tbuckley/cabot-search huggingface dataset:
Abstract LB302: circIPO7 dissociates caprin-1 from ribosomes and inhibits gastric cancer cell proliferation by suppressing EGFR and mTOR
Authors: Liling Niu, Jing Liu, Hui Li
Journal: Cancer Research (2024)

Abstract circIPO7 dissociates caprin-1 from ribosomes and inhibits gastric cancer cell proliferation by suppressing EGFR and mTORLiling Niu, Jing Liu, Hui Li*Purpose: Circular RNAs (circRNAs) are vital participant of various pathophysiological processes through unique mechanisms. We previously reported that circIPO7 (circBase ID: hsa_-circ_0005092) was positively associated with postoperative recurrence of gastric cancer (GC). In the present study, we aimed to explore the biological function of circIPO7 in GC development. Methods: CCK-8, clone formation, Edu proliferation assay and xenograft model were used to analyze the effects of circIPO7 and caprin-1 on the cell proliferation and tumor growth in vivo and in vitro. Mass spectrometry, RNA pull down, RIP and RNA-FISH experiments were used to identify the co-localization and interaction between caprin-1 and circIPO7. RIP sequencing was used to analyze the mRNAs binding with caprin-1. Rescue experiment was conducted to evaluate the translational regulation of circIPO7 on caprin-1 downstream effector molecule.Results: circIPO7 was downregulated in GC tissues and cells compared to paracarcinoma tissues and normal epithelial cells. circIPO7 overexpression significantly suppressed GC cell proliferation in vitro and in vivo. Mechanistically, circIPO7 directly binds with caprin-1, an RNA-binding protein involved in mRNA translation, sharing overlapping binding sites with G3BP1. Thus, the complex containing overexpressed circIPO7 blocked the caprin-1-G3BP1 interaction and dissociated caprin-1 and its target mRNAs (EGFR and mTOR) from ribosomes, resulting in their translational inhibition, followed by PI3K/AKT/mTOR pathway inactivation.Conclusion: We demonstrate that circIPO7 serves as an RBP sponge for caprin-1, inhibits the translation of downstream proliferation-related mRNAs, and ultimately suppresses malignant cell proliferation. Taken together, these results suggest that circIPO7 may be a potential therapeutic target for GC treatment. Citation Format: Liling Niu, Jing Liu, Hui Li. circIPO7 dissociates caprin-1 from ribosomes and inhibits gastric cancer cell proliferation by suppressing EGFR and mTOR [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB302.
Abstract LB365: Generation of a novel severely immunodeficient Sprague Dawley rat model for xenograft studies
Authors: Yanhui Nie, Meiqi Zhang, Wanling Zhong, Jia Feng, Bahetiyaer Huwatibieke, Zhaoxue Yu
Journal: Cancer Research (2024)

Abstract The recombinant-activating gene 2 (Rag2) plays a critical role in the recombination of the immunoglobulin and T cell receptor genes during the maturation of T and B cells. Loss of Rag2 protein leads to a lack of functional T and B cells, which eliminates the adaptive immune response. However, Rag2 deficiency alone may not guarantee the success of xenograft implantation, due to NK cells and other innate cells remaining. Il2rg is a key component of several cytokine receptors involved in differentiation and/or function of numerous adaptive and innate immune cells, including NK cells, mast cells, basophils, and dendritic cells. To generate a more severely immunodeficient rat model, both the Rag2 and Il2rg genes were knocked out in Sprague Dawley (SD) rats; this model was termed B-SDG rats. The immune profile and organ weights of thymus and spleen were investigated in B-SDG rats in comparison with Rag2-/- and wild-type SD rats. The spleen weights of both Rag2-/- and B-SDG rats were similar, but significantly reduced compared to wild-type SD rats. Notably, the thymus weights of B-SDG male rats were significantly smaller than those of Rag2-/- males. The immune cell profiles in thymus, spleen and blood were next evaluated by flow cytometry. A complete lack of B and T cells was observed in both Rag2-/- and B-SDG rats. B-SDG rats lacked CD161+ NK cells in the spleen and blood, which were maintained in Rag2-/- rats. Dendritic cells, monocytes, macrophages, and neutrophils were detected in all strains. In vivo xenograft implantation with human lung, bladder, breast, pancreas, acute monocytic and myelomonocytic leukemia tumor cell lines was next evaluated in B-SDG rats, which demonstrated successful engraftment. Furthermore, several efficacy studies were performed in B-SDG rats, including cisplatin chemotherapy on human breast invasive ductal carcinoma cell (HCC1954) and human large cell lung cancer cell (NCI-H460) xenografts, and a HER2-targeting ADC therapy was tested in B-SDG rats harboring human non-small cell lung cancer tumors (NCI-H1975). Taken together, these data confirm that B-SDG rats provide a powerful immunodeficient model for preclinical in vivo evaluation of novel drug candidates. Citation Format: Yanhui Nie, Meiqi Zhang, Wanling Zhong, Jia Feng, Bahetiyaer Huwatibieke, Zhaoxue Yu. Generation of a novel severely immunodeficient Sprague Dawley rat model for xenograft studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB365.
Abstract LB153: Spatial transcriptomics of mouse parathyroid gland cells expressing an activating variant of gcm2
Authors: Priyanka Bolel, Jeremie O. Pina, Fabio R. Faucz, Lee S. Weinstein, Sunita K. Agarwal
Journal: Cancer Research (2024)

Abstract Tumors of one or multiple parathyroid glands and elevated serum calcium and parathyroid hormone (PTH) are the common characteristics of primary hyperparathyroidism (PHPT). Genes associated with familial PHPT (hereditary parathyroid tumors) include - MEN1, CDKN1B, CDC73, RET, MAX and GCM2. The glial cells missing 2 (GCM2) gene functions as a transcription factor that is essential for parathyroid gland development. Heterozygous germline missense variants located within the C-terminal conserved inhibitory domain (CCID) of GCM2 have been reported in a subset of patients with familial PHPT. In functional assays, these missense variants enhance the transcriptional activity of GCM2, suggesting that GCM2 could act as a proto-oncogene in parathyroid neoplasia. A recurrent germline activating missense variant of GCM2, p.Y394S in patients with familial PHPT has been reported in various publications. To study the direct contribution of this missense variant in parathyroid neoplasia, we used the CRISPR/Cas9 system to generate a heterozygous germline knock-in of p.Y392S in the mouse Gcm2 gene (which corresponds to the human variant p.Y394S in GCM2). In GCM2-binding site mediated luciferase reporter assays, the mouse Gcm2 variant p.Y392S also exhibited the transcription enhancing effect that was observed for the human GCM2 p.Y394S variant. However, mice with this variant (Gcm2 +/Y392S) did not show obvious parathyroid tumors. Because the mouse Gcm2 variant p.Y392S exhibited enhanced transcriptional activity, we performed spatial transcriptomics of parathyroid glands from wildtype (WT) and Gcm2 +/Y392S mice to examine differentially expressed transcripts in parathyroid cells with the p.Y392S variant of Gcm2. Using the 10X Genomics Visium platform, spatially resolved RNA-seq analysis was performed on parathyroid gland cells of WT and Gcm2 +/Y392S mice specifically marked by the expression of Pth and Gcm2. Spatial transcriptomics and Pathway analysis was performed to evaluate transcripts with more than 2-fold increased expression in parathyroid cells from the p.Y392S variant of Gcm2 compared to WT. Further investigation of these genes and pathways in mouse and human parathyroid cells can provide insights into the functional consequences of GCM2 activating variants and the pathophysiology of parathyroid tumorigenesis. Citation Format: Priyanka Bolel, Jeremie O. Pina, Fabio R. Faucz, Lee S. Weinstein, Sunita K. Agarwal. Spatial transcriptomics of mouse parathyroid gland cells expressing an activating variant of gcm2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB153.
Abstract LB270: VRTX531, a potent and selective inhibitor of USP1 for treatment of BRAC1/2mut and HRD+ cancers
Authors: Uday Kumar Surampudi, Prashant Kashinath Bhavar
Journal: Cancer Research (2024)

Abstract Tumors characterized by deficiencies in DNA double-strand break (DSB) repair mechanisms, such as those harboring mutations in BRCA1/2, are commonly addressed through the administration of poly (ADP-ribose) polymerase-1 (PARP1) inhibitors or platinum-based chemotherapy. While these treatments offer clinical advantages, a significant number of patients eventually develop resistance, underscoring the necessity for innovative therapeutic strategies. USP1 belongs to the ubiquitin-specific processing (UBP) family of proteases, playing a pivotal role in modulating DNA damage response (DDR) pathways. VRTX531 is a novel potent, selective and allosteric inhibitor of USP1 with an IC50 of &amp;lt;50 nm in tested across a broad range of tumor lineages including MDAMB-436 and cell lines and UWB1.289. VRTX531, compound induces cell death through a pathway that is distinct from PARP inhibitors and compound demonstrates robust synergy when combined with first- or second-generation PARP inhibitors. Moreover, the compound exhibited profound activity alone and in combination with PARP inhibitor in BRCA1/2 mut and HRD+ tumors. VRTX531 exhibited exemplary pharmacokinetics and safety in preclinical studies and is expected to enter preclinical testing in H1, 2024. VRTX531 is being evaluated as a single agent and in combination with PARP1 inhibitor in patients with BRCA1/2 mut or HRD+ tumors that are naïve to PARP inhibitors and with prior PARP inhibitor history. Citation Format: Uday Kumar Surampudi, Prashant Kashinath Bhavar. VRTX531, a potent and selective inhibitor of USP1 for treatment of BRAC1/2mut and HRD+ cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB270.
Abstract LB224: Neoplastic immune mimicry potentiates breast cancer progression
Authors: Eric B. Berens, Sokchea Khou, Elaine Huang, Amber Hoffman, Briana Johnson, Zena Werb, Laura M. Heiser, Lisa M. Coussens
Journal: Cancer Research (2024)

Abstract Dedifferentiation programs are commonly enacted during breast cancer progression where they enable novel cellular phenotypes. Increased cellular plasticity within the neoplastic compartment of tumors correlates with disease aggressiveness, often manifesting as greater resistance to cytotoxic therapies or increased ability to metastasize to distant organs. Here we report that subpopulations of ostensibly stem-like neoplastic breast epithelial cells express canonical leukocyte cell surface receptor proteins, and have named this unique cellular program ‘immune mimicry’ (IM). We have documented neoplastic cells engaging in IM by examination of histopathological breast tumor specimens and their derived cell lines, public human breast tumor single-cell RNA-seq datasets, and in murine transgenic and cell line-derived mammary cancer models. Immune-mimicked neoplastic cells harbor hallmarks of dedifferentiation and appear enriched for developing aggressive and high-grade tumors. Experimental studies with breast cancer cell lines revealed that neoplastic cells expressing leukocyte surface features are elicited by growth-arresting conditions, such as conventional cytotoxic chemotherapeutic treatments and during metastatic dissemination in mice. In addition, using proof-of-concept studies, we leveraged the canonical leukocyte activation marker CD69, to demonstrate how its expression by neoplastic epithelial cells confers a proliferative advantage under low-density conditions. We conclude that neoplastic breast epithelial cells expressing leukocyte surface receptors may signify a particularly malignant and tumor-initiating cell state. Moving forward, neoplastic IM will be evaluated for prognostic utility in breast cancer to determine whether this unique cell state stratifies patients with increased risks for tumor recurrence and metastasis. The authors acknowledge NIH/NCI (K00 CA212132, T32 CA254888, P30 CA069533), the Collins Medical Trust, the Susan G Komen Foundation, and the National Foundation for Cancer Research for funding. Citation Format: Eric B. Berens, Sokchea Khou, Elaine Huang, Amber Hoffman, Briana Johnson, Zena Werb, Laura M. Heiser, Lisa M. Coussens. Neoplastic immune mimicry potentiates breast cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB224.
Abstract LB374: The microbial landscape of colorectal cancer across 11 countries
Authors: Ammal Abbasi, Ludmil Alexandrov
Journal: Cancer Research (2024)

Abstract Colorectal cancer (CRC) is the second most frequent cause of cancer-related deaths globally. CRC is influenced by the colorectal microbiome, which plays a pivotal role in inflammation, DNA damage, and production of cancer-promoting metabolites. Most prior CRC microbial studies have identified multiple microbes enriched in tumor samples, but these examinations have generally focused on CRC from a specific country and have not accounted for CRC patient’s tumor site, sex, diet, or geographical location. Further, the interconnection between somatic alterations and microbiome composition has not been comprehensively explored. Here, we examine the microbiome profiles of 963 whole-genome sequenced CRC and their matched-normal blood from 11 different countries with highly varying age-standardized incidence rate (ASR) for colorectal cancer. Matched normal blood samples exhibited a strong intra- and inter-microbial heterogeneity across the 11 countries. In contrast, while CRC tumors exhibited a higher microbial diversity when compared to their matched-normal samples, the top 10 most abundant CRC taxa were strikingly similar across all countries, suggesting a global convergence of the CRC microbiome composition. Moreover, a positive correlation was observed between the colorectal cancer ASR across 11 countries and the CRC microbial diversity (rho=0.91, p-value: 0.0002), suggesting that countries with high incidence rates also have high microbial diversities. After accounting for age, shipment batch, sex, and country-specific effects on the microbiome composition, we observed a core set of five microbial species enriched in CRC across all countries, which included Bacteroides fragilis,Phocaeicola Vulgatus, Faecalibacterium Prausnitzii, Fusobacterium Nucleatum, and Escherichia Coli. A strong correlation (rho=0.84, p-value: 0.0013) was observed between Bacteroides fragilis and a novel mutational signature characterized by A/T[C&amp;gt;G]T and T[T&amp;gt;G]N substitutions. No association was observed between polyketide synthase gene complex (pks)+ microbe and the presence of the pks-derived colibactin mutational signatures. Furthermore, additional associations were observed between the microbiome and other mutational signatures and driver genes. Overall, this study delivers a global atlas of the microbial landscapes of CRC genomes across 11 countries and their links with genetic changes and epidemiological risk factors. Citation Format: Ammal Abbasi, Ludmil Alexandrov. The microbial landscape of colorectal cancer across 11 countries [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB374.
Abstract LB323: Deciphering the immunomodulatory role of IL-19 in glioblastoma-promoting ecosystem: Insights into glioblastoma stem cell-tumor-associated macrophage symbiosis
Authors: Gilbert Aaron Lee, Cheng-Yu Chen
Journal: Cancer Research (2024)

Abstract Glioblastoma multiforme (GBM) stands out as a highly aggressive and resistant brain tumor, characterized by profound immunosuppression and chemoresistance, resulting in a dismal 5% survival rate at the five-year mark. Glioblastoma Stem Cells (GSCs) drive the progression of GBM, orchestrating tumor initiation, growth, and therapeutic resistance. The symbiotic interplay between GSCs and tumor-associated macrophages (TAMs) within hypoxic and perivascular niches is pivotal for sustaining tumorigenesis and immunosuppression. In this study, Interleukin-19 (IL-19), a member of the IL-10 family, was identified among the top five immune-related genes strongly associated with poor survival in patients with GBM from TCGA and Taiwan GBM cohorts. However, the function of IL-19 in glioblastoma is completely unknown. Genomic screening identified IL-19 as a predicted immunosuppressive cytokine in the peritumoral region, associated with poor survival in GBM patients. Blocking IL-19 inhibits both temozolomide (TMZ)-sensitive and TMZ-resistant tumor progression. Molecular studies revealed that IL-19 promotes TMZ-resistant GBM cell migration and invasion through a novel IL-19/β-catenin/WISP1 signaling. Single-cell transcriptome analysis showed that blocking IL-19 promotes T cell activation, upregulates the effector function of T cell subsets, and reprograms TAM subsets toward weakened pro-tumoral phenotypes with lower Arginase 1 expression. Silencing IL-19 significantly disrupts self-renewal GSC activity through a novel IL-19/S100A4/WISP1 signaling. Additionally, we identified that TAM-derived IL-19 positively regulates GSC self-renewal through the paracrine IL-19/WISP1 axis. Our study demonstrates IL-19 as a linchpin in the complex GSC-TAM symbiosis, leading to GSC maintenance and immunosuppression, providing critical insights into the immune landscape orchestrated by GSC-TAM symbiosis Citation Format: Gilbert Aaron Lee, Cheng-Yu Chen. Deciphering the immunomodulatory role of IL-19 in glioblastoma-promoting ecosystem: Insights into glioblastoma stem cell-tumor-associated macrophage symbiosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB323.
Abstract SY03-03: Thinking outside the chromosome: Interrogating epigenetic mechanisms in noncanonical chromatin species
Authors: Yael David
Journal: Cancer Research (2024)

Abstract The epigenetic regulation of DNA-templated processes is intricately tied to numerous events that determine cell phenotype and fate. The abrogation of epigenetic cascades drives various disease states, including cancer. Many of these pathological phenomena involve major chromosomal arrangements that can include the generation of non-canonical chromatin structures existing in the primary nuclei or encapsulated in spatially distinct micronuclei. Recently, we undertook a mechanistic approach to investigate the properties of unique non-chromosomal structures, revealing significant epigenetic contributions to their regulation. We found that micronuclei, the result of chromosomal instability in cancer, assume altered epigenetic landscapes upon departure from the nucleus. Moreover, chromosomes sequestered in micronuclei retain the epigenetic "scars" after reintegration into the primary nucleus, contributing to epigenetic reprogramming and heterogeneity in cancer. Additionally, we turned our attention to the Hepatitis B Virus' (HBV) covalently closed circular DNA (cccDNA) minichromosome, which forms from viral DNA and human histones following infection. We found that chromatinization drives the expression of the key viral oncogene, HBx, and thus promotes viral infection. Elucidating this new mechanism enabled us to halt infection by inhibiting histone remodeling, creating a potential first-in-class therapy for HBV. These exciting findings demonstrate the key role of chromatin in biomedical events and how a fundamental understanding of these processes can lead to the identification of new therapeutic avenues. Citation Format: Yael David. Thinking outside the chromosome: Interrogating epigenetic mechanisms in noncanonical chromatin species [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr SY03-03.
Abstract LB091: A multigene signature for immunotherapy in patients with high risk non-muscle-invasive bladder cancer
Authors: Seung-Woo Baek, Seon-Kyu Kim, Sun-Hee Leem, In-Sun Chu
Journal: Cancer Research (2024)

Abstract Introduction: Approximately 80% of bladder cancer patients are initially diagnosed with non-muscle invasive bladder cancer (NMIBC). However, most NMIBC patients have a high recurrence rates, and up to 45% progress to muscle-invasive bladder cancer (MIBC) and metastatic disease. Treatment for NMIBC includes transurethral resection and, depending on the risk of recurrence or progression, intravesical chemotherapy or immunotherapy, such as Bacillus Calmette-Guérin(BCG). Our aim is to use a multigene signature in patients with high-risk NMIBC to determine whether patients may benefit from improved ICIs compared to conventional PD-L1 expression and to evaluate the clinical utility. Methods: A multi-gene signature obtained from the various NMIBC data was applied to stratify the UROMOL2021 cohort (n=535) using consensus clustering. Each subtype was distinguished by biological pathway analysis. Validation analysis was performed in three independent cohorts including the IMvigor210 (n=298), IMvigor010 (n=377) and ABACUS (n=148) clinical trials treated with PD-L1 inhibitors. The log-rank test, chi-square test, Fisher’s exact test, and cox regression analysis were used to evaluate clinical utility. Results: Based on consensus cluster analysis, NMIBC patients in the UROMOL2021 cohort were classified into five subgroups exhibiting unique characteristics, including DNA damage repair (DDR). Cross-validation was performed using two independent NMIBC cohorts and one MIBC cohort. Survival analysis showed that the subgroup associated with DDR (DDR and DDR+Tcell) had the highest rates of relapse and disease progression (progression-free survival, p&amp;lt;0.001) and benefited from Immune checkpoint inhibitors (ICIs) (response, p=0.01; overall survival, p=0.004). Conclusions: This study suggests that the multi-gene signature may play a role to enhance the responsiveness of ICIs for high-risk NMIBC. Additionally, it is important to help improve ICI treatment approaches that currently focus on PD-L1 expression on cancer cells, allowing more patients to receive priority consideration for ICI therapy. Citation Format: Seung-Woo Baek, Seon-Kyu Kim, Sun-Hee Leem, In-Sun Chu. A multigene signature for immunotherapy in patients with high risk non-muscle-invasive bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB091.