furthermore, 3-oxo-LCA significantly suppressed tumor growth in cancer cell-derived xenograft model mice. Crucially, the 3-oxo-LCA-FXR interaction transcriptionally regulated key apoptotic genes, encouraging cancer cell death. These discoveries highlight the therapeutic promise of incorporating 3-oxo-LCA into strategies for treating CRC.
Citation Format: Fei Sun, Xingchen Dong, Ming Qi, Ting Fu. Microbial bile acid, 3-oxo-LCA, inhibits colorectal cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2167.
Abstract 2176: Differences in gut microbial composition alter pancreatic tumorigenesis
Authors: Howell Rian M. , Ortiz Jose Enriquez , Roux Olivia Le , Chandra Vidhi , Li Le , Bhattacharya Pratip K. , McAllister Florencia 
Published: March 2024

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is predicted to become the second leading cause of cancer-related deaths by 2030, and currently has a 5-year survival rate of roughly 10%. With long-term survival rates in patients being exceedingly low, understanding what factors delineate survival is imperative. When comparing spontaneous transgenic mouse models of pancreatic cancer housed in geographically distinct vivaria, regardless of a common lineage, we observed drastically different phenotype states in the respective locations. We hypothesize that the gut microbiome results in different gene expression profiles, leading to alterations in pancreatic tumorigenesis. Using various sequencing techniques, including 16s rRNA and RNA sequencing of the gut, we identified unique signatures at these respective institutions. Subsequent fecal microbiota transplantation and single bacterial species colonization experiments were performed to evaluate the ability of microbiomes/specific microbiota to alter the rate of tumorigenesis. In addition to probing the gut microbiome, circulating metabolites from individual mice were quantified, and correlated to phenotype state. Following identification of potentially tumorigenic bacterially derived metabolites, single bacteria colonization experiments were utilized to determine the downstream effects of identified metabolites as well as the ability of directly altering the metabolic landscape to drive tumorigenesis. Additionally, murine derived pancreatic cancer cells were exposed to both identified bacteria alone or bacterially produced metabolite and analyzed by metrics such as proliferation and relative expression of transcription factors associated with cancer development in vitro. Taken together, these data demonstrate the ability of distinct gut microbiomes to directly alter the metabolic landscape in mice, thus differentially altering the progression of pancreatic lesions. By better understanding the factors that stratify survivorship, we can begin to employ clinically actionable methodologies in the treatment or prevention of pancreatic cancer.
Citation Format: Rian M. Howell, Jose Enriquez Ortiz, Olivia Le Roux, Vidhi Chandra, Le Li, Pratip K. Bhattacharya, Florencia McAllister. Differences in gut microbial composition alter pancreatic tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2176.
Abstract 2195: Intrauterine device use and risk of invasive epithelial ovarian cancer: A population-based case-control study
Authors: Phung Minh Tung , Wang Yuting , Lee Alice W. , Pike Malcolm C. , Wu Anna H. , Pearce Celeste Leigh 
Published: March 2024

Abstract
Introduction: Ovarian, fallopian tube, and primary peritoneal cancers (hereafter referred to as ovarian cancer) are the most fatal gynecologic cancers. Thus, it is imperative to identify strategies that can reduce the risk of the disease. Several contraceptive methods have been shown to be associated with a reduced risk of ovarian cancer, including combined oral contraceptives, injectable progestins, and tubal ligation. However, the use of these contraceptive methods has been decreasing in the U.S., with a growing preference for intrauterine devices (IUDs) for pregnancy prevention. Previous case-control studies on the association between IUD use and ovarian cancer risk have found inconsistent results. Notably, previous studies had small sample sizes and did not restrict to invasive epithelial tumors. The current analysis assessed the association between IUD use and risk of invasive epithelial ovarian cancer in a large population-based case-control study.
Methods: This analysis used data from 1,713 people diagnosed with primary invasive epithelial ovarian cancer (cases) and 2,348 cancer-free people (controls) participating in a case-control study conducted in Los Angeles, CA from 1992-2010. The study consisted of four waves of recruitment with similar enrollment and data collection methods. Logistic regression models were fit to assess the association between IUD use and risk of invasive epithelial ovarian cancer. All models were adjusted for age, race/ethnicity, education, first-degree family history of ovarian cancer, endometriosis, body mass index, duration of combined oral contraceptive use, parity, duration of breastfeeding, tubal ligation, and study wave. Heterogeneity across the study waves and the ovarian cancer histotypes was evaluated using standard meta-analysis techniques.
Results: There was no statistically significant association between IUD use and risk of invasive epithelial ovarian cancer (odds ratio=1.09, 95% confidence interval 0.93-1.28). This result was consistent across the study waves and the ovarian cancer histotypes (p-values for heterogeneity&gt;0.05).
Conclusion: IUD use was not associated with the risk of invasive epithelial ovarian cancer. Analysis by IUD type (i.e., hormone-releasing vs copper IUDs) was not possible in this study as these data were not collected. Future research should examine whether the type of IUD (i.e. copper versus hormone-releasing) may have different effects on risk of ovarian cancer.
Citation Format: Minh Tung Phung, Yuting Wang, Alice W. Lee, Malcolm C. Pike, Anna H. Wu, Celeste Leigh Pearce. Intrauterine device use and risk of invasive epithelial ovarian cancer: A population-based case-control study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2195.