tbuckley/cabot-search huggingface dataset:
Abstract 6159: Single cell analysis of circulating peripheral blood mononuclear cells in African American men with prostate cancer and their association with lethal disease
Authors: Md Shakir Uddin Ahmed, Tiffany Dorsey, Stefan Ambs
Journal: Cancer Research (2024)

Abstract Prostate cancer is a leading cause of cancer-related deaths among men in the United States and affects African American (AA) men more so than other men. We and others previously described a distinct tumor immunobiology in AA prostate cancer patients. Furthermore, we discovered a serum proteome-defined suppression of tumor immunity signature that is prevalent among these patients and associated with lethal prostate cancer. In the current study, we sought to investigate the composition of circulating peripheral blood mononuclear cells (PBMCs) in AA and European American (EA) prostate cancer patients and their association with patient group and lethal prostate cancer. We obtained high-quality RNA-sequencing data for 277336 single cells representing circulating PBMCs from 59 AA and EA men. In the analysis, being an AA patients associated with an increased abundance of exhausted T cells, higher numbers of plasma B cells and CD16+ monocytes. Gene signatures indicative of T cell exhaustion and Treg activity were generally elevated in AA PBMCs while T cell effector function features were decreased. Within the overall cell population, interferon gene signatures were robustly elevated in AA than EA patients. This gene signature pattern that we observed in AA patients also associated with lethal prostate cancer, namely the T cell exhaustion, Treg activity and elevated interferon signaling gene signatures, may contribute to immune dysfunction and immune injury; pointing to potential clinical implications. Lastly, the interferon-induced transmembrane protein (IFITM3), interferon alpha inducible protein (IFI6), cysteine rich protein-1 (CRIP1), and the RAC family small GTPase2 (RAC2) were notably upregulated in AA patient-derived immune cells. In summary, we show that circulating immune cell populations and the associated gene signatures differ between men of African and European descent. Those elevated in AA patients correlated with lethal prostate cancer. Citation Format: Md Shakir Uddin Ahmed, Tiffany Dorsey, Stefan Ambs. Single cell analysis of circulating peripheral blood mononuclear cells in African American men with prostate cancer and their association with lethal disease [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 6159.
Abstract 4309: Establishment of intratumor heterogeneity using patient derived lung cancer cells
Authors: Tomoko Funazo, Hiroaki Ozasa, Takahiro Tsuji, Yusuke Shima, Keiichiro Suminaga, Kentaro Hashimoto, Hiroshi Yoshida, Tatsuya Ogimoto, Kazutaka Hosoya, Hitomi Ajimizu, Takashi Nomizo, Hironori Yoshida, Toyohiro Hirai
Journal: Cancer Research (2024)

Abstract Overcoming cancer treatment resistance is a problem that must be solved to improve the prognosis of cancer patients. In recent years, genome analysis has revealed the existence of multiple subgroups with different properties within a single tumor, and intratumor heterogeneity is a cause of treatment resistance. It has also been reported that. However, the mechanism of intratumor heterogeneity remains unclear. Previous research on intratumor heterogeneity has mainly focused on analyzing patient cancer cells, classifying subgroups, and estimating characteristic factors. This method has two drawbacks. One is limitations in including all subgroups as research subjects, and other is lack of verification of whether characteristic factors are actually involved in intratumor heterogeneity in patients. Therefore, it is necessary to use a model of "early intratumor heterogeneity" in which monoclonal cells are divided into subgroups with different properties, and to verify the discovered factors using patient-derived cancer cell lines. In alectinib-resistant cell line (H2228-AR1S) created from monoclonal ALK-positive lung cancer cell line (H2228) by exposing to alectinib in vitro, existence of two fractions with different appearances. Using flow cytometry, it was revealed that H2228-AR1S bimodally expresses EpCAM, and the EpCAM-low fraction has high migration ability. In EpCAM-low fraction, epithelial markers were decreased, and mesenchymal markers were increased using immunoblotting. It suggests that EpCAM low subpopulation has undergone epithelial-mesenchymal transition (EMT). Additionally, we established a BRAF-positive lung cancer cell line (KTOR83) collected with consent from patients attending Kyoto University Hospital. Cells after in vitro dabrafenib exposure to KTOR83 showed bimodal EpCAM expression, and the EpCAM-low fraction has high migration ability. We established an intratumor heterogeneous model using commercially available cells and a patient-derived lung cancer cell line. Furthermore, we will explore factors common to the two models and examine factors involved in intratumor heterogeneity. Citation Format: Tomoko Funazo, Hiroaki Ozasa, Takahiro Tsuji, Yusuke Shima, Keiichiro Suminaga, Kentaro Hashimoto, Hiroshi Yoshida, Tatsuya Ogimoto, Kazutaka Hosoya, Hitomi Ajimizu, Takashi Nomizo, Hironori Yoshida, Toyohiro Hirai. Establishment of intratumor heterogeneity using patient derived lung cancer 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 4309.
Abstract 2409: Circulating differential methylation allele fraction (DMAF) strongly correlates with circulating tumor DNA (ctDNA) variant allele fraction (VAF)
Authors: Preethi Srinivasan, Tzu-Chun Chen, Ehsan Haghshenas, Misagh Kordi, Ilker Tunc, Wenching Chan, Omid Shams Solari, Joshua Babiarz, Yoshiaki Nakamura, Takayuki Yoshino, Alexey Aleshin, Trupti Kawli, Johannes G. Reiter
Journal: Cancer Research (2024)

Abstract Measurement of ctDNA has been established as a prognostic biomarker of cancer disease burden. Emerging evidence has demonstrated that differential methylation patterns can serve as an accurate biomarker both for cancer detection and for predicting the tissue of origin. While it is important to distinguish cancer-positive from cancer-negative patients, clinical decision making increasingly depends on the exact level of the measured biomarker. To that end, we report on the correlation between ctDNA VAF and DMAF across patients with colorectal cancer (CRC). Pre-surgical plasma samples from patients with CRC (N=70) were sourced from the prospective GALAXY, observational arm of ongoing CIRCULATE-Japan study trial (UMIN000039205). Samples classified as ctDNA-positive by a tumor-informed ctDNA assay (SignateraTM) were included in this analysis and ctDNA VAF (%) was calculated. We performed deep methylation sequencing (Illumina Novaseq) across multiple target regions using two independent target sets. DMAF was calculated computationally, which estimates the fraction of differential methylation alleles for circulating cell-free DNA across target regions. Among 70 CRC patients, 68 had positive ctDNA results. Median age at testing was 64.0 years and male individuals represented 55.9% (n=38) of the cohort. Among them, 9 (13.2%) were stage I, 24 (35.3%) were stage II, 22 (32.3%) were stage III, 8 (11.7%) were stage IV, and 5 (7.3%) had unknown staging. The correlation of DMAF with ctDNA VAF was 0.894 (Spearman’s Rank Correlation Coefficient) and was independent of disease stage, histology, age, and sex. Among MSS (micro-satellite stable; n=58) and MSI-H (micro-satellite unstable n=10) patients, the DMAF correlation was 0.9 and 0.915, respectively. The correlation between two target sets evaluating DMAF with differing numbers of targeted regions was high (0.89). These data demonstrate that abundance of differential methylation in CRC patients correlates with VAF regardless of clinicopathologic features of patients with CRC. Methylation-based assays are a promising tool for cancer detection and quantifying the disease burden. Citation Format: Preethi Srinivasan, Tzu-Chun Chen, Ehsan Haghshenas, Misagh Kordi, Ilker Tunc, Wenching Chan, Omid Shams Solari, Joshua Babiarz, Yoshiaki Nakamura, Takayuki Yoshino, Alexey Aleshin, Trupti Kawli, Johannes G. Reiter. Circulating differential methylation allele fraction (DMAF) strongly correlates with circulating tumor DNA (ctDNA) variant allele fraction (VAF) [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 2409.
Abstract 6499: The landscape of MET exon 14 skipping mutations in non-small cell lung cancer patients identified by next-generation sequencing
Authors: Chen Shi, Gao Ning, Zong Qinglan
Journal: Cancer Research (2024)

Abstract Background: MET exon 14 skipping mutations (METex14) account for approximately 0.9%-4% in patients with non-small cell lung cancer (NSCLC). The primary detection methods are DNA and RNA-based next-generation sequencing (NGS). However, the effect of amplicon-based library construction (ALC) and capture-based library construction (CLC) on the detection characteristics of METex14 during the NGS process is not yet fully understood. Here we described the landscape of METex14 in NSCLC patients, as identified by NGS using two different library construction methods. Methods: A total of 6811 samples with NSCLC were enrolled in this study, including 3839 samples performed by DNA-based NGS with CLC, 64 samples performed by RNA-based NGS with CLC and 2908 samples performed by the synchronous DNA-based and RNA-based NGS with ALC. Only the pathogenic mutations and likely pathogenic mutations in clinical significance were rolled into our analysis. Results: The ranking of different methods, as determined by the positive rates for METex14, was RNA-based NGS with ALC (71/2908, 2.44%), RNA-based NGS with CLC (1/64, 1.56%), DNA-based NGS with CLC (54/3839, 1.41%) and DNA-based NGS with ALC (14/2908, 0.48%). Out of 2908 samples performed by the synchronous DNA-based and RNA-based NGS with ALC, 73 samples (2.51%) had METex14 detected at either the DNA or RNA level. METex14 were only detected at the RNA level in 59 patients, while they were only detected at the DNA level in 2 patients. This might be due to the limited probe design at DNA level and the Y1003 site which could not be detected at RNA level. As revealed by DNA-based NGS, the mutation forms causing METex14 include point mutations, indels, and large segment duplications. And the highest mutation rate is in the splice donor site (30.9%), the lowest is observed at position Y1003 (2.9%). Additionally, METex14 is more prevalent in patients over 60 years of age in Chinese NSCLC, with a statistically significant difference (P=0.0043). Conclusion: RNA-based detection of MET 14 skipping yielded a higher detection rate compared to DNA-based NGS, regardless of ALC or CLC. Combining DNA and RNA analysis is more suitable for detecting MET exon 14 skipping and increases the positive rate. Citation Format: Chen Shi, Gao Ning, Zong Qinglan. The landscape of MET exon 14 skipping mutations in non-small cell lung cancer patients identified by next-generation 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 6499.
Abstract 6506: SOS1 inhibition in combination with HER2 inhibition in models of HER2-driven cancer
Authors: Robyn L. Schenk, Kaja Kostyrko, Johannes Popow, Christina Gewinner, Anke Baum, Christoph Albrecht, Melanie Hinkel, Robin Jacob, Tom Madensky, Regina Ruzicka, Eva Strauss, Hengyu Lyu, Anastasia M. Lopez, Ningping Feng, Christopher P. Vellano, Joseph R. Marszalek, Timothy P. Heffernan, Mark Pearson, Marco H. Hofmann
Journal: Cancer Research (2024)

Abstract Cancers driven by amplifications or mutations of the gene ERBB2 (coding for the receptor tyrosine kinase (RTK) HER2) have been the focus of HER2-targeting antibodies as well as small molecule inhibitors. Despite initial efficacy, resistance to these HER2-targeted therapies inevitably develops. One strategy to tackle this resistance is to identify rational combinations to address common pathways/factors that contribute to resistance. One such common mechanism of resistance is reactivation of the Mitogen-activated protein kinase (MAPK) pathway. SOS1 is a guanine nucleotide exchange factor (GEF) which regulates the MAPK pathway by catalyzing the exchange of RAS-GDP (inactive) to RAS-GTP (active). SOS1 is activated by multiple different RTKs - upon RTK-ligand binding, autophosphorylation of the RTK recruits the GRB2-SOS1 protein complex to the plasma membrane, enabling the complex to bind and activate RAS-GDP. Given SOS1’s role downstream of RTKs and upstream of the MAPK pathway, we sought to investigate the potential of a SOS1 inhibitor (SOS1i) in combination with a HER2 inhibitor (HER2i) in preclinical models of cancer driven by HER2 mutation or gene amplification. Using in vitro and in vivo models we found evidence of added benefit of SOS1i in combination with HER2i, as well as enhanced inhibition of MAPK signaling, as seen by decrease in ERK activation and expression of MAPK effector genes such as DUSP6. Taken together, we propose that SOS1 inhibition combined with HER2 inhibition may be a rational strategy for deeper and more prolonged responses to HER2 inhibitor treatment by preventing resistance via the MAPK pathway. Citation Format: Robyn L. Schenk, Kaja Kostyrko, Johannes Popow, Christina Gewinner, Anke Baum, Christoph Albrecht, Melanie Hinkel, Robin Jacob, Tom Madensky, Regina Ruzicka, Eva Strauss, Hengyu Lyu, Anastasia M. Lopez, Ningping Feng, Christopher P. Vellano, Joseph R. Marszalek, Timothy P. Heffernan, Mark Pearson, Marco H. Hofmann. SOS1 inhibition in combination with HER2 inhibition in models of HER2-driven 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 6506.
Abstract 107: Application of MSD on the lung cancer associated idiopathic pulmonary fibrosis
Authors: Wei Bao, Ying-Ji Li, Jin-Fan Gu, Cong-Lin Yang, Yi-Da Wang, Tie-Jun Bing, Wen-Jen Yu
Journal: Cancer Research (2024)

Abstract Idiopathic pulmonary fibrosis (IPF) is a progressive and irreversible chronic disease that kill ten thousand of people in China every year. The risk of IPF is highly correlated with smoke, air pollution, dust, virus infection and aging. Average survival period of patients diagnosed as IPF is around 2.8 years which is less than several types of cancers, therefore, IPF is also thought to be a lung cancer-like disease. In the past few decades, many animal models were created to mimic human IPF, however, induction materials, animal species and strain differences, sex, physiology structure and progress of disease make the choice of IPF animal models selection more difficult. In addition, lack of strong evidence of cytokines biomarker detection hampered the discovery of anti-IPF drugs. Meso Scale Discovery (MSD) instrument is an efficient tool to high throughput analyze the lowest level of several cytokines and other biomarkers in the same time and was used to detect the bleomycin (BLM) induced mouse lung fibrosis. Meanwhile, animal sex and dose effects of BLM were also tested to define the proper mouse model for anti-IPF drugs development. Our results indicated that 0.6-0.8 mg/kg of intratracheal injection of single dose BLM is sufficient to create the IPF model without sex differences by examining the lung weight, lung ratio, soluble hydroxyproline, HE staining and mason staining. However, male mice were more resistant to the lethal effect of BLM due to the larger size or bodyweight. Using MSD detection, several mouse cytokines were measured simultaneously and showed that IFN-γ, IL-5, TNF-α, and IL-10 were increased in the IPF mouse model and were recovered after pirfenidone treatment at day 14 which mimics the cytokines profile in IPF patients. In summary, the MSD detection and pathological evaluation prove that male mouse treated with 0.8 mg/kg BLM through intratracheal injection is a suitable mouse model for the development of anti-IPF dugs. Citation Format: Wei Bao, Ying-Ji Li, Jin-Fan Gu, Cong-Lin Yang, Yi-Da Wang, Tie-Jun Bing, Wen-Jen Yu. Application of MSD on the lung cancer associated idiopathic pulmonary fibrosis [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 107.
Abstract 2978: Extracellular ATP induced senescence in human lung cancer cells
Authors: Ryan A. Ward, Arabella Hunt, Nora Anderson, Xiaozhuo Chen
Journal: Cancer Research (2024)

Abstract In tumors, extracellular ATP (eATP) concentrations are 1,000 to 10,000 times higher than is found in normal tissues and eATP is up taken through macropinocytosis leading to a large increase in intracellular ATP levels. eATP is also linked to the TGF-β signaling pathway as exocytosis of ATP is induced that is then used in an autocrine fashion activating the P2 × 7 purinergic receptor1. Through these mechanisms, eATP has also been recently shown to induce EMT, CSC formation, and drug resistance1. One of the mechanisms through which these processes may be induced is a senescent cell precursor2. Senescence is a generally irreversible epigenetically controlled process characterized by a complete exit from the cell cycle in response to either DNA damage, stressful conditions, or aging. Recent mounting evidence has shown that senescence can be a cancer promoting mechanism by entering this state in response to stress such as during chemotherapy, but they can utilize it to enhance their malignant capabilities, including the ability to escape their senescent state with heightened stem cell characteristics, which can lead to a higher chance of relapse after treatment2. Senescent cells have recently been named a hallmark of cancer3. This study shows the time dependent induction of a senescent like state in human lung cancer A549 cells after only 2 hours of treatment with 0.5mM eATP, the concentration found in the tumor microenvironment, through analysis of transcriptional markers using total polyA RNAseq as well as chromogenic and flow cytometric assays for senescence associated beta-galactosidase activity. Additionally, inhibitors of macropinocytosis and purinergic receptors have been used to gain insight into the mechanisms of action that this pathway takes. This demonstrates a novel use of ATP within the tumor microenvironment for aiding in cancer progression and drug resistance. After EMT, CSC formation, and drug resistance, senescence is added to the long list of eATP mediated cancer promoting processes. 1. Song J, Qian Y, Evers M, Nielsen CM, Chen X. Cancer Stem Cell Formation Induced and Regulated by Extracellular ATP and Stanniocalcin-1 in Human Lung Cancer Cells and Tumors. IJMS. 2022;23(23):14770. doi:10.3390/ijms232314770 2. Zhang D, Monteiro MJ, Liu J, Gu W. Mechanisms of cancer stem cell senescence: Current understanding and future perspectives. Clin Exp Pharma Physio. 2021;48(9):1185-1202. doi:10.1111/1440-1681.13528 3. Hanahan D. Hallmarks of Cancer: New Dimensions. Cancer Discovery. 2022;12(1):31-46. doi:10.1158/2159-8290.CD-21-1059 Citation Format: Ryan A. Ward, Arabella Hunt, Nora Anderson, Xiaozhuo Chen. Extracellular ATP induced senescence in human lung cancer 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 2978.
Abstract 5067: Exploring the genomic landscape of de novo neuroendocrine prostate cancer: Insights for innovative therapies from spatial gene expression analysis
Authors: Ryuta Watanabe, Noriyoshi Miura, Mie Kurata, Riko Kitazawa, Tadahiko Kikugawa, Takashi Saika
Journal: Cancer Research (2024)

Abstract Introduction &amp; Objectives Neuroendocrine prostate cancer (NEPC) accounts for less than 1% of all prostate cancers but has a worse prognosis than androgen receptor-positive prostate adenocarcinoma (ARPC). Rare cases exist where both de novo NEPC and ARPC are found in the same tissue sample. Our study examines one such unique case: a 78-year-old male treated at Ehime University Hospital who was diagnosed with both ARPC and adjacent de novo metastatic NEPC. This case provides an excellent opportunity for studying gene expression in these two types of prostate cancer. Materials &amp; Methods We used Visium CytAssist Spatial Gene Expression technology from 10x Genomics to analyze formalin-fixed, paraffin-embedded (FFPE) tissue samples from this unique patient. Results We observed elevated expression levels of specific neuroendocrine markers like PEG10, DLL3, NCAM1, SYP, and CHGA in de novo NEPC regions. In contrast, androgen receptor markers such as KLK3, ACPP, TMPRSS2, and NKX3.1 were more prevalent in ARPC areas. Furthermore, genes like Chek1, BRCA1/2, TOP2A, and FANCA were also elevated in NEPC, suggesting that PARP and TOP2 inhibitors could be effective. Expression levels of Rbfox3 and SFRTM2 were lower in NEPC areas, implying possible roles in epithelial-mesenchymal transition (EMT) and Wnt signaling pathways. Additionally, fibrotic markers like HGF, HMOX1, ELN, and GREM1 were upregulated, suggesting that de novo NEPC tumors might be 'immune cold,' thus requiring treatments to boost the effectiveness of immune checkpoint inhibitors. Conclusion The data from additional cases could open the door for new treatment options for NEPC and improve survival rates for castration-resistant prostate cancer patients. Our research serves as a pioneering application of Visium CytAssist on FFPE samples and is the first to examine gene expression in both ARPC and de novo NEPC. A subset of these findings was published in the International Journal of Molecular Science (IJMS) in May 2023. Citation Format: Ryuta Watanabe, Noriyoshi Miura, Mie Kurata, Riko Kitazawa, Tadahiko Kikugawa, Takashi Saika. Exploring the genomic landscape of de novo neuroendocrine prostate cancer: Insights for innovative therapies from spatial gene expression analysis [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 5067.