bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1533: Characterizing tumor-immune surveillance in Li-Fraumeni syndrome
Authors: Giovino Camilla , Fischer Nicholas , Ong Noel , Kissoondoyal Ashby , Kafri Ran , Malkin David 
Published: March 2024

Abstract
Li-Fraumeni Syndrome (LFS) is a cancer predisposition syndrome associated with germline TP53 mutations and increased lifetime risk of developing multiple cancers. p53, the protein encoded by TP53, plays a role in regulating various aspects of immune cell biology. Accordingly, inactivation of p53 in tumor cells shapes interactions with the immune system and influences the anti-tumor immune response. Mutation or deletion of p53 in immune cells also favors tumor development and progression. However, to date, a comprehensive study of immune cell populations and the anti-tumor immune response has not been undertaken in the context of LFS. We hypothesized that germline TP53 mutation carriers possess dysfunctional immune cells and/or immune responses, supporting LFS-associated tumor progression. Our preliminary data indicate a profound defect in tumor-immune surveillance in an LFS murine model. We observed that MC38 cancer cells develop significantly faster into tumors when injected into LFS mice (harboring a gain-of-function mutation Trp53R172H/WT) compared to wildtype (WT) control mice. Importantly, we identified significant alterations in immune cell compositions and phenotypes within the tumor microenvironment as well as immune organs using flow cytometry. We are currently using ex vivo proliferation assays and cytotoxicity assays to investigate the impact of mutant p53 on the tumor-killing ability of immune effector cells. Altogether, an improved understanding of anti-tumor immune dysfunction in the context of germline TP53 mutation may reveal the potential for innovative therapies to target different facets of the immune system to intercept cancer progression in LFS patients.
Citation Format: Camilla Giovino, Nicholas Fischer, Noel Ong, Ashby Kissoondoyal, Ran Kafri, David Malkin. Characterizing tumor-immune surveillance in Li-Fraumeni syndrome [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 1533.
Abstract 1565: USP13 influences metastatic features in fallopian tube-originated high-grade serous carcinoma
Authors: Mok Boram , Kwon Juntae , Zhang Jinmin , Allsup Samuel , Choi Hyeongjwa , Han Cecil 
Published: March 2024

Abstract
High-grade serous ovarian carcinoma (HGSOC), originating from the fallopian tube, stands as a formidable challenging gynecologic malignancy with the highest mortality rate worldwide. Ubiquitin-specific peptidase 13 (USP13) has garnered attention due to the highly frequent USP13 gene copy amplification in human ovarian cancer. However, its precise pathological role in ovarian cancer remained elusive. To uncover the underlying role of USP13 in HGSOC, we developed a novel genetically engineered mouse model (GEMM) of HGSOC. Ovgp1-iCreERT2;Trp53flox/flox;Ptenflox/flox mouse (OPT) was crossed with Rosa26−LSL-Usp13 knockin mouse model (U), generating Ovgp1-iCreERT2;Trp53flox/flox;Ptenflox/flox ; Rosa26−LSL-Usp13 mouse model (OPTU). Usp13 overexpression with loss of p53 and Pten was induced specifically in fallopian tube secretory epithelial cells in OPTU mice. OPTU mice demonstrated the development of STIC and early HGSOC in the fallopian tube as well as invasive metastatic HGSOC. While OPT tumors largely retained mucinous and HGSOC subtypes, displaying limited metastatic behavior, OPTU tumors exhibited more complex ovarian tumor subtypes, including mucinous, HGSOC, and Mixed Mesodermal Mullerian Tumor (MMMT) histology. Furthermore, OPTU tumors showed invasive and metastatic phenotypes, characterized by an increased incidence of ovary invasion, metastasis to distant organs, and ascites development. Importantly, OPTU-driven HGSOC tumors closely resemble human HGSOC histology features, making the OPTU model a valuable tool for exploring fallopian tube-originated ovarian cancer. Primary ovarian cancer cells established from ascites of the OPTU mouse reproduced metastatic HGSOC tumorigenesis in the syngeneic mouse study. Stable USP13 knockdown in OPTU cells exhibited reduced cell proliferation and metastatic abilities in 2D and 3D cultures. In summary, this study underscores the pivotal role of USP13 in facilitating metastasis in fallopian tube-originated HGOSC. Our findings may provide a promising avenue for future therapeutic strategies aimed at mitigating the aggressive nature of USP13-amplified fallopian tube-originated HGOSC.
Citation Format: Boram Mok, Juntae Kwon, Jinmin Zhang, Samuel Allsup, Hyeongjwa Choi, Cecil Han. USP13 influences metastatic features in fallopian tube-originated high-grade serous 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 1565.
Abstract 163: Role of macrophages in the development of ovarian cancer stem-like cells during chemotherapy
Authors: Cruz Luisjesus S. , Stevenson Denay , Robinson Mikella , Mathew Steffy , Amador Isabella , Jordan Gregory , House Carrie D. 
Published: March 2024

Abstract
Ovarian cancer is a poorly understood disease with 75% death rate when identified after metastasis. Drug resistance and tumor recurrence are likely due to cancer stem-like cells (CSCs) that evade chemotherapy and induce relapse with phenotypes that are distinct from bulk tumor cells. It remains unclear how CSCs facilitate relapse and what role the tumor microenvironment (TME) plays in this process. Our preliminary data show that a secreted cytokine, tumor necrosis factor-like weak inducer of apoptosis (TWEAK), and its receptor Fn14 are overexpressed in ovarian tumors and increase after chemotherapy. TWEAK is a strong inducer of stem cell features and enhances survival of CSCs during chemotherapy exposure. The source of TWEAK has not been clarified, although clinical data from human ovarian tumors show that TWEAK mRNA was primarily observed in a subset of infiltrating immune cells known as tumor associated macrophages (TAMs). When we evaluated TWEAK expression in cells found in the ovarian TME, including PBMC and THP-1-derived macrophages, IMR-90 activated fibroblasts, and ovarian cancer cell lines, we found that PBMC macrophages were the primary source of TWEAK production. Since cytotoxic chemotherapy can enrich for different TAM populations, we propose that TWEAK producing TAMs support CSC survival and expansion and contribute to the high rate of relapse in ovarian cancer patients. We further found that treatment with a small molecule inhibitor of TAM polarization leads to decreased TWEAK production, fewer CSCs, and prolonged remission in mouse models of ovarian cancer relapse as compared to vehicle. Currently we are testing whether knockout of Fn14 in ovarian cancer cells co-cultured with TAMs reduces stem cell features dependent on TWEAK-Fn14 signaling. Identification of immune populations responsible for TWEAK production could lead to new therapeutic strategies for patients with high rates of relapse.
Citation Format: Luisjesus S. Cruz, Denay Stevenson, Mikella Robinson, Steffy Mathew, Isabella Amador, Gregory Jordan, Carrie D. House. Role of macrophages in the development of ovarian cancer stem-like cells during chemotherapy [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 163.
Abstract 1662: Evaluation of TEAD inhibitor, VT03989 treatment on growth of aggressive meningioma preclinical models
Authors: Desai Siddhi , Shivanna Anil Thaghalli , Stavnichuk Mariya , Hayes Elizabeth , Patel Sonam , McNamara James , DeSantis Anita , Sanai Nader , Tien An-Chi , Mehta Shwetal 
Published: March 2024

Abstract
Background: Aggressive meningiomas (WHO grade II/III) are incurable brain tumors and despite surgery and radiation therapy, tumors recur frequently without approved systemic treatment options. Hence, there is an unmet need for targeted inhibition therapy and biomarkers that predict vulnerability to targeted therapies in aggressive meningioma patients. Hippo signaling pathway has been shown to be dysregulated in meningioma, resulting in activation of its target TEAD as a transcriptional factor. We hypothesize that targeted inhibition of TEAD in recurrent high-grade meningioma with NF2 loss will lead to increased inhibition of tumor growth. Here, we investigated the effect of VT3989, a potent TEAD inhibitor, in meningioma cell lines with NF2 wild-type or NF2 loss genotype.
Methods: Two meningioma cell-lines: IOMM-Lee (NF2 wild-type) and MG309, a grade III meningioma patient-derived cell line with NF2 loss were treated with various doses of VT3989 and cell viability was assessed. Relative expression of direct targets of TEAD including CTGF and CYR61 was determined with quantitative PCR (qPCR) to ensure target engagement. Global transcriptomic changes were examined via RNAseq analysis on RNA isolated from MG309 cells treated with VT03989 compared to vehicle treated cells.
Results: VT3989 treatment significantly decreased viability of both IOMM-Lee and MG309 cells. Canonical downstream targets of TEAD such as CTGF, CYR61, BIRC5, BCL-2 were downregulated in VT3989 treated cells compared to control. Furthermore, VT03989 treatment resulted in downregulation in cell cycle regulation and DNA damage response (DDR) pathway genes. Ongoing work is focused on combining VT3989 with agents targeting cell cycle and DDR pathways.
Conclusion: VT3989 treatment led to downregulation of TEAD direct targets CTGF and CYR61 and inhibited cell viability of both IOMM-Lee cell and MG309 meningioma lines. RNA-seq analysis identified cell cycle and DDR pathway genes to be downregulated upon TEAD inhibition.
Citation Format: Siddhi Desai, Anil Thaghalli Shivanna, Mariya Stavnichuk, Elizabeth Hayes, Sonam Patel, James McNamara, Anita DeSantis, Nader Sanai, An-Chi Tien, Shwetal Mehta. Evaluation of TEAD inhibitor, VT03989 treatment on growth of aggressive meningioma preclinical models [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 1662.
Abstract 1681: Characterizing signaling and localization of Daple-FLT3 gene fusion in leukemia cells
Authors: Acquazzino Michael , Ear Jason 
Published: March 2024

Abstract
Receptor tyrosine kinases (RTKs) are cell surface receptors that regulate cell survival, cell proliferation, and cell migration upon ligand binding. Genetic mutations leading to hyperactivation of RTKs are often seen in cancer and allow signaling pathways to be constitutively active. In some hematological malignanices, the coiled-coil domain (CCD) of Daple, a cell signaling scaffold protein, has been found in gene fusions with the RTKs FLT3 and PDGFRB, and to the intracellular kinase JAK2. It is hypothesized that this gene fusion product causes the tyrosine kinase domain of FLT3 to become activated and mislocalizes in the cell, leading to rampant cell signaling of either the MAPK, AKT, and STAT5 signal transduction cascades. Using fluorescently tagged Daple-FLT3, it was shown that the gene fusion product is subcellularly localizes to the peri-centrosome space across all leukemia cell lines tested. Ectopic expression demonstrated activation of the kinase domain and subsequent increases in phosphorylation of STAT5α and AKT, but no significant increase in the phosphorylation of MAPK was observed. Further investigation is needed to identify direct substrates of the Daple-FLT3 gene fusion and transcriptional changes. Identifying the direct kinase substrates and insights gained through understanding the gene fusion localization, affects on cell signaling, and changes in gene expression, may unveil novel therapeutic strategies into targeting this protein in cancer.
Citation Format: Michael Acquazzino, Jason Ear. Characterizing signaling and localization of Daple-FLT3 gene fusion in leukemia 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 1681.
Abstract 17: Metabolic screening of T cells guides the enrichment of stem cell memory phenotype
Authors: Lauer Anthony , Karassina Natasha , Sylvester Kayla , Vidugiriene Jolanta 
Published: March 2024

Abstract
The efficacy of T cell-mediated immunotherapy is improved by the proliferation of T cells with a stem cell memory phenotype (Tscm). These cells are capable of long-term persistence, self-renewal, multipotency, and robust engagement with cancer cells. This study focuses on refining T cell activation protocols to bolster the presence of Tscm within the therapeutic arsenal against cancer. Through a series of cell health and metabolic assays, we traced the activation-induced metabolic reprogramming that results from Tscm enrichment. Ex vivo activation was characterized by a rapid 2.5-3 fold increase in ATP production and a 2 fold shift in intracellular reducing potential, paralleling the metabolic demands of Tscm in the cancer microenvironment. Progression of activation intensified the metabolic flux through catabolic and anabolic pathways, with significant fluctuations in metabolites such as glucose, lactate, glutamine, glutamate, branched chain amino acids, and pyruvate. These metabolic alterations were accompanied by a 2 fold increase in the prevalence of Tscm cells, and demonstrated a dependency on media composition. Our findings reveal that metabolic profiling during T cell activation provides early and actionable insights into the enrichment of Tscm, and may serve as a strategic guideline for the enhancement of cancer immunotherapies.
Citation Format: Anthony Lauer, Natasha Karassina, Kayla Sylvester, Jolanta Vidugiriene. Metabolic screening of T cells guides the enrichment of stem cell memory phenotype [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 17.
Abstract 1768: Investigating oncogene amplifications in brain metastasis of esophageal adenocarcinoma samples
Authors: Lawson Nora , Ye Lingqun , Zhao Bo , Futreal Andy , Akdemir Kadir 
Published: March 2024

Abstract
Esophageal Adenocarcinoma (EAC) exhibits a rising incidence and dismal survival rate in the US, primarily attributed to frequent distant metastases. Brain metastasis, though uncommon is an aggressive tumor type, remains poorly understood in EAC. To address this knowledge gap, we conducted a comprehensive analysis of 9 brain metastasis samples, profiling their whole-genome with matched normal and comparing them to the primary EAC tumors, other EAC metastasis types and other brain metastasis types, including the Hartwig Institute and PCAWG. Overall, our sample size comprised over 4,500 tumor whole-genome data and we utilized a uniform data analysis pipeline for robust comparisons between cohorts. Our analysis revealed that brain metastasis samples have significantly higher single-nucleotide variants, however, the structural variant burden in brain metastases closely resembled those observed in the primary tumor. Notably, the incidence of whole genome doubling is significantly higher in brain metastasis compared to other primary cancer types and metastases. This significant difference stems from the higher WGD incidence in primary EACs compared to other tumor types. Mutational signature analysis revealed no significant changes compared to the primary tumor, and we observed an enrichment of SBS 17a/b, previously associated with tumor progression in primary esophageal adenocarcinoma, along with a prevalent presence of the APOBEC mutagenesis signature in most samples. Notably, ERBB2 and TP53 emerged as prominent driver genes present in most brain metastasis samples. We also observed an upregulation of ERBB2 expression in brain metastasis samples. Interestingly, ERBB2 appeared to play a more significant role in brain metastasis progression compared to the primary tumor and other metastasis types, suggesting its potential as a therapeutic target. These findings advance our comprehension of brain metastasis in EAC, providing crucial insights into genomic alterations and mutational processes that could inform future therapeutic strategies and clinical management for this previously understudied metastatic type.
Citation Format: Nora Lawson, Lingqun Ye, Bo Zhao, Andy Futreal, Kadir Akdemir. Investigating oncogene amplifications in brain metastasis of esophageal adenocarcinoma samples [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 1768.
Abstract 1785: The role of BRCA1 on metabolic pathways in an in vivo system
Authors: Hembruff Stacey L. , Dekonenko Alexander , Thyfault John , Sardiu Mihaela , Washburn Michael , Jensen Roy A. , Harlan-Williams Lisa M. 
Published: March 2024

Abstract
The role of BRCA1 in cellular metabolism is not well characterized and what we do understand has been mostly demonstrated in vitro. Our studies aim to fully characterize the role of BRCA1 in metabolic pathways in a whole-body system. In vivo studies using C57BL/6 wild-type and transgenic humanized BRCA1 mice demonstrate the effect of human BRCA1 on the whole-body metabolic phenotype and start to elucidate the mechanism by which this occurs. We used Promethion metabolic chambers and glucose tolerance tests to measure a number of metabolic outputs of male and female mice that had either normal mouse Brca1 gene expression (wild-type/WT mice) or a knock-out mouse Brca1/knock-in human BRCA1 (humanized/HU mice). Humanized BRCA1 mice are more lean, hyperactive and demonstrate a sexual dimorphism in glucose tolerance when compared to wild-type mice on the same genetic background. To begin to elucidate the mechanisms behind the observed metabolic phenotype, we used a metabolic tissue, female mouse skeletal muscle, to perform mass spectrometry, SuperArray, and Western blot analysis. Proteomic samples were sent to the IDeA National Resource for Quantitative Proteomics at the University of Arkansas Medical Sciences for processing and analysis. Proteomic and genomic analysis showed changes in a number of metabolic pathways that may be implicated in the observed whole body metabolic phenotype. We can conclude that changing the expression levels of BRCA1 in an in vivo model altered the overall metabolic profile of C57BL/6 mice. This is the first in vivo evidence demonstrating the effects of BRCA1 expression in whole body metabolism.
Citation Format: Stacey L. Hembruff, Alexander Dekonenko, John Thyfault, Mihaela Sardiu, Michael Washburn, Roy A. Jensen, Lisa M. Harlan-Williams. The role of BRCA1 on metabolic pathways in an in vivo system [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 1785.
Abstract 180: LINC00261 is functionally linked to tumor DNA mutational burden and tumor immune microenvironment composition in lung adenocarcinoma
Authors: Castillo Jonathan , Xue Tianchun , Norwood Mayela , Joseph Samantha , Epstein Alan L. , Wallace William D. , Kim Anthony W. , Marconett Crystal N. 
Published: March 2024

Abstract
Immunotherapy has emerged as a breakthrough in the improvement of survival outcomes for lung adenocarcinoma (LUAD), however effective response requires the combination of blocking inhibitory signals on the tumor surface and antigen presentation to the tumor surface for proper immune recognition. Several commercially available and robust methods exist for identification of tumors displaying immune-inhibitory surface receptors, such as PD-L1, however it is currently difficult to predict effectiveness of antigen presentation on the cell surface. To address this, we utilized clinical and next-generation sequencing data from The Cancer Genome Atlas (TCGA) to identify gene signatures that are correlated to tumor mutational burden (TMB) within cancers of epithelial origins as a surrogate for neoantigen signatures. We identified LINC00261 as a top gene correlated to TMB, whose expression activates DNA damage response pathways in vitro along with resistance to cisplatin. LINC00261 expression was also significantly correlated to MHC class I and II genes involved in endogenous neoantigen presentation expression within the TCGA-LUAD cohort. This relationship was confirmed in vitro through ectopic reintroduction of LINC00261 for key MHC class II presentation genes. Interferon gamma-induced MHC gene activation in vitro was also able to induce endogenous expression of LINC00261. Staining of primary human lung cancer sections suggested that loss of LINC00261 is associated with an immunosuppressive tumor microenvironment. Taken together, our results suggest there is a mechanistic relationship in the silencing of LINC00261 in LUAD and compromised DNA repair, accumulation of mutations, and reduced antitumor immune response.
Citation Format: Jonathan Castillo, Tianchun Xue, Mayela Norwood, Samantha Joseph, Alan L. Epstein, William D. Wallace, Anthony W. Kim, Crystal N. Marconett. LINC00261 is functionally linked to tumor DNA mutational burden and tumor immune microenvironment composition in lung adenocarcinoma [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 180.
Abstract 1820: Investigating the anticancer effects and pharmacological mechanisms of phenanthridine Amaryllidaceae alkaloid in bladder cancer
Authors: Su Yu-Chi , Chen Mei-Chuan 
Published: March 2024

Abstract
Bladder cancer (BC) ranks as the tenth most common malignancy worldwide. Despite the improved five-year survival rate of around 80% for bladder cancer patients, 25% of cases progress to muscle-invasive bladder cancer with associated metastases, leading to a notable five-year survival of 5%. This underscores the urgent clinical necessity for the development of novel therapeutic strategies in the management of bladder cancer. In this study, we demonstrate the anticancer potential of a phenanthridine Amaryllidaceae alkaloid (PAA), and investigate its underlying mechanisms in bladder cancer. The data demonstrates the selective cytotoxicity of PAA towards bladder cancer cells, revealing IC50 values of 2.47 μM in RT112 cells and 8.99 μM in normal uroepithelial SV-HUC-1 cells. Protein array analysis further showed that PAA attenuated phosphorylation of several kinases, which functions as critical regulators of cell survival and proliferation. PAA induces S phase retardation and increases the phosphorylation of ATM, potentially enhancing DNA damage capability. Furthermore, PAA induced apoptosis, as evidenced by the accumulation of sub-G1 cells and caspase activation. In summary, our findings demonstrate that PAA exerts diverse effects on cell cycle regulation and apoptosis. These results suggest that PAA holds promise as a potential candidate for the treatment of bladder cancer.
Citation Format: Yu-Chi Su, Mei-Chuan Chen. Investigating the anticancer effects and pharmacological mechanisms of phenanthridine Amaryllidaceae alkaloid in bladder 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 1820.