tbuckley/cabot-search huggingface dataset:
Abstract 5286: The acquisition of CD11a via trogocytosis by gastric cancer cells after contact with T cells increases adhesion to endothelial cells
Authors: Hideyo Miyato, Eri Suizu, Rei Takahashi, Misaki Matsumiya, Hirofumi Sonoda, Hideyuki Ozawa, Hironori Yamaguchi, Naohiro Sata, Joji Kitayama
Journal: Cancer Research (2025)

It has been revealed that plasma membrane and membrane molecules are frequently transferred upon cell-to-cell contact, which is named as trogocytosis, and that this phenomenon between immune cells plays an important role in the immune responses. However, the physiological roles of trogocytosis between cancer cells and immune cells are poorly understood. In this study, we hypothesized that the transfer of membrane molecules from immune cells to cancer cells arrows cancer cells to acquire the functions involved in extravasation, which results in increased metastatic ability. Gastric cancer cell line, OCUM-1 was co-cultured with T cells whose plasma membrane was stained with PKH26. Flowcytometric analysis revealed that OCUM-1 became positive for PKH26 at 3 hours and the positive rate increased over time. The acquisition of PKH26 was dependent on cell-to-cell contact and suggested to be attributed to trogocytosis. Among various immunological synapse molecules of T cells, OCUM-1 came to express CD45, CD3, CD4 and CD11a after 8 hours of coculture (positive rate, CD45: 64.0%, CD3: 36.0%, CD4: 11.3%, CD11a: 16.8%). We focused on CD11a, which belongs to β2 integrins and aids immune cells to adhere endothelial cells and extravasate. After co-culture OCUM-1 with T cells on which CD11a was fluorescently labelled with anti-CD11a antibody, CD11a was transferred from T cells to OCUM-1. The expression level of CD11a on OCUM-1 was accelerated after co-culture with activated T cells (positive rate, with T cells: 12.6% vs with activated T cells: 65.9%) and the adhesion rate on endothelial cells increased in a CD11a dependent manner (adhesion rate, monoculture: 2.0±0.64%, co-culture: 6.3±2.0%, co-culture (pre-treat with CD11a antibody): 2.3±1.4%, n=10, monoculture vs co-culture: p&amp;lt;0.0001, co-culture vs pre-treat: p&amp;lt;0.0001).These results suggest that after escape from attack of T cells, cancer cells could acquire CD11a from T cells and increase the adhesive property on endothelial cells of target organs, which might result in promotion of intravenous metastasis. Citation Format: Hideyo Miyato, Eri Suizu, Rei Takahashi, Misaki Matsumiya, Hirofumi Sonoda, Hideyuki Ozawa, Hironori Yamaguchi, Naohiro Sata, Joji Kitayama. The acquisition of CD11a via trogocytosis by gastric cancer cells after contact with T cells increases adhesion to endothelial cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5286.
Abstract 5731: BGB-C354, a novel B7H3 ADC with high DAR stability and strong bystander effect, demonstrates robust antitumor activity in preclinical models
Authors: Xiao Ding, Charng-Sheng Tsai, Mei-Hsuan Tsai, Maggie Tang, Liu Xue, Chi Guan, Meiling Tan, Yiren Xiao, Yuanyuan Xie, Kunpeng Lyu, Xiaotong Chen, Wenhao Li, Qi Liu, Yun Chen, Jie Pan, Wenjin Yao, Yang Lyu, Kaiying Jia, Chang Song, Weiwei Song, Ce Wang, Fan Wang, Zhitao Wan, Mingming Guo, Beibei Jiang, Xiaomin Song, Wei Jin, Qiansheng Ren, Yu Shen, Zhirong Shen
Journal: Cancer Research (2025)

Abstract B7H3 is a type I transmembrane protein belonging to the B7 immunoregulatory family. B7H3 is overexpressed on a wide range of solid tumors such as lung cancers, gastrointestinal cancers and gynecological cancers, but its expression is absent or low in normal tissues, making it an attractive target for anticancer therapies. BGB-C354 is a B7-H3-targeting antibody-drug conjugate (ADC) composed of a humanized anti-B7-H3 monoclonal antibody conjugated via a cleavable linker to a novel TOP1i payload, and the drug to antibody ratio (DAR) is approximately 8. Utilizing a stable ring-open conjugator, BGB-C354 demonstrated improved ADC stability and sustained high DAR in vivo, which may enable more efficient payload delivery to B7H3-expressing tumors. In nonclinical pharmacological studies, BGB-C354 exhibited strong target binding activity, high target-dependent internalization, and potent cytotoxicity toward B7H3-expressing tumor cells. In addition, BGB-C354 demonstrated strong bystander killing effect in the presence of B7H3-expressing cell lines to potentially overcome the tumor heterogeneity. Notably, robust anti-tumor activity was observed in a panel of cell-derived xenograft (CDX) models with varying levels of B7-H3 expression, as well as in patient-derived xenograft (PDX) models. Consistent with its mechanism of action, DNA damage and apoptosis biomarker changes were induced by BGB-C354 in a dose-dependent manner after single dosing in preclinical models. Recently, a phase I study of BGB-C354 has been initiated to investigate its potential safety and preliminary efficacy in patients with B7H3-expressing advanced solid tumors (NCT06422520). Citation Format: Xiao Ding, Charng-Sheng Tsai, Mei-Hsuan Tsai, Maggie Tang, Liu Xue, Chi Guan, Meiling Tan, Yiren Xiao, Yuanyuan Xie, Kunpeng Lyu, Xiaotong Chen, Wenhao Li, Qi Liu, Yun Chen, Jie Pan, Wenjin Yao, Yang Lyu, Kaiying Jia, Chang Song, Weiwei Song, Ce Wang, Fan Wang, Zhitao Wan, Mingming Guo, Beibei Jiang, Xiaomin Song, Wei Jin, Qiansheng Ren, Yu Shen, Zhirong Shen. BGB-C354, a novel B7H3 ADC with high DAR stability and strong bystander effect, demonstrates robust antitumor activity in preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5731.
Abstract 4134: An inhibitor of the atypical protein kinase C-ζ impede the growth of gastric cancer cells by inducing apoptosis
Authors: Abiral Hasib Shourav, Abigail Olatunji, Mahfuza Marzan, Radwan Ebna Noor, Mildred Acevedo-Duncan
Journal: Cancer Research (2025)

The global statistics on gastric cancer suggest that it is the fifth most common type of cancer in terms of prevalence and third-most common type in terms of death rate. The considerably high mortality of gastric cancer is mainly because of the fact that it is mostly diagnosed when the disease has progressed to the advanced stage. While the bacterium Helicobacter pylori is known to be the most common cause of gastric cancer, other notable risk factors also include high salt intake, age and diets lacking in fruits and vegetables. Demographic data have revealed that the regions of East Asia, Eastern Europe and South America are notable hotspots of this type of cancer. Endoscopic resection is considered as the major treatment procedure for early detected gastric cancer while those diagnosed in later stages are treated with surgeries such as D2 lymphadenectomy. Previously, the Atypical Protein Kinases C (aPKCs) - ζ and ι - have been documented to play significant roles in elevated cell proliferation in various cancer types. Here, an inhibitor of the aPKC-ζ, known as ζ-stat (8-hydroxy-1,3,6- naphthalenetrisulfonic acid), that specifically inhibits the aPKC-ζ on a gastric cancer cell line (i.e., AGS) was used to observe its effects on cell proliferation. In separate trials, AGS cells were treated with ζ-stat for 72 hours (about 3 days). An assortment of drug concentrations for the inhibitor was tried and the analysis of the cell count demonstrated that the cell proliferation decreases were statistically significant for the drug in all concentrations. The highest decrease was observed at 10 µM (P &amp;lt; 0.0001) as the number of cells diminished to approximately 44%. Our previous research has revealed that ζ-stat downregulates the aPKC-ζ by interfering with established cancer pathways to cause cell deaths. Henceforth, Western Blot analysis of AGS cells treated with ζ-stat have shown evidence of apoptosis. There have been considerable decreases in the levels of total PARP, Caspase 3 and Survivin. Likewise, levels of cleaved-Caspase 3 and cleaved-PARP have also increased along with the mitochondrial apoptotic marker Cytochrome C. Current investigations include how ζ-stat play into some of the well-established gastric cancer pathways to lead to cell deaths with techniques such as Western Blot analysis, Immunoprecipitation Assays and Flow cytometry. Citation Format: Abiral Hasib Shourav, Abigail Olatunji, Mahfuza Marzan, Radwan Ebna Noor, Mildred Acevedo-Duncan. An inhibitor of the atypical protein kinase C-ζ impede the growth of gastric cancer cells by inducing apoptosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4134.
Abstract 2422: Fine-grained inflammatory cell segmentation in histopathology with deep learning
Authors: Pierre-Antoine Bannier, Benjamin Adjadj, Sebastien Mandela, Guillaume Horent, Thomas Mathieu, Ulysse Marteau, Valentin Gaury, Laura Dumont, Aurore Lyon, Reda Belbahri, Benoit Schmauch, Kathryn Schutte, Lucie Gillet, Katharina Von Loga, Caroline Hoffmann
Journal: Cancer Research (2025)

Abstract Introduction: Deep learning can advance clinical research by improving patient subtyping and uncovering biological insights. However, many models have limited interpretability, reducing clinical utility. To address this, we developed a model that detects, segments, and classifies cells on hematoxylin and eosin (H&amp;E) slides, including understudied types like neutrophils, eosinophils, and plasmocytes, enabling novel biomarkers related to the tumor microenvironment (TME). Methods: We collected a novel training set composed of 1,479 patches of size 112μm x 112μm from H&amp;E-stained TCGA slides across five indications: bladder cancer (n=400), colon adenocarcinoma (n=242), lung adenocarcinoma (n=231), lung squamous cell carcinoma (n=220), and mesothelioma (n=386). We collected two external validation sets including patches from muscle invasive bladder cancer (MIBC) (n=79) and mesothelioma (n=48) cohorts. For both training and validation, three expert pathologists annotated cells into seven classes: cancer cells, lymphocytes, fibroblasts, neutrophils, eosinophils, plasmocytes, and others. We used a consensus rule to resolve discrepancies at the cell level between pathologists. In total, 151,404 nuclei were annotated in the training set and 9,565 in the validation set. We trained a model in 3-fold cross-validation on the training set. We independently evaluated its performance on our validation sets and on the Lizard dataset (colorectal cancer). For each cell type we report the panoptic quality (PQ), which combines detection accuracy and segmentation quality. Results: Conclusion: Our model demonstrates consistent performance across multiple validation cohorts, including understudied cell types for which it even outperforms models trained in-domain on Lizard. This reliability highlights its potential for broader clinical applications. By enabling the identification of immune cells, the model paves the way for designing novel interpretable TME-related biomarkers. Citation Format: Pierre-Antoine Bannier, Benjamin Adjadj, Sebastien Mandela, Guillaume Horent, Thomas Mathieu, Ulysse Marteau, Valentin Gaury, Laura Dumont, Aurore Lyon, Reda Belbahri, Benoit Schmauch, Kathryn Schutte, Lucie Gillet, Katharina Von Loga, Caroline Hoffmann. Fine-grained inflammatory cell segmentation in histopathology with deep learning [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2422.
Abstract 4127: Oncogenic BRAF suppresses p53 function in melanoma through direct protein protein interaction
Authors: Kayla T. O'Toole, Adamaris Martinez, Brandon Murphy, Deevya Baral, Anastasia Proveyeka, Fatima Al-Sudani, Joshua Andersen, Robert Judson-Torres, Martin McMahon
Journal: Cancer Research (2025)

Oncogenic BRAF is a driver of approximately 8% of all cancers, with a particular prevalence in lung cancer, thyroid cancer, and cutaneous melanoma. BRAFV600E is the most common oncogenic alteration, accounting for about 50% of cutaneous melanoma cases. Combined inhibition of BRAFV600E plus MEK1/2 is the current targeted therapeutic option approved for the treatment of BRAFV600E-driven melanoma and lung cancer. Unfortunately, many patients only experience short-term therapeutic benefit with a mean progression-free survival of 7 to 14 months in non-small cell lung cancer and melanoma, respectively. Thus, this highlights the need to identify better therapeutic targets for BRAF-driven cancers. BRAFV600E is often referred to as a monomer as BRAFV600E signals independent of RAS-GTP and RAF dimerization. However, oncogeneic BRAF may still be dependent on other scaffolding proteins for optimal signaling. Thus, to evaluate this, we used gel filtration chromatography and immunoblotting analysis to visualize BRAF signaling complexes. These data revealed that BRAFV600E exists in a large multiprotein complex. Pharmacological inhibition of BRAFV600E shifted the elution of BRAFV600E complexes into lower molecular weight fractions. We further investigated this BRAFV600E signaling complex by implementing the proximity labeling technique, TurboID. Coupled with mass spectrometry, this technique enabled the unbiased identification of novel BRAF interactors and helped us understand how targeted therapy impacts this BRAF interactome. Here, we identified a multitude of unique wild-type BRAF and BRAFV600E interactors, with the tumor suppressor p53 being of particular interest. Intriguingly, TP53 alterations are infrequent in melanoma, prompting the hypothesis that by interacting with p53, BRAFV600E may influence p53 function. We show that BRAFV600E expression alters p53 subcellular localization, significantly reduces native p53 activity, and prevents p53 activation following UVB radiation and MDM2 inhibition. Ultimately, these findings provide unique mechanistic insight into the mechanisms by which BRAFV600E drives cancer development and may clarify why TP53 is infrequently altered in melanoma. Citation Format: Kayla T. O'Toole, Adamaris Martinez, Brandon Murphy, Deevya Baral, Anastasia Proveyeka, Fatima Al-Sudani, Joshua Andersen, Robert Judson-Torres, Martin McMahon. Oncogenic BRAF suppresses p53 function in melanoma through direct protein protein interaction [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4127.
Abstract 4290: Long chain fatty acid elongase 6 is a novel therapeutic target for breast cancer
Authors: Linxiang Gong, Susumu Kohno, Chiaki Takahashi
Journal: Cancer Research (2025)

Abstract Cancer cells alter the quality of lipids to grow and survive. De novo synthesized fatty acids need to be elongated to provide numerous varieties to lipids. Despite the critical functions of lipid metabolism in cell function, how specific elongase contributes to tumor progression remains incompletely understood. In breast cancer (BRCA), retinoblastoma 1 (RB1) mutation or deletion is considered as one of the key factors promoting tumor progression. We previously reported that loss of RB1 transcriptionally upregulates the elongation of long chain fatty acid family member 6 (ELOVL6). We observed that BRCA cells with lower RB1 expression tend to show high ELOVL6 expression. ELOVL6 inhibition reduced cell proliferation in all subtypes of BRCA cells in vitro and in vivo. Moreover, RB1 loss sensitized these cells to undergo apoptosis following ELOVL6 depletion. These data indicate that ELOVL6 may have synthetic lethal relationship with RB1. We tried to elucidate the mechanism whereby ELOVL6 inhibition causes anti-tumor effects from a metabolic perspective. We noticed that ELOVL6 depletion reduced p-AKT levels in BRCA cells. Using a lipidomic approach, we observed that ELOVL6 depletion caused significant increase in the amount of intracellular ceramide and glycosphingolipids and decrease in sphingomyelin. Cell death associated with enhanced accumulation of ceramide was observed in cells in which both RB1 and ELOVL6 depletion. Inhibition of serine palmitoyltransferase 1 (SPTLC1) restored the p-AKT level and cell proliferation. These results suggest that ELOVL6 inhibition reduces p-AKT level by enhancing ceramide accumulation thereby suppressing cell proliferation. Taken together, our observations suggest that ELOVL6 is a promising therapeutic target in BRCA. Citation Format: Linxiang Gong, Susumu Kohno, Chiaki Takahashi. Long chain fatty acid elongase 6 is a novel therapeutic target for breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4290.
Abstract 5734: Advancing ADC discovery with a highly versatile linker-camptothecin library
Authors: Meijun Xiong, Qingsong Wu, Yanchun Li, Chong Liu, Yajun Sun, Zengyan Mu, Xinju Gao, Yanwen Feng, Haibo He, Paul H. Song, Gang Qin
Journal: Cancer Research (2025)

Abstract Camptothecin derivatives have gained prominence as payloads in investigational antibody-drug conjugates (ADCs), exemplified by the clinical success of Trodelvy and Enhertu. The precise design of these linker-camptothecins has been instrumental in achieving optimal safety and efficacy for specific therapeutic indications. Growing evidence suggests that a single linker-payload design cannot accommodate the diverse requirements of various therapeutic targets. For instance, while the linker-payload of Enhertu (GGFG-DXd) has shown exceptional efficacy in HER2-targeted therapies, its performance is less promising in TROP2- and HER3-targeted indications. This highlights the critical need for linker-camptothecin systems with greater diversity in drug release mechanisms, kinetics, and payload potency to address varying therapeutic needs. To address the limitations of existing linker-camptothecin designs, including issues with stability, release efficiency, and specificity, we have developed a comprehensive library of linker-camptothecins with enhanced molecular diversity. Our design strategy incorporates a range of stimuli-responsive release mechanisms, such as cathepsin-, legumain-, and glucuronidase-mediated cleavage, as well as pH-sensitive linkers. Multiple camptothecin derivatives, including SN38, Exatecan, and TopoIx, were selected based on their distinct pharmacological properties—such as antitumor efficacy, lipophilicity, and half-life—and were conjugated to various linkers, creating a versatile library with broad applicability. This molecular diversity facilitates optimized release profiles and payload activities, tailored to specific therapeutic scenarios. Leveraging this library, we constructed a series of highly refined ADCs targeting different antigens and evaluated them systematically in both in vitro and in vivo preclinical models. These studies revealed that the ADCs incorporating the novel linker-camptothecin designs demonstrated significantly enhanced therapeutic efficacy and improved safety profiles compared to conventional linker-payload systems. In summary, we have established a novel linker-camptothecin library with diverse release behaviors optimized for specific therapeutic contexts. This approach facilitates the discovery and development of potent ADC candidates with superior efficacy and safety profiles, providing a robust platform for precision drug development targeting diverse indications. Citation Format: Meijun Xiong, Qingsong Wu, Yanchun Li, Chong Liu, Yajun Sun, Zengyan Mu, Xinju Gao, Yanwen Feng, Haibo He, Paul H. Song, Gang Qin. Advancing ADC discovery with a highly versatile linker-camptothecin library [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5734.
Abstract 4106: Glutamine deficiency drives epigenetic silencing of <i>GLS2</i> to promote survival and metastasis from the core region of colorectal cancer
Authors: Ji-Yeon Lee, So Hyun Kwon, Su Chan Park, Taehan Yoon, Jumi Kim, Hyunwoo Kim, Eun Jung Park, Ji Min Lee
Journal: Cancer Research (2025)

Abstract Rapid, uncontrolled proliferation is one representative hallmark of cancer. As tumor masses grow, the core regions receive inadequate blood supply, leading to severe nutrients and oxygen deprivation. Glutamine—regarded as non-essential for normal cells—has emerged as a critical nutrient that supports cancer cell metabolism. While glutamine deprivation typically induces cell death in the tumor core, some cancer cells survive by leveraging adaptive epigenetic mechanisms. However, the molecular mechanisms underlying this adaptation remain poorly understood. Using ATAC-seq and RNA-seq analyses, we revealed that glutamine deprivation induces the epigenetic silencing of GLS2, an enzyme that converts glutamine to glutamate, in colorectal cancer cells through increasing H3K27Me3 histone modification. This epigenetic silencing suppresses ferroptosis, an iron-dependent form of cell death, that enables cancer cells to survive and proliferate under glutamine-scarce conditions. With patient-derived colorectal cancer sample, we further confirmed a significant downregulation of GLS2 within the tumor core, specifically in regions that remained actively proliferative despite nutrient deprivation. Additionally, tumor core cells deprived of glutamine exhibited increased invasion and migration abilities, indicating an enhanced metastatic potential towards nutrient-rich compartments or distal sites. Treatment with histone methylation inhibitors successfully reversed GLS2 silencing, restored ferroptosis sensitivity, and suppressed metastatic behavior, which together emphasizes the potential of targeting epigenetic dysregulation as a therapeutic strategy. Combining epigenetic therapies to restore GLS2 expression with ferroptosis-inducing drugs offers a promising, integrative approach to target resilient cancer cells in nutrient-deprived tumor cores. This strategy holds significant clinical potential for improving outcomes in patients with aggressive colorectal cancer, particularly those exhibiting resistance to ferroptosis-targeting anticancer drugs due to metabolism reprogramming. Citation Format: Ji-Yeon Lee, So Hyun Kwon, Su Chan Park, Taehan Yoon, Jumi Kim, Hyunwoo Kim, Eun Jung Park, Ji Min Lee. Glutamine deficiency drives epigenetic silencing of GLS2 to promote survival and metastasis from the core region of colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4106.