tbuckley/cabot-search huggingface dataset:
Abstract 1052: Integrating geographical and socioeconomic data with genomic information for enhanced prediction of cancer risk using large language models and knowledge graphs
Authors: Ofek Mendel, Michael S. Sinclair, Kathleen M. Jagodnik, Till Krenz, Jeronimo Pissinis, Vasileios Stathias, Alon Bartal, Stephan Schürer
Journal: Cancer Research (2025)

Cancer remains a leading cause of mortality worldwide, with risk and survival outcomes influenced by a complex interplay of genetic, environmental, and socioeconomic factors. Traditional cancer risk prediction models often focus on genetic, lifestyle, and family history factors but frequently overlook the critical roles of geographical location and social determinants of health (SDoH). This study introduces a novel approach that integrates diverse multimodal datasets—including environmental exposures, healthcare access, socioeconomic conditions, and genomic data—within a geographic framework to develop more comprehensive and spatially contextualized cancer risk prediction and survival models. First, we developed a data model to integrate the various data modalities. We leverage our internal Sylvester Data Portal Informatics Platform to manage and map the various data types and metadata. Using the GPT-4o Large Language Model, we identified entities and their relationships from semi-structured and unstructured data sources, and used them to construct a multimodal knowledge graph (KG). Our KG comprises 700,000+ nodes spanning 32 entity types (e.g., genes, 5 cancer types) and 2.134 million edges/links across 107 relationship types (e.g., has_genotype, from_race, from_sex). Graph Neural Networks (GNNs) were then trained on this KG to predict cancer risk and survival outcomes based on demographic factors, location, and tumor genetics. Querying our KG using Graph Retrieval Augmented Generation (GraphRAG) and predicting links using our trained GNN, we uncovered novel insights into the relationships among genetics, demographics, environmental exposures, and cancer statistics, highlighting potential complex gene-environment interactions that contribute to cancer risk and survival disparities, and suggesting directions for future research to reduce cancer risk and improve health outcomes. Citation Format: Ofek Mendel, Michael S. Sinclair, Kathleen M. Jagodnik, Till Krenz, Jeronimo Pissinis, Vasileios Stathias, Alon Bartal, Stephan Schürer. Integrating geographical and socioeconomic data with genomic information for enhanced prediction of cancer risk using large language models and knowledge graphs [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 1052.
Abstract 92: The role of AKT3 in prostate cancer
Authors: Dineen Vogler, Seamus Degan, Henry Withers, Irwin Gelman
Journal: Cancer Research (2025)

Abstract The five-year survival rate for metastatic prostate cancer (mPC) patients remains significantly lower than that of patients with primary prostate cancer (PC). The loss of PTEN, a lipid phosphatase that negatively regulates PI3K/AKT pathway, is one of the most frequent mutations in prostate cancer. Although AKT inhibitors seem promising for mCRPC patients, they often perform poorly in the clinic as monotherapies. We hypothesize that this poor response to AKT inhibitors may be due to a failure to account for the distinct and opposing roles of AKT isoforms. Previously published data from our lab suggests that AKT2 and possibly AKT3, are the mediators of PC progression while AKT1 is responsible for PC development. To further investigate the mechanisms underlying AKT isoform plasticity in the context of PTEN loss, we conducted a phosphoproteomics analysis that identified Akt isoform-specific substrates using T402 (mouse prostate epithelial cells with PTEN-/-/Rb-/-) and T402[PTEN] (T402 cells with PTEN re-expression). We identified both canonical (RXRXXS/T*P) and novel non-canonical phosphorylation motifs. Interestingly, more substrates were associated with Akt3 compared to Akt1 and Akt2, indicating that Akt3 may be an underappreciated driver of PC progression. Furthermore, Akt3 was found to preferentially phosphorylate substrates with non-canonical motifs. However, the direct mechanisms through which AKT3 and its substrates contribute to PC progression and metastasis remain unclear. From our phosphoproteomics analysis, we identified PAK4S181 as a potential Akt3 direct substrate. Knockdown of PAK4 in PTEN deficient PC cells resulted in a greater reduction in chemotaxis compared to PTEN intact PC cells. We hypothesize that AKT3 directly phosphorylates PAK4S181 to promote PC metastatic progression. These studies will provide a functional characterization of the downstream activity of AKT3, through substrate usage, to aid in the development of an AKT3 specific inhibitor. This research highlights the importance of discovering biomarkers to unveil a more targeted approach toward treating advanced stage prostate cancer patients. Citation Format: Dineen Vogler, Seamus Degan, Henry Withers, Irwin Gelman. The role of AKT3 in prostate 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 92.
Abstract 262: APOBEC4, a novel regulator of p53-dependent cell cycle arrest, senescence, and apoptosis
Authors: Dipesh Thapa, Atul Ranjan, Elizabeth Thoenen, Alejandro Parrales, Shigeto Nishikawa, Jay Vivian, Tomoo Iwakuma
Journal: Cancer Research (2025)

Abstract Introduction: The tumor suppressor protein p53 (p53) is a transcription factor that can transactivate downstream target genes like p21, PUMA, NOXA, BAX, and GADD45a to cause cell cycle arrest, senescence, apoptosis, and other biological processes. However, its function is frequently compromised in tumorigenesis, with approximately half of human cancers harboring mutations in the TP53 gene. Notably, even in cases retaining wild-type p53 (wtp53), it gets degraded or inhibited through various mechanisms, including, the overexpression of its E3 ubiquitin ligase MDM2. MDM2 antagonists such as Nutlin-3a are promising strategies to restore p53 function and suppress tumor growth. However, the factors/biomarkers regulating the efficacy of MDM2 antagonists and p53-mediated tumor suppression remain unclear. Identifying such factors and understanding their functions are important to develop optimal therapeutic strategies targeting p53. Experimental procedures: Through a human whole-genome shRNA library screen, we attempted to identify factors regulating p53-mediated tumor suppression by treating osteosarcoma U2OS cells with an MDM2 antagonist. This screening and subsequent validation identified APOBEC4 as a factor that is required for p53-mediated suppression of colony formation following Nultin-3a treatment. Summary of data: Knocking down APOBEC4 mitigated Nutlin-3a-induced activation of p53 as a transcription factor, as well as p53-mediated cell cycle arrest and apoptosis in multiple p53-proficient cancer cells. Cellular senescence induced by H2O2 was also reduced upon APOBEC4 knockdown. Moreover, APOBEC4 overexpression enhanced x-ray irradiation-induced apoptosis in a manner dependent on p53. Conclusion: Our data suggest that APOBEC4 is a novel regulator required for p53-dependent cell cycle arrest, cellular senescence, and apoptosis. Citation Format: Dipesh Thapa, Atul Ranjan, Elizabeth Thoenen, Alejandro Parrales, Shigeto Nishikawa, Jay Vivian, Tomoo Iwakuma. APOBEC4, a novel regulator of p53-dependent cell cycle arrest, senescence, and 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 262.
Abstract 924: Tumor-initiating stem cells fine-tune the plasticity of neutrophils to sculpt a protective niche
Authors: Weijie Guo, Jingyun Luan, Yuxuan Miao
Journal: Cancer Research (2025)

Abstract The abundant accumulation of neutrophils in various solid cancers has been well recognized, but the functions of tumor-associated neutrophils (TANs) remain controversial. TANs have long been believed to be immune suppressive and have thus been referred to as “myeloid-derived suppressor cells”. However, effective tumor control induced by immunotherapy was recently found to be associated with strong neutrophil signatures. These seemingly contradictory findings highlight the unexpected degree of plasticity and heterogeneity unique to TANs. How the cellular plasticity and functional heterogeneity of TANs are regulated remains unknown. Here, we show that, while anti-PDL1/CD40 agonist immunotherapy can induce interferon responses to reprogram many TANs, allowing them to regain anti-tumor activities in squamous cell carcinomas, a subset of TANs residing at the tumor-stroma interface can preserve their immune suppressive state. Importantly, we identified a group of Sox2Hi tumor-initiating stem cells (tSCs) at the tumor-stroma interface that could upregulate Fatty Acid Desaturase 1 (Fads1) to produce arachidonic acid. This tSC-specific pathway enhances the autocrine prostaglandin E2 (PGE2) signaling in TANs, which can disrupt their interferon responsive potentials, preventing the interferon-mediated reprogramming. Thus, by fine-tuning the plasticity of neutrophils, tSCs shape neutrophil heterogeneity, and sculpt a protective micro-niche to survive from immunotherapy and drive cancer relapse. Citation Format: Weijie Guo, Jingyun Luan, Yuxuan Miao. Tumor-initiating stem cells fine-tune the plasticity of neutrophils to sculpt a protective niche [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 924.
Abstract 919: Regulation of PS externalization on tumor cells by TMEM16F and P2X7 receptors
Authors: Rachael Pulica, Varsha Gadiyar, David C. Calianese, Mariana De Lorenzo, Raymond B. Birge
Journal: Cancer Research (2025)

Abstract Immune evasion in the tumor microenvironment (TME) is critical for tumor progression, and many therapeutic strategies are under development to activate host anti-tumor immunity. Tumors avoid immune detection and clearance through several mechanisms, one of which is the chronic externalization of the phospholipid phosphatidylserine (PS) to the outer leaflet of the plasma membrane. Externalized PS on tumor cells alters the tumor microenvironment to an immunosuppressive phenotype. Immune cells expressing PS-binding TAM (Tyro3, Axl, MerTK) receptors interact with the tumor-exposed PS and release immunosuppressive cytokines, leading to the polarization of the TME to pro-tumorigenic. While it is understood how PS is externalized by calcium-induced scramblase TMEM16F in non-pathological conditions and caspase-cleaved scramblase Xkr8 in apoptotic conditions, the mechanism through which the constitutive externalization of PS on tumor cells occurs is still unknown. We hypothesize that the increased concentration of calcium in tumor cells activates TMEM16F to externalize PS, and the increased levels of extracellular ATP bind P2X7 receptors (P2X7R), further leading to PS externalization in the TME. To better understand the mechanisms of PS exposure under oncogenic stress, we have developed both TMEM16F and P2X7R CRISPR knockout EO771 breast cancer cell lines. These cells are unable to externalize PS when subjected to their respective triggers (calcium or ATP). They have additionally been shown to be unable to upregulate immune-suppressive MerTK signaling upon exposure to their PS-externalizing triggers, whereas wild-type EO771 cells show large upregulation in MerTK binding upon treatment. Orthotopic injection into the mammary fat pad of C57/Bl6 mice yielded a reduction in tumor size in TMEM16F knockout tumors compared to the wild-type EO771 tumors (P2X7R knockout tumor experiments are ongoing). Based on these studies, we show that both calcium-induced TMEM16F and ATP-binding P2X7R contribute to the externalization of PS and immune suppression in the TME, resulting in tumor growth and progression. Our studies add new insights to how PS acts as an immunosuppressive signal in the tumor microenvironment. Citation Format: Rachael Pulica, Varsha Gadiyar, David C. Calianese, Mariana De Lorenzo, Raymond B. Birge. Regulation of PS externalization on tumor cells by TMEM16F and P2X7 receptors [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 919.
Abstract 29: The utilization of patient-derived organoids as a platform for drug screening: Chemotherapy, targeted therapy, and immunotherapy
Authors: Na-Gyeong Lee, Misun Park, Sang-Eun Park, Hyeon-A Kim, Sang-yeon Lee, Jinguen Rheey, Ji-Yeon Park
Journal: Cancer Research (2025)

Abstract Cancer is one of a leading cause of mortality worldwide, with current treatments facing limitations such as drug resistance and relapse. To address these issues, the use of advanced in vitro models, such as patient-derived organoids (PDOs), is crucial. Unlike conventional 2D cultures, PDOs closely resemble the biological characteristics of tumors, thereby allowing the prediction of responses to drugs and supporting personalized therapies. Gradiant Bioconvergence (GBCC) has established a biobank comprising over 800 PDOs derived from tissue or metastatic samples of patients with lung, colorectal, gastric, pancreatic, and ovarian cancers. The biobank also includes NGS datasets of genomics and transcriptomics, as well as clinical information, including treatment history, and autologous peripheral blood mononuclear cells (PBMCs) or tumor infiltrating lymphocytes (TILs). PDOs are highly effective models for evaluating drug efficacy in vitro, capable of predicting clinical drug responses and providing valuable insights for the development of new therapeutics. GBCC has developed two distinct organoid-based drug screening platforms for evaluating various cancer therapies. The first drug screening platform employs organoids alone to evaluate anti-cancer drugs, including chemotherapy and targeted therapy. Additionally, the platform is capable of supporting mono or combination drug screenings. Of note, lung PDOs with driver mutations, such as EGFR and KRAS, demonstrated responsiveness to targeted drugs, with results that aligned with the patient’s treatment history. Antibody-drug conjugates (ADCs), including Trastuzumab Deruxtecan (T-DXd), exhibited sensitivity in HER2-overexpressing gastric cancer organoids and lung cancer organoids with HER2 mutations. To evaluate immune checkpoint inhibitors (ICIs), the GBCC has developed a second drug screening platform using autologous T cell co-culture with organoid models. Flow cytometry was employed to ascertain organoid viability and cytokine release by T cells, thereby confirming that the viability of cancer organoids was reduced in the presence of ICIs. The results demonstrate that our organoid-based drug screening platforms can be utilized to assess drug responsiveness, thus representing a valuable tool for the preclinical evaluation of drugs, and supporting the advancement of precision medicine and the discovery of new anti-cancer drugs. Citation Format: Na-Gyeong Lee, Misun Park, Sang-Eun Park, Hyeon-A Kim, Sang-yeon Lee, Jinguen Rheey, Ji-Yeon Park. The utilization of patient-derived organoids as a platform for drug screening: Chemotherapy, targeted therapy, and immunotherapy [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 29.
Abstract 1815: Targeting the serine metabolism-NRF2 axis to overcome radiation resistance in pancreatic cancer
Authors: Prince Kumar, Hüseyin Ayhan, Lobna Abdulrahman, Justine Bailleul, Jonathan Ng, Erina Vlashi
Journal: Cancer Research (2025)

Abstract Pancreatic ductal adenocarcinomas (PDAC) have very poor prognosis largely due to extreme resistance to existing therapies, including radiation therapy (RT). Metabolic reprogramming has been shown to promote therapy resistance in PDAC, but little in known in the context of RT. Here, we present findings of a critical intersection between serine metabolism and antioxidant defenses following RT of PDAC that place serine metabolism in a radioprotective role. We find that this is enabled, in part, by the upregulation of the NRF2 (nuclear factor (erythroid-derived 2)-like 2) pathway following RT, beyond basal, mKRAS-induced levels. Our discovery is in line with the role that the serine metabolism coupled with one-carbon metabolism (1CM) plays in generating antioxidants for offsetting oxidative damage, as well as generating nucleotide precursors for DNA repair. Our TCGA analysis on patient PDAC shows a significant correlation between tumor NRF2 expression and SLC1A5 serine transporter, PSPH (the last enzyme in serine synthesis) and NADPH-producing enzymes of 1CM. Moreover, co-overexpression of PHGDH and NRF2 correlates with poorer overall survival, underscoring the intersection of serine metabolism and NRF2-regulated antioxidant responses in human PDACs. In pre-clinical models we show that RT enhances PDAC cellular glucose consumption in excess of anabolic basal levels, and this is accompanied by increased gene expression levels of enzymes that drive the de novo serine biosynthesis pathway (SBP), a branch of glycolysis. PDAC radiosensitization can be achieved by interfering with serine metabolism, be it through inhibiting the first SBP enzyme, phosphoglycerate dehydrogenase, or by removing exogenous serine. The radiation-induced antioxidant pathway involving NRF2 is also implicated in metabolic PDAC reprogramming in part by promoting upregulation of glucose consumption following RT and driving flux of glucose carbons into the SBP. In keeping with this, PDAC radiosensitization can also be achieved by inhibiting the NRF2 pathway (in vitro and in vivo). Our findings suggest that NRF2-serine-metabolism axis generates a synchronized metabolic response that protects PDAC from lethality in the aftermath of RT and constitutes a promising and novel radiotherapeutic target. Citation Format: Prince Kumar, Hüseyin Ayhan, Lobna Abdulrahman, Justine Bailleul, Jonathan Ng, Erina Vlashi. Targeting the serine metabolism-NRF2 axis to overcome radiation resistance in pancreatic 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 1815.
Abstract 114: Unraveling the origin of Ewing sarcoma using zebrafish transgenic models
Authors: Elena Vasileva, Claire Arata, Gage Crump, James Amatruda
Journal: Cancer Research (2025)

Abstract Ewing sarcoma (ES) is a pediatric cancer of bones and soft tissues with enigmatic origin. Ewing sarcoma cells are characterized by the presence of a driver fusion oncogene, most frequently EWSR1-FLI1. Previous reports have suggested that bone-marrow mesenchyme or/and neural crest cells may serve as potential cells of origin for Ewing sarcoma. These hypotheses have never been tested in vivo, largely due to the absence of a representative mouse model as the EWSR1-FLI1 fusion causes severe developmental toxicity in most cell types. To address these questions, we developed a stable zebrafish transgenic model enabling tissue-specific expression of the human EWSR1-FLI1 oncofusion in neural crest cells (Vasileva et al., 2024). Using this model, we demonstrated that expression of human EWSR1-FLI1 oncofusion in neural crest cells can lead to their transformation and the development of tumors in vivo. Single-cell analysis of tumor initiation shows that EWSR1::FLI1 reprograms neural crest-derived cells to a mesoderm-like state, strikingly resulting in ectopic fins formation throughout the body. EWSR1-FLI1 hindered the normal differentiation of neural crest cells into glial and neuronal lineages. Instead, EWSR1-FLI1 strongly reprogrammed neural crest cells by hijacking developmental enhancers and upregulating the expression of mesodermal regulators, including the key mesodermal regulator tbxta (Brachyury or T) transcription factor. tbxta/TBXT expression was maintained in subset of zebrafish and human Ewing sarcomas. Our model provides a mechanism by which a neural crest cell lineage can be transformed to Ewing sarcoma, a malignancy with predominant mesenchymal features. Taken together, these findings show how a single mutation profoundly alters embryonic cell fate decisions reprogramming neural crest cells to a mesoderm-like state to initiate a devastating childhood cancer. Citation Format: Elena Vasileva, Claire Arata, Gage Crump, James Amatruda. Unraveling the origin of Ewing sarcoma using zebrafish transgenic 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 114.