tbuckley/cabot-search huggingface dataset:
Abstract 1348: Investigation of sex disparity in hepatocarcinogenesis using a hydrodynamic tail vein injection mouse model
Authors: Araceli Selena Bernal, Morgana McLaughlin, Ankur Tiwari, Brittany Barre, Francisco Cigarroa, LuZhe Sun
Journal: Cancer Research (2025)

Abstract The incidence of hepatocellular carcinoma (HCC), the major form of liver cancer, is two to three times higher in men than in women. Understanding the gender disparity in HCC incidence is challenging due to HCC development being multifactorial, including variations in risk factors, behaviors, and hormones. The liver is a sexually dimorphic organ, and estrogen has been proven to have a protective effect against the development of HCC, although the mechanism is not fully understood. We used the hydrodynamic tail vein injection (HTVI) mouse model of HCC to investigate potential mechanisms underlying the sex disparity of HCC incidence. This model eliminates social and behavioral aspects of gender disparity and allows us to determine if there is biological sex disparity and what role estrogen and androgens play in tumor development. In our preliminary study, the expression vectors of oncogenes, ΔN90-β-catenin and c-MET, to be integrated into the hepatocyte genome via transposons, were co-injected with a Sleeping Beauty (SB) transposase to induce HCC in FVB/NJ mice. Based on plasma alpha-fetoprotein (AFP), an HCC blood biomarker, male FVB/NJ mice had a significantly higher mean AFP trend in comparison to females, indicating that the males developed liver tumors at a faster rate than females. ΔN90-β-catenin and c-MET gene copy number were confirmed to be equally transfected and integrated in both male and female FVB/NJ tumors by quantitative PCR (qPCR). The expression of ΔN90-β-catenin and c-MET transgenes was also shown to be similar between male and female mouse HCC tumors by RT-qPCR and RNA-seq. We plan to repeat the HTVI of ΔN90-β-cat, c-MET, and SB to validate that the males will develop liver tumors at a faster rate than female mice. We will also Western Blot to determine if there is sex disparity in the abundance of the transfected oncogene proteins. In addition, we will compare the abundance of various types of immune cells present in the tumor immune microenvironment (TIME) to interpret potential sex-dependent immune cell differences in the tumor liver. Our research has the potential to uncover mechanisms underlying the sex-dependent disparity in HCC development and progression and the contribution of immune cells to the sex disparity. Citation Format: Araceli Selena Bernal, Morgana McLaughlin, Ankur Tiwari, Brittany Barre, Francisco Cigarroa, LuZhe Sun. Investigation of sex disparity in hepatocarcinogenesis using a hydrodynamic tail vein injection mouse model [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 1348.
Abstract 2126: LY6G6D targeting with a T cell engager is a promising therapeutic for MSS colorectal cancer
Authors: Burcu Yigit, Prasuna Paluru, Egle Jurgaityte, Kevin Nuno, Jason Chen, Nathan Fisher, Alex Martinko, Max Mumbach, Ann Easton, Rose Guerrero, Maeve O’Huallachain, Priya Ram, Jeffrey Verboon, Maggie Lu, Jeffrey Granja, Dan Rock, David Kugler
Journal: Cancer Research (2025)

T cell engagers (TCEs) are proving to be a potent therapeutic strategy for the treatment of solid tumors. Clinical data have shown that TCEs can drive T cell activity in "cold" tumors, including colorectal cancer. However, identifying highly specific tumor antigen targets is crucial for delivering doses that achieve optimal tumor exposure and maximize therapeutic efficacy. Analysis of primary patient samples indicated enrichment of LY6G6D in microsatellite stable (MSS) and instability-low (MSI-L) colorectal cancer (CRC). A highly potent, stable, and manufacturable CB21 TCE was designed to optimally engage LY6G6D and CD3. Strong binding affinity to the LY6G6D target antigen, and an optimized CD3 affinity, maximized T cell activation and cytokine production yielding significant cytotoxic effects across multiple cell lines with differing physiologically relevant levels of LY6G6D. Additionally, in endogenous LY6G6D expressing xenograft models the CB21 TCE displayed robust tumor growth inhibition in a dose-dependent manner. A pharmacokinetics (PK) and tolerability study with the cynomolgus cross-reactive CB21 TCE was administered to nonhuman primates. Exposure levels multiple times higher than the predicted clinical exposures were achieved with no significant cytokine release or meaningful alterations in clinical blood chemistry observed. Human PK were predicted to have antibody-like characteristics. Combined with the PK and PD data, human dose predicts efficacy with a favorable therapeutic window. An accelerated phase I clinical plan is presented. Utilizing our ATLAS platform, we identified LY6G6D as the most promising target in MSS CRC due to its specific expression in malignant cells, high antigen surface stability, and persistence in both primary and metastatic CRC. The data presented support that the CB21 TCE has been meticulously engineered to be a potentially first and best-in-class TCE targeting LY6G6D. Citation Format: Burcu Yigit, Prasuna Paluru, Egle Jurgaityte, Kevin Nuno, Jason Chen, Nathan Fisher, Alex Martinko, Max Mumbach, Ann Easton, Rose Guerrero, Maeve O’Huallachain, Priya Ram, Jeffrey Verboon, Maggie Lu, Jeffrey Granja, Dan Rock, David Kugler. LY6G6D targeting with a T cell engager is a promising therapeutic for MSS 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 2126.
Abstract 63: Orai1 regulates collagen secretion in pancreatic stellate cells and is enriched in fibrotic cancer-associated fibroblasts in PDAC
Authors: Zoltan Pethö, Ilka Neumann, Andrea Oeckinghaus, Albrecht Schwab, Rieke Schleinhege
Journal: Cancer Research (2025)

Introduction: Pancreatic ductal adenocarcinoma (PDAC) is characterized by a desmoplastic stroma driven by pancreatic stellate cells (PSCs) and cancer-associated fibroblasts (CAFs). The Ca2+-permeable ion channel ORAI1 is known to influence PSC proliferation and activation, but its role in collagen secretion and tumor fibrosis remains unclear. Experimental Procedures: Using the PSC cell line PS-1, we developed and validated a high-throughput fibrosis assay based on the collagen-binding peptide CNA-35-tdTomato. Collagen secretion was assessed following treatment with transforming growth factor β1 (TGF-β1) and/or vitamin C, with ORAI1 inhibition achieved via siRNA or Synta-66. In vivo, Orai1 expression was examined by immunohistochemistry in the genetically engineered murine PDAC model KPfC (Kraswt/LSL-G12D Tp53fl/+ PDX1Cre+). The intracellular Ca2+ concentration was assessed with the fluorescent Ca2+ indicator Fura-2. Results: TGF-β1 and vitamin C synergistically enhanced collagen deposition in PSCs, a process regulated by ORAI1. Vitamin C induced a significant rise in intracellular Ca2+ in PSCs, which was attenuated by the ORAI inhibitor Synta-66. ORAI1 expression was detected in αSMA+ CAFs in KPfC-derived PDAC tissue, with a higher prevalence in collagen-rich fibrotic tumor regions compared to non-fibrotic areas or non-tumorous tissue. In addition, vessel-lining endothelial cells also express ORAI1. Conclusions: Our findings highlight ORAI1 as a regulator of collagen secretion in PSCs and reveal its enrichment in CAFs within fibrotic PDAC stroma, underscoring its potential role in PDAC-associated desmoplasia. Citation Format: Zoltan Pethö, Ilka Neumann, Andrea Oeckinghaus, Albrecht Schwab, Rieke Schleinhege. Orai1 regulates collagen secretion in pancreatic stellate cells and is enriched in fibrotic cancer-associated fibroblasts in PDAC [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 63.
Abstract 1687: Estrogen-related receptor gamma (ERRγ) as a therapeutic target and the synergetic anti-tumor effect of DN200434 (ERRγ inverse-agonist) and MK2206 (Akt inhibitor) in non-small cell lung carcinoma (NSCLC)
Authors: Thoudam Debraj Singh
Journal: Cancer Research (2025)

Abstract Introduction: Non-small cell lung cancer (NSCLC) accounts for over 85% of all lung cancer cases and has the greatest mortality rates among both men and women, making it the primary cause of cancer-related fatalities globally. Estrogen Related Receptor Gamma (ERRγ), a member of the NR3B nuclear receptor subfamily, holds therapeutic promise in various cancer treatments. This study delves into the mechanistic understanding of ERRγ expression in NSCLC cells to gauge its therapeutic potential and examine the anti-tumor impact of combining DN200434 (ERRγ inverse agonist) with MK2206 (Akt inhibitor) in vitro. Experimental procedures: Expression of ERRγ were investigated in different NSCLC cell lines (A-549, H-1299, H-460) by western blot. Different dose of DN200434 was treatment to study the proliferation effect in NSCLC cells. CCK-assay was used to measure the IC50 value post DN200434 or/and MK2206 in NSCLC cells after 24 hours. NSCLC cells were treated with single drug or in combination to assess their inhibitory effect, apoptosis, cell cycle arrest, colony formation efficiency, migration potential, and spheroid forming ability and the markers of the corresponding events was validated by western blot. Summary of unpublished findings (Results): ERRγ was found to be overexpressed in the NSCLC cells. Treatment of DN200434 in NSCLC cells inhibit cell proliferation via apoptosis and cell cycle arrest in dose dependent manner. DN200434 in combination with MK-2206 demonstrate synergetic killing effect in NSCLC cells. Combination treatment inhibits cell proliferation via apoptosis and cell cycle-arrest, colony formation efficiency, migration potential, and sphere forming ability of NSCLC cells. This combination not only reduced the toxic concentration of both the drug but also target multiple key driving factors of NSCLC progression. Further, DN200434/MK-2206 reduced the stemness property of NSCLC cell-derived spheroids. Conclusions: Our present findings thus demonstrate that ERRγ functions as a positive regulator of NSCLC progression and a potential therapeutic target. DN200434, inverse agonist of ERRγ, along with MK-2206 suppresses cancer growth and represses the expression of ERRγ mediated signalling. This combination is certainly providing a new strategy to proceed towards clinical trial. Citation Format: Thoudam Debraj Singh. Estrogen-related receptor gamma (ERRγ) as a therapeutic target and the synergetic anti-tumor effect of DN200434 (ERRγ inverse-agonist) and MK2206 (Akt inhibitor) in non-small cell lung carcinoma (NSCLC) [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 1687.
Abstract 88: Ephrin receptor A4 is a regulator of metastatic colonization in triple negative breast cancer
Authors: Wenchao Liu, Hoi Wan Lee, Madeline H. Bungert, Geetha P. Yerradoddi, Marsha R. Rosner
Journal: Cancer Research (2025)

Abstract Triple negative breast cancer (TNBC) is the most aggressive breast cancer subtype, affecting more than 40, 000 people in the US. Most TNBC patient deaths are due to distal metastasis, a stage for which effective treatment is not yet available. Metastasis is an inefficient, multi-step process. The bottleneck for establishing the life-threatening macro-metastasis is considered to be metastatic colonization, the step at which cancer cells exit the circulation, survive in the new microenvironment and re-initiate aggressive growth. Numerous studies have found that cancer cell adhesion and migration pathways are required for metastatic colonization. However, the mechanisms by which these pathways are modulated are incompletely understood. Ephrin and Ephrin receptors are a family of proteins with conserved functions related to modulation of cell repulsion and adhesion, particularly in the regulation of pattern formation during development. Here we show that Ephrin Receptor A4, a cell surface receptor tyrosine kinase, regulates cell-cell interactions, migration and metastatic formation in TNBC, similar to its role in development. Depletion of EPHA4 in either human xenograft MDA-MB-231 or mouse syngeneic 4T1 TNBC tumors does not significantly alter tumor growth, but results in differential expression of genes involved in cell-cell adhesion, cell-matrix adhesion, and cell migration. In vitro assays suggest that EphA4 loss promotes collective rather than single cell migration, which can lead to increased metastatic formation. Metastatic lung colonization assays in mice indicate that loss of EphA4 increases metastatic lesions and/or metastatic burden in the MDA-MB-231 and 4T1 tumor models. Consistent with these findings, Ephrin Receptor A4 expression in TNBC is downregulated at metastatic sites relevant to the primary tumor. These results suggest that EphA4 regulates cell adhesion in cancer cells to reduce the efficacy of metastatic colonization. Citation Format: Wenchao Liu, Hoi Wan Lee, Madeline H. Bungert, Geetha P. Yerradoddi, Marsha R. Rosner. Ephrin receptor A4 is a regulator of metastatic colonization in triple negative 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 88.
Abstract 1095: Machine learning models predict tumor-specific total mRNA expression associated with clinical outcomes across 14 cancer types
Authors: Ankita Paul, Shuangxi Ji, Jessica C. Lal, Carissa Fong, Suraksha Vinod, Huiying Hu, Kevin Chen, Matthew Montierth, Quang Tran, Wenyi Wang
Journal: Cancer Research (2025)

Abstract Understanding unique cancer tumor phenotypes is critical in determining disease progression, drug response, and clinical outcomes. Tumor cell-specific total mRNA expression (TmS) which quantifies total mRNA content within tumor cells, has been shown as a robust biomarker to unravel genetic makeup of tumors and their surrounding environments. Currently, quantifying TmS from transcriptomic data is time consuming and resource intensive. Moreover, the unavailability of matched DNA/RNAseq data with clinical annotations limits the translation of TmS to clinical settings. Machine learning (ML) is powerful to create blackbox models that utilize raw high-dimensional omic data to predict clinical outcomes. In this work, we propose TmSNet, TmS prediction by ensemble Network. It is an ML framework that extracts cancer-type-specific gene expression, methylation, and miRNA profiles from 14 cancer types in TCGA cohort (Train =70%, test =30%) to predict TmS. For each cancer type, we extracted relevant features with an ensemble feature extractor block, using random forest (RF), gradient boosting (GB), lasso, and elastic net (EN) models. The extracted features from each model were used to train an ensemble of ML models consisting of variational auto encoder (VAE), model agnostic meta learning (MAML), support vector machine (SVM), and multi-layer perceptron (MLP). TmSNet achieved strong predictive performance across all cancer types (Table 1). Our findings suggest that TmSNet effectively predicts TmS from limited data, with strong performance and limited overfitting. The predicted TmS values from TmSNet successfully stratifies patient survival within early and late-stage cancer. This can serve as a valuable prognostic tool for multi-omic analyses in cancer, with implications for tumor phenotyping, cancer screening, and therapeutic intervention. Citation Format: Ankita Paul, Shuangxi Ji, Jessica C. Lal, Carissa Fong, Suraksha Vinod, Huiying Hu, Kevin Chen, Matthew Montierth, Quang Tran, Wenyi Wang. Machine learning models predict tumor-specific total mRNA expression associated with clinical outcomes across 14 cancer types [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 1095.
Abstract 2669: Solid tumor microenvironments cause more mutations than liquid or soft tumor microenvironments -- even before selection
Authors: Dennis E. Discher, Markus Sprenger
Journal: Cancer Research (2025)

Abstract Sequencing of many types of tumors shows that solid tumors are far more mutated than liquid tumors and soft tumors such as brain tumors, but it is unclear whether the differences are caused by induction of more mutations or subsequent selective pressures. Our pan-cancer analyses of clinical data shows increased chromosomal changes associate with collagen-I and further shows that genetic variance between patients also increases with the mean for a given tumor type. Using a 3D hydrogel-based model with tunable stiffness and of cancer spheroids, we discover that matrix stiffness increases mitotic aberrations including micronuclei and also increases chromosome loss as detected using live cell chromosome reporters (ChReporters). However, stiffness suppresses growth and size variation, which indicates more mistakes per division. Our approach is &amp;gt;10-fold more sensitive than sequencing approaches, and we quantify colonies of ChReporter-negative cells within cancer spheroids. Our results are consistent with Luria-Delbruck’s theory of heritable genetic changes which predicts inter-spheroid variance greatly exceeds Poisson statistics. Knockdown of myosin-II, a well-known mechanosensor, increases chromosomal loss and variance without affecting spheroid growth, consistent with a tumor suppressor role. Various drug strategies provide deeper insight into mechanisms, and use of clinically deployed CDK4/6-inhibitor reveals this drug on its own drives micronuclei formation and genetic variation. Citation Format: Dennis E. Discher, Markus Sprenger. Solid tumor microenvironments cause more mutations than liquid or soft tumor microenvironments -- even before selection [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 2669.
Conscious artificial intelligence and biological naturalism
Authors: Anil K Seth
Journal: Behavioral and Brain Sciences (2025)

Abstract As artificial intelligence (AI) continues to advance, it is natural to ask whether AI systems can be not only intelligent, but also conscious. I consider why people might think AI could develop consciousness, identifying some biases that lead us astray. I ask what it would take for conscious AI to be a realistic prospect, challenging the assumption that computation provides a sufficient basis for consciousness. I'll instead make the case that consciousness depends on our nature as living organisms – a form of biological naturalism. I lay out a range of scenarios for conscious AI, concluding that real artificial consciousness is unlikely along current trajectories, but becomes more plausible as AI becomes more brain-like and/or life-like. I finish by exploring ethical considerations arising from AI that either is, or convincingly appears to be, conscious. If we sell our minds too cheaply to our machine creations, we not only overestimate them – we underestimate ourselves.
Abstract 926: Myeloperoxidase limits tumor-associated neutrophils mediated immunosuppression in pancreatic cancer
Authors: Angisha Basnet, Kaitlyn M. Landreth, Tracy W. Liu
Journal: Cancer Research (2025)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease with a survival rate under 13%. Treatments like immunotherapy and chemotherapy are ineffective in PDAC due to the immunosuppressive tumor microenvironment, in which tumor-associated neutrophils (TANs) are a major component. The immunosuppressive function of TANs has been shown to depend upon increased production of reactive oxygen species, with myeloperoxidase being a major source of it. We investigated the contribution of myeloperoxidase in mediating tumor-associated neutrophils immunosuppression using orthotopic PDAC models in wild-type and syngeneic myeloperoxidase-deficient mice. We observed a significant delay in tumor growth and improved clinical scores when myeloperoxidase was deficient. Additionally, treatment with the myeloperoxidase-specific inhibitor verdiperstat delayed tumor growth. Flow cytometry analysis of the tumor microenvironment revealed a significant increase in CD8+ T cells and natural killer (NK) cells in MPO-deficient mice, accompanied by elevated granzyme B levels in both cell subsets. Additionally, MPO deficiency was associated with increased expression of activation and memory markers among both CD8+ and CD4+ T cells. Ex vivo studies with isolated TANs from tumor-bearing mice showed reduced CD8+ T cell and NK cell suppression, and reactive oxygen species level in the absence of myeloperoxidase. These data suggests that loss of myeloperoxidase in TANs results in decreased immunosuppressive functions and increased cytotoxic and activated T cells and NK cells within the tumor microenvironment. Depletion of NK cells in myeloperoxidase-deficient mice abolished the antitumor effects observed with myeloperoxidase loss, underscoring the critical role of NK cells as key mediators of the antitumor response in the absence of myeloperoxidase. Additionally, we observed an enhanced chemotherapy (Gemcitabine) and immunotherapy (anti-PD1 and ant-CTLA4) response with myeloperoxidase deficiency. Overall, our results demonstrate the contribution of myeloperoxidase in regulating PDAC tumor progression, TAN immunosuppression, treatment response and immune cell infiltration using an orthotopic PDAC model. Citation Format: Angisha Basnet, Kaitlyn M. Landreth, Tracy W. Liu. Myeloperoxidase limits tumor-associated neutrophils mediated immunosuppression 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 926.