bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2966: Senescent cancer cell vaccines induce cytotoxic T cell responses targeting primary tumors and disseminated tumor cells
Authors: Liu Yue , Pagacz Joanna , Wolfgeher Donald J. , Kron Stephen J. 
Published: March 2024

Abstract
Diverse conventional cancer therapies, including genotoxic agents and cell cycle or cell division-targeting drugs, can trigger cancer cell senescence. Senescent cells (SnCs) induced by cancer therapy often display unrepaired chromosomal damage but persist indefinitely. SnCs remain metabolically active and display distinct alterations in transcription, secretion, and membrane protein expression/presentation. While initially viewed as a favorable outcome and likely tumor-suppressive mechanism, therapy-induced senescence has more recently been recognized as contributing to resistance, recurrence and metastasis. Adverse effects may be mediated in part by release of inflammatory mediators as components of the senescence-associated secretory phenotype (SASP). Recent studies have argued for reconsidering the potential benefits of therapy-induced senescence, especially in modulating the tumor microenvironment to potentiate anti-tumor immunity and potentiate immunotherapy. We have explored the potential for SnCs to serve as vaccines, building upon prior findings where we demonstrated the immunogenic senescence triggered by the combination of ionizing radiation (IR) and the PARP1/2 inhibitor veliparib. We find that SnCs are avidly taken up by type I conventional, CD11c+/CD103+ dendritic cells (DCs), promoting their activation and maturation. Thereby, SnCs promote DC function in T cell priming and stimulation. The capacity of SnCs to activate DCs depends on how the SnCs are formed, with our results confirming IR+veliparib induces high immunogenicity and implicating a distinct SASP in these effects. On the other hand, blocking STING signaling limits SnC activation of DCs. In vivo experiments with the murine tumor models CT26 and 4T1 suggest that both SnCs and SnC-pulsed DCs serve as effective anti-tumor vaccines. They not only confer protective immunity against tumor engraftment but also act as therapeutic vaccines, inhibiting both primary and disseminated tumor growth, and synergize with radiotherapy and immune checkpoint blockade. While direct administration of tumor-derived SnCs to patients may raise safety concerns, pulsing autologous DCs with tumor SnCs may help drive anti-tumor immune response, offering a promising path toward personalized cancer immunotherapy.
Citation Format: Yue Liu, Joanna Pagacz, Donald J. Wolfgeher, Stephen J. Kron. Senescent cancer cell vaccines induce cytotoxic T cell responses targeting primary tumors and disseminated tumor cells [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 2966.
Abstract 2979: Pancreatic cancer cells upregulate LPAR4 in response to isolation stress to create a fibronectin-rich extracellular matrix niche and promote tumor initiation
Authors: Wu Chengsheng , Rakhshandehroo Taha , Wettersten Hiromi I. , Campos Alejandro , Von Schalscha Tami , Jain Shashi , Yu Ziqi , Tan Jiali , Mose Evangeline , Childers Betzaira G. , Lowy Andrew M. , Weis Sara M. , Cheresh David A. 
Published: March 2024

Abstract
Tumor initiation is an inefficient process in which tumor cells must develop cell-autonomous mechanisms to survive harsh microenvironments, establish colonies, and thereby overcome “isolation stress.” We report that pancreatic cancer cells transiently upregulate lysophosphatidic acid receptor 4 (LPAR4), a G-protein coupled receptor, in response to microenvironmental stress or chemotherapy, which promotes stress tolerance, drug resistance, and tumor initiation. Even without exogenous LPA, LPAR4 drives the expression of a subset of extracellular matrix (ECM) genes via an AKT/CREB axis, including fibronectin and versican, which are established drivers of cancer stemness. The upregulation of fibronectin is indispensable for LPAR4-induced tumor initiation in vivo and anchorage-independent growth in vitro. Furthermore, the ligation of this fibronectin-containing ECM created by LPAR4-positive cells via integrins α5β1 or αvβ3 can transfer cancer stemness and stress tolerance to LPAR4-negative cells by activating Yes-associated protein 1 (YAP). Our findings reveal that in response to isolation stress, pancreatic tumor cells that upregulate LPAR4 can autonomously generate a fibronectin-enriched ECM niche and thereby initiate tumor formation.
Citation Format: Chengsheng Wu, Taha Rakhshandehroo, Hiromi I. Wettersten, Alejandro Campos, Tami Von Schalscha, Shashi Jain, Ziqi Yu, Jiali Tan, Evangeline Mose, Betzaira G. Childers, Andrew M. Lowy, Sara M. Weis, David A. Cheresh. Pancreatic cancer cells upregulate LPAR4 in response to isolation stress to create a fibronectin-rich extracellular matrix niche and promote tumor initiation [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 2979.
Abstract 3011: The loss of an orphan nuclear receptor NR2E3 augments Wnt/β-Catenin signaling via epigenetic dysregulation that links to the Sp1-β catenin-p300 interactions in hepatocellular carcinoma
Authors: Leung Yuet-Kin , Lee Sung-Gwon , Wang Jiang , Ho Shuk-Mei , Rusch Nancy , Park Chungoo , Kim Kyounghyun 
Published: March 2024

Abstract
Hepatocellular carcinoma (HCC) stands as the fourth leading cause of global cancer-related mortality due to late-stage detection, tumor heterogeneity, and drug resistance. The pivotal role of epigenetic factors in HCC development and progression necessitates the identification of critical epigenetic regulators. The orphan nuclear receptor NR2E3 (Nuclear receptor subfamily 2 group E, Member 3), primarily associated with retinal development, has emerged as a potential tumor suppressor. Earlier studies showed that the loss of NR2E3 leads to epigenetic repression of the estrogen receptor α (ER) through the involvement of Lysine Specific histone Demethylase 1 (LSD1). NR2E3 also forms a transcriptional complex with Sp1, governing the aryl hydrocarbon receptor (AHR) expression, a crucial factor in liver xenobiotic metabolism. In vivo, NR2E3 ablation results in p53 inactivation and severe liver injuries when exposed to liver toxicants, highlighting its role in activating p53. Nonetheless, the precise tumor suppressive and epigenetic role of NR2E3 in HCC remains unclear. HCC patients expressing low NR2E3 exhibit unfavorable clinical outcomes, aligning with heightened activation of the Wnt/β-catenin signaling pathway. The murine HCC models utilizing NR2E3 knockout mice show accelerated liver tumor formation and progression accompanied by enhanced activation of the Wnt/β-catenin signaling pathway and inactivation of the p53 signaling pathway. At a cellular level, losing NR2E3 increases the acquisition of aggressive cancer cell phenotype and tumorigenicity and upregulates vital genes in the Wnt/β-catenin pathway with enhanced chromatin accessibility. This event is mediated through the increased formation of active transcription complex involving Sp1, β-catenin, and p300, a histone acetyltransferase, on the promoters of target genes. Correspondingly, treatment of p300 inhibitor C646 decreased the expression of critical genes in the Wnt/β-catenin signaling pathway. These findings demonstrate that the loss of NR2E3 promotes Wnt/β-catenin signaling activation at cellular, organismal, and clinical levels. In summary, NR2E3 is a novel tumor suppressor that maintains epigenetic homeostasis, thereby preventing activation of Wnt/β-catenin signaling that promotes HCC formation.
Citation Format: Yuet-Kin Leung, Sung-Gwon Lee, Jiang Wang, Shuk-Mei Ho, Nancy Rusch, Chungoo Park, Kyounghyun Kim. The loss of an orphan nuclear receptor NR2E3 augments Wnt/β-Catenin signaling via epigenetic dysregulation that links to the Sp1-β catenin-p300 interactions in hepatocellular 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 3011.
Abstract 3012: Characterizing the functional significance of "variant of uncertain significance" of the tumour suppressor CDH1
Authors: Wen Jasmine , Singh Ajay , Nguyen David , Meier-Ross Kaitlynn , Martin Ben , Khan Vedanta , Dhami Kiran , Chao Jesse 
Published: March 2024

Abstract
We aim to develop a new approach to systematically characterize the functional significance of “variant of uncertain significance (VUS),” focusing on the tumor suppressor gene CDH1. Genetic testing is a powerful clinical tool for identifying individuals at risk of developing inherited or familial cancers. If a potential cancer-causing genetic variant (mutation) is found, clinicians can begin managing the patient’s risk early by initiating surveillance or prophylactic treatment. For an aggressive form of inherited stomach cancer called hereditary diffuse gastric cancer (HDGC), the most commonly mutated gene is CDH1, which encodes the tumor suppressor E-Cadherin. However, due to insufficient clinical evidence, over 50% of all publicly reported CDH1 variants either have conflicting interpretations or cannot be classified, thus are not actionable. Consequently, almost 1 in 2 patients who undergo genetic testing for HDGC will not have a definitive test result and cannot benefit from early screening, causing strain on the healthcare system and psychological burden for the patients. To overcome this challenge, we developed a single-cell screening system to accurately classify CDH1 variants using a combination of functional assays, machine learning, and deep learning. Our hypothesis, now supported by preliminary data, is that pathogenic variants will disrupt normal E-Cadherin’s ability to control its signaling partner beta-catenin. Thus, loss-of-function (LoF) CDH1 variants would cause protein mislocalization and altered signaling which lead to abnormal proliferation, an early indicator for carcinogenesis. We express CDH1 variants in human cell lines and use multiplexed high-content imaging to visualize E-Cadherin and beta-catenin. Next, our deep learning pipeline extracts single-cell phenotypic profiles, and our classifier then classifies variants as functional or LoF. Initial analysis of prioritized variants show that our pipeline can accurately separate clinically pathogenic and benign variants based on their functional status as predicted by our pipeline. The outcomes of this project will contribute to a systematic approach to reclassify VUS.
Citation Format: Jasmine Wen, Ajay Singh, David Nguyen, Kaitlynn Meier-Ross, Ben Martin, Vedanta Khan, Kiran Dhami, Jesse Chao. Characterizing the functional significance of "variant of uncertain significance" of the tumour suppressor CDH1 [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 3012.
Abstract 3019: Dissecting in vivo functions of R-Loops in Brca1-associated DNA replication stress and mammary tumorigenesis
Authors: Chiang Huai-Chin , Qi Leilei , Hu Yanfen , Li Rong 
Published: March 2024

Abstract
Germ-line BRCA1 mutations are associated with a significantly increased incidence of breast cancer in women. Although BRCA1-associated breast tumors are basal-like and estrogen receptor α negative (ERα−), they originate from luminal progenitor cells. At the molecular level, BRCA1 is best known for its roles in resolution of DNA replication stress and promotion of homologous recombination (HR)-based double strand break (DSB) repair. In addition, BRCA1 is implicated in reduction of R-loops, a DNA-RNA hybrid structure and transcriptional byproduct associated with genome instability and transcriptional regulation. Our published findings suggest that BRCA1-dependent R-loop mitigation contributes to luminal cell-specific transcription and differentiation (Zhang et al, 2017, Nature Communications, 8:15908), which could in turn suppress Brca1-associated tumorigenesis. Using cell type-specific mouse genetics, we investigate a direct impact of R-loop removal on Brca1-associated mammary epithelial tumor formation. R-loop formation in mammary epithelial cells is efficiently reduced by over-expression of RNase H1, an R-loop-specific ribonuclease. R-loop removal does not affect mammary duct development or function. However, it drastically increases ɣH2AX foci in proliferating BRCA1-deficient epithelial cells without external DNA damage. This suggests a role of R-loops in attenuating elevated DNA replication stress caused by the loss of Brca1. While R-loop removal does not appear to affect the overall Brca1-associated mammary tumor incidence, it promotes cell differentiation from ERα− luminal progenitor cells to ERα+ mature luminal cells. Accordingly, unlike their counterparts, a significant percentage of Brca1-associated mammary tumors with RNase H1 overexpression tend to be ERα+. Thus, our findings provide in vivo evidence for a previously unappreciated role of R-loop dynamics on Brca1-associated DNA replication stress and tumor development in mammary epithelium.
Citation Format: Huai-Chin Chiang, Leilei Qi, Yanfen Hu, Rong Li. Dissecting in vivo functions of R-Loops in Brca1-associated DNA replication stress and mammary 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 3019.
Abstract 3053: PTEN as a double-edged sword regulates EGFRL858R-induced lung cancer progression
Authors: Hung Jan-Jong 
Published: March 2024

Abstract
Lung cancer is the major cause of death worldwide. Activation of oncogenes or inhibition of tumor suppressors causes cancer formation. Previous studies have indicated that Pten, as a tumor suppressor, inhibits cancer formation. In this study, we studied the role of Pten in EGFRL858R-induced lung cancer in vivo. Interestingly, loss of Pten increased bronchial cell hyperplasia but decreased alveolar cell hyperplasia in EGFRL858R*Pten−/−-induced lung cancer. Syatematic analysis of gene expression by RNA-seq showed that a number of genes related to ciliogenesis were upregulated in EGFRL858R*Pten−/−-induced lung cancer and subsequently showed that bronchial ciliated cells were hyperplastic. Several critical ciliogenesis-related genes, such as mucin5a, DNAI2 and DNAI3, were found to be regulated by NR2F1. Next, NR2F1 was found to be inhibited by overexpression of Pten, indicating that Pten negatively regulates NR2F1, thereby inhibiting the expression of ciliogenesis-related genes and leading to the inhibition of bronchial cell hyperplasia during EGFRL858R-induced lung cancer progression. In addition, we also found that Pten decreased Akt phosphorylation in A549, Kras mutant, and H1299 cells but increased Akt phosphorylation in PC9, EGFRL858R, and H1299L858R cells, suggesting that Pten may function as a tumor suppressor and an oncogene in lung cancers with Kras mutation and EGFR mutation, respectively. PTEN acts as a double-edged sword that differentially regulates EGFRL858R-induced lung cancer progression in different genomic backgrounds. Understanding the Pten in lung cancer with different genetic backgrounds will be beneficial for therapy in the future.
Citation Format: Jan-Jong Hung. PTEN as a double-edged sword regulates EGFRL858R-induced lung 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 3053.
Abstract 3056: Copper chelation modulates YTHDF2 RNA-binding protein localization and global translation, in neuronal cancers
Authors: Bell Jessica L. , Abruzzese Domenico K. , Kasiou Erin , Pham Vu Vu , Bertoldo Jean B. , Michniewicz Filip , Vittorio Orazio 
Published: March 2024

Abstract
Cancers are dependent on copper for growth, angiogenesis and metastasis and copper chelators are in clinical trials against breast cancer, however the mechanisms of this emerging cancer treatment are still largely unexplored. We previously demonstrated that copper chelation has efficacy in mouse models of neuroblastoma and glioma. Multiomics analyses in neuronal cancers suggested that RNA-binding proteins were deregulated by copper chelator treatment. We found that the “RNA Binding” gene set was the most significantly ranked molecular function list using differentially expressed RNAs after copper chelation treatment (GO:0003723, p-value 1.02e−32). We subsequently found that the copper chelator drug decreased global protein synthesis, MYC/MYCN expression, as well as the amount a key methylated (m6A) RNA-binding protein called YTHDF2 in glioma cells, by RNA-seq (-log2FC 0.3, p-value 0.005) and western blot. This downregulation was also clear in neuroblastoma and glioblastoma cell lines. Interestingly, copper chelation also shifted YTHDF2 protein location into the nucleus. YTHDF2 knock-out (DepMAP Chronos dependency score, -0.32) and knock-down studies (siRNA pool, 38% decrease in cell confluence) in neuroblastoma cell lines and others, indicated that YTHDF2 depletion is selective against neuronal cancer cell growth. YTHDF2 was found to be a MYCN transcriptional target. Moreover, as YTHDF2 protein also binds MYCN transcripts (the principal oncogene in neuroblastoma), and copper signaling mRNAs, it appears that copper signaling, YTHDF2 and MYCs operates in an oncogenic-axis. Ongoing studies are investigating novel YTHDF2 inhibitors and their neuronal cancer efficacy. Our work represents a significant breakthrough in drugging oncogenic post-transcriptional processes either directly, or indirectly via depleting copper.
Citation Format: Jessica L. Bell, Domenico K. Abruzzese, Erin Kasiou, Vu Vu Pham, Jean B. Bertoldo, Filip Michniewicz, Orazio Vittorio. Copper chelation modulates YTHDF2 RNA-binding protein localization and global translation, in neuronal cancers [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 3056.
Abstract 3076: Unveiling the therapeutic potential of β-catenin inhibition in triple negative breast cancers: Targeting the Warburg effect
Authors: Umar Sheikh Mohammad , kahol Shruti , JR Arundhathi Dev , Kashyap Akanksha , Mathur Sandeep R. , Gogia Ajay , Deo S.V.S , Prasad Chandra 
Published: March 2024

Abstract
Introduction: Triple Negative Breast Cancer (TNBC) exhibits increased glycolysis, known as the Warburg effect. Recent research, including our own Nanostring nCounter studies, identify β-catenin as an oncoprotein linked to elevated glycolysis in TNBC tumors. Our current research explores the impact of β-catenin inhibitors on glycolysis in TNBC cell lines and an in vivo CDX model.
Method: We employed immunohistochemistry to assess 98 TNBCs for the presence of β-catenin, PFKP, LDH-A, and MCT1 proteins, exploring their correlation with clinicopathological factors. In in-vitro experiments using MDA-MB-231, MDA-MB-468, and 4T1 cell lines, we investigated how β-catenin inhibitors (XAV939 & Axitinib) affected aerobic glycolysis components, and TNBC cell characteristics (proliferation, migration, invasion, and stemness). For in-vivo validation, 4T1 TNBC xenografts were employed to confirm our findings.
Results: Among the 98 TNBC patients, 63 (64%) displayed cytoplasmic/or nuclear β-catenin staining. Additionally, cytoplasmic accumulation of PFKP was observed in 52/98 (53%), increased cytoplasmic LDH-A expression in 57/98 (58%), and membranous MCT-1 expression in 50/98 (51%) TNBC patients. Notably, significant positive correlations were found between nuclear/cytoplasmic β-catenin and cytoplasmic PFKP (p = 0.001) as well as membranous MCT1 (p = 0.014). Furthermore, β-catenin, PFKP, LDHA, and MCT1 proteins were overexpressed in all TNBC cell lines thereby supporting their glycolytic nature. Comparative analyses between XAV939 and Axitinib revealed that Axitinib significantly reduced various TNBC cell parameters, including migration, invasion, lactate production, colony-forming ability, and expression of aerobic glycolytic pathway proteins. In the in-vivo studies, 30mg/kg Axitinib in a female Balb/c-4T1 xenograft model resulted in a substantial reduction in tumor volume and weight.
Conclusion: Our findings show that increased levels of β-catenin play an important role in regulating aerobic glycolysis in TNBCs. Furthermore, our findings also highlight Axitinib's potential as an effective therapeutic agent for the treatment of β-catenin-positive TNBCs.
Citation Format: Sheikh Mohammad Umar, Shruti kahol, Arundhathi Dev JR, Akanksha Kashyap, Sandeep R. Mathur, Ajay Gogia, S.V.S Deo, Chandra Prasad. Unveiling the therapeutic potential of β-catenin inhibition in triple negative breast cancers: Targeting the Warburg effect [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 3076.