bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2946: Characterizing the genomic landscapes of breast and lung tumors using cost-effective whole genome sequencing
Authors: Benjamin Hila , Soifer Ilya , Shem-Tov Doron , Levy Maya , Tuncay Islam Oguz , Oh Baek-Lok , Shin Jong-Yeon , Ju Young Seok , Lee Sangmoon , Barad Omer , Lipson Doron 
Published: March 2024

Abstract
Whole Genome Sequencing (WGS) has emerged as a pivotal tool for unraveling the intricate genomic alterations underlying cancer, enabling the detection of a broad spectrum of somatic changes in cancer genomes, including single nucleotide variants, insertions, deletions, copy number variations, and structural rearrangements. Characterizing somatic variants across the entire genome significantly benefits from novel cost-efficient sequencing platforms, such as UG100. In the current study, we aim to demonstrate the utility of UG100 WGS in characterizing the landscape of somatic events in breast and lung cancer.
Over 35 tumor-normal cancer sample pairs were profiled using UG100 WGS (mean tumor coverage: &gt;100x; normal: &gt;50x). Variant calling was done using a somatic deep-variant algorithm, optimized to UG100 data. Results were compared to Illumina sequencing and high concordance was observed, with over 97% of SNVs and over 93% of indels detected by Illumina identified also by UG100. UG100 sequencing was deeper and allowed for identification of a larger number of genomic variations, including known driver events in cancer-related genes. The somatic mutational signatures by UG100 were concordant with the Illumina platform, with a cosine similarity higher than 99%. Copy number variation and structural variation analysis was performed on all sample pairs, revealing a wide range of genomic aberrations.
The integration of genetic sequencing into routine clinical oncology practices has proven instrumental in identifying actionable mutations, predicting treatment responses, and monitoring minimal residual disease. Moving from targeted sequencing to WGS provides a more comprehensive and unbiased assessment of the entire genome, uncovering rare or unexpected mutations that might be missed by targeted approaches. WGS allows for the simultaneous evaluation of both coding and non-coding regions of the genome, providing a deeper understanding of the regulatory elements influencing gene expression. This broader scope enhances our understanding of cancer biology and contributes to a more accurate assessment of the tumor's functional landscape.
Citation Format: Hila Benjamin, Ilya Soifer, Doron Shem-Tov, Maya Levy, Islam Oguz Tuncay, Baek-Lok Oh, Jong-Yeon Shin, Young Seok Ju, Sangmoon Lee, Omer Barad, Doron Lipson. Characterizing the genomic landscapes of breast and lung tumors using cost-effective whole genome sequencing [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 2946.
Abstract 2972: Senescent macrophages drive tumorigenesis by limiting antitumor immunity
Authors: Prieto Luis I. 
Published: March 2024

Abstract
A big challenge in oncology is tumor heterogeneity, as the same type of tumor can manifest differently across patients. Our current cancer therapies focus on targeting malignant cells without considering how the tumor microenvironment influence tumorigenesis or changes in response to treatment. Therefore, identifying effective therapies that restrict tumor growth and progression while restoring optimal tissue and organ function is imperative. Here, we propose a potential strategy to delay the frequency of lung tumorigenesis and reduce progression by selectively targeting tumor-promoting senescent cells that arise with advancing age, prolonging antitumor immunity.
Using lung tumor-prone mice, we found that senescent cells, specifically senescent alveolar macrophages, accumulate early in hyperplastic lesions. Mechanistically, these macrophages upregulate the cell cycle regulator p16Ink4a; express the cell surface protein CXCR1; they are distinct from other established subsets; are sensitive to senolytic interventions; have a tumor-promoting secretome, including SPP1; and express immunosuppressive factors that modulate the antitumor immune response. Selective clearance of senescent macrophages attenuates adenoma development, indicating they, at least in part, promote tumorigenesis. Importantly, we observed alveolar macrophages with these properties accumulating in treatment-naive human early-stage lung adenocarcinoma in situ, indicating that the cellular senescence program in macrophages is a conserved etiology. We also found that senescent alveolar macrophages accumulate in otherwise naturally aged normal mouse lungs and their persistence correlates with increased inflammation. Collectively, our findings suggest that targeting senescent macrophages may constitute a potential therapeutic intervention to postpone or attenuate lung cancer during the early stages of the disease.
Citation Format: Luis I. Prieto. Senescent macrophages drive tumorigenesis by limiting antitumor immunity [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 2972.
Abstract 2994: MIR99AHG promotes ERα expression and ER-positive breast cancer cells proliferation via activating Hippo signaling
Authors: Wang Wende , Lin Danping , Lin Ziyang , Yan Yangyang , Qin Yusen , Liang Yuanke , Lin Haoyu , Zeng De 
Published: March 2024

Abstract
Background: Estrogen receptor (ER) positive breast cancer is the most common subtype of breast cancer. Elucidation of the regulatory network in estrogen receptor pathway is critical to develop and deliver potent targeted therapy for ER-positive breast cancer. The Mir-99a-let-7c cluster host gene MIR99AHG is a long non-coding RNA involving in a variety of tumor formation and disease progression processes. However, the biological functions of MIR99AHG in ER-positive breast cancer have not been reported.
Methods: The Western-blot, qRT-PCR, Immunofluorescence and fluorescence in-situ hybridization were used to identify potential target genes and regulatory pathway of estrogen receptor α (ERa), which is a key proliferative driver of ER-positive breast cancer cells. The cell proliferation assay, clone formation assay, xenograft tumor model and rescue assay were used to investigate the effect of differential expression of MIR99AHG on the proliferative capacity of ER-positive breast cancer cells MCF7 and T47D. In addition, correlation analysis was performed to verify the relation of the expression of MIR99AHG, LATS1, LATS2, CYR61, CTGF and ESR1 from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) cohorts. And survival analysis was used to predict the prognostic impact of MIR99AHG in breast cancer patients.
Results: MIR99AHG expression was significantly higher in ER-positive breast cancer cells MCF7 and T47D than in ER-negative breast cancer cells SKBR3, MDA-MB-231 and BT549. The high expression of MIR99AHG predicted poor prognosis in ER-positive breast cancer patients. In vitro and in vivo assays demonstrated that MIR99AHG positively regulated the proliferation of MCF7 and T47D cells. Importantly, the Hippo signaling was identified to be down-stream mediators of MIR99AHG in modulating ERα transcription. Furthermore, XMU-MP-1, which targets the Hippo signaling upstream kinase MST1/2, was able to reverse the effect of MIR99AHG on MCF7 cell proliferation.
Conclusions: MIR99AHG up-regulates ERα expression and promotes proliferation in ER-positive breast cancer cells through activating Hippo signaling pathway. Targeting MIR99AHG/Hippo pathway is a potential strategy for the treatment of ER-positive breast cancer.
Citation Format: Wende Wang, Danping Lin, Ziyang Lin, Yangyang Yan, Yusen Qin, Yuanke Liang, Haoyu Lin, De Zeng. MIR99AHG promotes ERα expression and ER-positive breast cancer cells proliferation via activating Hippo signaling [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 2994.
Abstract 3025: Germline p53 R181 variants and DNA binding cooperativity in tumorigenesis
Authors: Moses Renyta , Hausler Ryan , Kelly Gregory , Indeglia Alexandra , Miller Sven , Karanicolas John , Murphy Maureen , Maxwell Kara 
Published: March 2024

Abstract
TP53 is the most frequently mutated gene in cancer, and its encoded protein p53 has many tumor-suppressive functions. There are several different classes of mutant p53 acquired in human cancer and inherited in cancer-prone families with Li-Fraumeni Syndrome, where individuals have an 80-90% increased risk of cancer. These include structural mutations that are generally (e.g R175H) or locally (e.g Y220C) misfolded, DNA contact mutations (e.g R273H); and oligomerization mutations (A347D). Cooperativity mutations affect binding of the p53 tetramer to DNA via disruption of a salt bridge formed by the negatively charged glutamic acid (E) 180 residue of one p53 monomer and the positively charged arginine (R) 181 residue of another. p53 “cooperativity” mutations at the R181 residue (R181H and R181C) have been increasingly identified in cancer-prone families undergoing genetic testing; however, the mechanism by which these variants disrupt p53 tumor suppression in humans is not understood. We show that the purified DNA binding domains of p53 variants R181H and R181C bind less cooperatively to the p53 binding site in the CDKN1A (p21) promoter, despite retaining wild-type levels of structural stability. RNA-sequencing of CRISPR knock-in colorectal and breast cancer cell lines shows reduced ability of R181H and R181C to transactivate a curated set of ~300 known p53 target genes. Upon treatment with p53 activating molecule Nutlin-3a, the R181-mutant cells fail to cell cycle arrest in the G1 phase and maintain high proliferative rates. Interestingly, we observe some residual apoptotic activity in R181H and R181C mutant cells treated with DNA-damaging agent 5-fluorouracil, despite losing the transactivation of proapoptotic p53 targets; this suggests that these mutants retain the p53 transcription-independent mechanism of apoptosis which is observed in other p53 variants such as P47S and A347D. These studies will define the pathogenicity of R181 variants and guide therapeutic intervention for patients that harbor these p53 mutations.
Citation Format: Renyta Moses, Ryan Hausler, Gregory Kelly, Alexandra Indeglia, Sven Miller, John Karanicolas, Maureen Murphy, Kara Maxwell. Germline p53 R181 variants and DNA binding cooperativity in 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 3025.
Abstract 3049: Similarities between ovarian cancer and endometriosis: The role of STAT3
Authors: Kloeckner Allison A. , Walker Sarah R. 
Published: March 2024

Abstract
Endometriosis is a painful gynecological disease that affects over 190 million women worldwide. This disease is classified by the presence of endometrial-like cells growing in and around the female reproductive system. Instead of lining the uterus, these ectopic cells shed off and cluster together forming lesions that attach to different surfaces of the female reproductive system. In particular, endometriosis cells interact with and form lesions within the mesothelial cells that line the peritoneum. There is currently no cure, and many of the therapies aiming to help with pain management come with unfavorable tradeoffs. Our research on ovarian cancer led us to investigate potential overlapping characteristics with endometriosis. Growing ovarian cancer cells in 3D causes spheroids to form which mimic the physical features of tumors and are also able to better represent cell-cell and cell-environment interactions. Analysis of the endometriosis cell lines 12Z and hEM3 demonstrated that they could also form spheroids. As both ovarian cancer cells and endometriosis cells interact with mesothelial cells, we wanted to determine if endometriosis spheroids were able to clear the mesothelial layer comparable to ovarian cancer spheroids. Evaluation of 12Z and hEM3 cell lines demonstrated that endometriosis spheroids were able to undergo mesothelial clearance. While the exact cause of endometriosis is not known, different proteins have been identified as important factors in the progression of endometriosis. The Signal Transducer and Activator of Transcription 3 (STAT3) is a transcription factor involved in cell differentiation, proliferation, apoptosis resistance, angiogenesis, and metastasis. In endometriosis cell lines, STAT3 is constitutively active, which makes it a promising potential therapeutic target. To verify that STAT3 is important in endometriosis, siRNA was used to reduce the expression of STAT3 in two endometriosis cell lines, 12Z and hEM3. Both cell lines showed a decrease in cell viability. In addition, reducing the expression of STAT3 in the endometriosis cells appeared to decrease mesothelial clearance ability. Our lab previously identified statins as potential STAT3 inhibitors by using the Broad Institute’s CLUE tool. After statin treatment, 12Z and hEM3 spheroids showed a decrease in cell viability and clearance ability. Taken together, these data suggest that STAT3 plays a key role in endometriosis and that the repurposing of statins may provide a benefit to patients with endometriosis.
Citation Format: Allison A. Kloeckner, Sarah R. Walker. Similarities between ovarian cancer and endometriosis: The role of STAT3 [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 3049.
Abstract 3054: Investigating novel players involved in AR cistrome reprogramming
Authors: Gardner Ephraim Jeremiah 
Published: March 2024

Abstract
Advancements in the treatment of aggressive prostate cancer (PCa) have led to the development of second-generation AR-targeted therapeutics for advanced PCa. Unfortunately, many patients who initially respond to these treatments develop resistance and progress. Several mechanisms of resistance are being studied. We have focused on the roles of a reprogrammed AR cistrome from a canonical to a non-canonical cistrome in resistant disease. The premise of this study is based on previous studies by others and studies in our lab that suggest enrichment in non-canonical AR activity and adaptation to enzalutamide in advanced PCa cell lines and patient-derived xenografts. We aim to develop an ecosystem map of canonical and non-canonical AR activity to understand the drivers of therapeutic resistance and their vulnerabilities. We hypothesize that through combined transcriptomic/chromatin accessibility profiling at single-cell resolution and proteomics studies, we can holistically capture non-canonical AR activity. To provide invaluable information, as PCa is highly heterogeneous and not all cancer cells may be contributing to the resistance pathway that is of interest, we use castrate-resistant PCa (CRPC) and enzalutamide-resistant CRPC patient-derived xenograft (PDX) models and patient tissue samples as our disease models on our multi-omic assay platform to capture and study dynamic interplays and novel players driving a non-canonical AR cistrome and treatment resistance. Our preliminary data revealed potential transcriptional factor (TF) candidates that may modulate non-canonical AR cistrome. We verified the enrichment of these TF in PDX models of treatment-resistant PCa at the gene and protein level. Integration of our ongoing global proteomic studies will provide a holistic view of the contributions of the TF to the AR non-canonical switch.
Citation Format: Ephraim Jeremiah Gardner. Investigating novel players involved in AR cistrome reprogramming [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 3054.
Abstract 3062: Unraveling the role of RCC2 in glioblastoma by mutational analysis and a murine model of glioma
Authors: Ho Wayne L.H. , Or Penelope M.Y. , Chan Andrew M. 
Published: March 2024

Abstract
Glioblastoma (GBM) is a brain malignancy characterized by being highly aggressive, lethal, yet treatment modalities remain limited. Recent studies have implicated Regulator of Chromosome Condensation 2 (RCC2), a guanine nucleotide exchange factor (GEF) for RalA, as a potential regulator in glioblastoma pathogenesis. RCC2 has been shown to play a role in promoting glucose metabolism through BACH1-dependent upregulation of hexokinase II (HK2)(1). In this study, we investigated the functional mechanism of RCC2 in gliomagenesis using two complementary approaches. First, the relevance of RCC2 structural regions on its downstream functions were examined. By superimposing the three-dimensional crystal structure of RCC2 onto RCC1 (Regulator of Chromosome Condensation 1), a related GEF, we identified several unique regions within the RCC1-like domain of RCC2. A panel of point, substitution, and deletion mutants were generated, and pulldown experiments were performed to assess their relative binding affinity with BACH1. Additional assays to assess their relative ability to modulate the expression of HK2 and other cellular parameters will be discussed. The structure-functional characterization of distinct regions within RCC2 may identify unique sequences within RCC2 that could have relevance to glucose metabolism, cell proliferation and cell motility. Additionally, we have established a murine glioma model utilizing a Pten heterozygous mice expressing a GFAP-Cre-recombinase transgene (Gfap-cre;Ptenfl/+). Glioma were induced by stereotaxically injected lentiviral constructs expressing either with HRasV12 oncogene alone or together with RCC2. Neurological symptoms were monitored over a period of 7 months, and histopathological analysis was performed to evaluate the morphological and molecular features of the tumors. We showed that co-expression of HRasV12 and RCC2 exhibited earlier emergence of neurological manifests in both male and female groups (Log-rank test, p&lt;0.05) when compared to HRasV12 alone. Overall, our study provides insights into both the structural mechanism of RCC2 in gliomagenesis through mutational analysis of RCC2 and the functional relevance through a murine model of glioma.
(1)Liu, T. et. al. Cancer Lett (2022) 549:215914.
Funding: This work is supported by a General Research Fund grant (#14113519) from the University Grants Committee of Hong Kong.
Citation Format: Wayne L.H. Ho, Penelope M.Y. Or, Andrew M. Chan. Unraveling the role of RCC2 in glioblastoma by mutational analysis and a murine model of glioma [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 3062.
Abstract 3099: A new HTS ELISA for monitoring NRAS activity to expedite drug discovery
Authors: Park Hyun Min , Weber Julie , Carlson Michelle , Jelinek Mary Anne 
Published: March 2024

Abstract
Oncogenic mutations in the KRAS, HRAS, and NRAS isoforms of the RAS gene family alter GTP binding and hydrolysis leading to errant over activation of the MAPK/ERK pathway. While the total of all such RAS mutations drives some 20-25% of all human cancers, each isoform tends to favor particular mutations that are cancer specific. Many evolving treatment strategies for these cancers target these mutant isoforms to minimize off target effects. NRAS mutations are seen in about one-fifth of cutaneous melanomas and patients with NRAS mutation melanomas have a poorer prognosis due to the high aggressiveness of RAS mutant tumors, a lack of efficient targeted therapies, or rapidly emerging resistance to existing treatments. Furthermore, there is no currently authorized targeted treatment for NRAS-mutated melanoma. As a result, there is a growing need for assays which can quantify activated NRAS. Here we describe the development of a highly specific and sensitive ELISA for determining the active NRAS protein in high throughput compatible (HTS) format.
A NRAS specific recombinant antibody was developed via cloning of immunoglobulin variable regions from antigen positive B cells isolated by FACS from rabbits immunized with a NRAS peptide corresponding to a region of low homology between the RAS isoforms. Immunoblotting and a bead-based multiplex ELISA with all three RAS isoforms were used to confirm antibody specificity with recombinant HRAS, KRAS, and NRAS proteins over a wide concentration range.
The new immunoassay enables in-well lysis of cells cultivated in 96-well plate. Activated NRAS in the lysate is collected on the test plate and detected using the NRAS specific antibody via chemiluminescence. We anticipate that this assay will further the discovery of novel NRAS specific therapeutics. EGF treatment of MCF7 cells demonstrated activation in cells expressing wildtype NRAS in preliminary assay validation. Evaluation of assay performance in mutant NRAS melanoma cell lines will be presented.
Citation Format: Hyun Min Park, Julie Weber, Michelle Carlson, Mary Anne Jelinek. A new HTS ELISA for monitoring NRAS activity to expedite drug discovery [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 3099.