tbuckley/cabot-search huggingface dataset:
Abstract 5036: CAPTATe: a novel tool for enhanced artifact filtering and precise variant detection in single-cell DNA sequencing data
Authors: Luigi Ferraro, Fulvio D'Angelo, Anna Lasorella, Antonio Iavarone, Michele Ceccarelli
Journal: Cancer Research (2025)

Abstract Bulk sequencing has proven inadequate in capturing the full complexity of cancer heterogeneity, shifting focus toward cellular resolution. Single-cell DNA sequencing (scDNA-seq) technologies offer an effective approach for analyzing subclonal molecular architecture of tumor with greater granularity, facilitating the identification of somatic genetic mutations (single nucleotide variants, SNVs, and short indels) and copy number variants (CNVs) at single-cell resolution. This capability holds multiple promises, such as the characterization of timing and hierarchy of molecular events driving tumor initiation and progression. However, traditional scDNA-seq methods are hindered by significant artifacts during genome amplification, causing issues like allelic dropout and imbalance that compromise variant detection accuracy. The introduction of the Primary Template-directed Amplification (PTA) addressed these limitations by providing higher genome coverage and uniformity; however, further refinement in filtering amplification-induced artifacts remains necessary for accurate variant calling. Here, we present CAPTATe (Characterize Artifacts in PTA Technology), a novel tool developed for improved artifact filtering and enhanced detection of SNVs, indels, and CNVs in scDNA-seq data. CAPTATe employs allele-specific CNV calling by addressing fluctuations in the read-depth ratio (RDR) through a multi-channel joint segmentation approach at the subclonal level. The tool leveraged an extension of the variational framework recently developed for single-cell RNA-seq (de Falco et al. Nature Communications 2023) and integrates both B-allele frequency (BAF) and RDR for accurate CNV detection. Additionally, SNV and indel artifact filtering are performed through a machine learning-based approach. This model accounts for allelic imbalance by evaluating the ratio between observed variant allele frequency (VAF) and expected BAF. Genetic tumor subclones can be accurately identified by clustering cells based on their genomic alteration profiles. The increased precision and accuracy in single-cell genomic variant identification using CAPTATe overcome the main limitations of PTA scDNA-seq profiling, enabling precise characterization of genetic tumor heterogeneity at individual cell resolution. Citation Format: Luigi Ferraro, Fulvio D'Angelo, Anna Lasorella, Antonio Iavarone, Michele Ceccarelli. CAPTATe: a novel tool for enhanced artifact filtering and precise variant detection in single-cell DNA sequencing data [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 5036.
Abstract 2049: The 27-gene IO Score on the Ion Torrent Platform for classification of the tumor immune microenvironment
Authors: Tyler J. Nielsen, Jim Fee, Geoff Bien, Brock Schweitzer
Journal: Cancer Research (2025)

Abstract Background: The tumor immune microenvironment (TIME) plays a critical role in modulating cancer progression and therapeutic response, especially for immune checkpoint inhibitors (ICIs). DetermaIO, a 27-gene signature assay, has demonstrated clinical utility in predicting immune checkpoint inhibitor responsiveness through classification of the TIME. This study focuses on adapting DetermaIO to the Ion Torrent platform as a research-use-only (RUO) kit, OncoTIME. This assay enables precise and reproducible gene expression profiling of the immune system, tumor biology, and surrounding stromal biology in solid tumors, using this to derive the OncoTIME Score. Method: OncoTIME was designed as a multiplexed targeted RNA sequencing assay using Ion AmpliSeq technology to quantify the expression of 27 immune-related genes and 5 housekeeping (HK) genes. Target regions for the 27-gene panel guided by prior design of the DetermaIO assay. HK genes were identified through a composite approach, combining three methodologies: Expression Stability: Evaluated consistency across tissue types and tumor states using datasets from The Cancer Genome Atlas (TCGA) and internal NGS datasets. Variance Filtering: Selected genes with minimal inter-sample variance within experimental datasets. Biological Context: Ensured HK genes were biologically non-variable and minimally involved in immune-related pathways. These methods ensured robustness of normalization across diverse sample types and RNA input qualities. The assay design used Thermo Fisher's Ion Torrent GeneStudio platform, leveraging its efficient library preparation and sequencing workflow. Results: The OncoTIME panel demonstrated: High specificity and coverage of target regions for all 27 immune-related genes. Reproducibility assessed across intra- and inter-run precision studies. Consistent normalization using the 5 HK genes, enabling accurate quantification of immune signatures across a dynamic range of tumor microenvironment profiles. Preliminary studies confirmed that OncoTIME recapitulates the DetermaIO Score. Conclusion: OncoTIME democratizes access to TIME classification for research use and provides a scalable, reproducible, and cost-effective assay for the Ion Torrent platform. This RUO kit recapitulates DetermaIO while enabling broader utility in characterizing the TIME and its potential biological associations. Citation Format: Tyler J. Nielsen, Jim Fee, Geoff Bien, Brock Schweitzer. The 27-gene IO Score on the Ion Torrent Platform for classification of the tumor immune microenvironment [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 2049.
Abstract 7483: A new spatial multi-omics approach to deeply characterize human cancer tissue using a single slide: a new spatial muti-omics approach to deeply characterize human cancer tissue using a single slide
Authors: yasmine adimi, clement Levin, Emilia Puig Lombardi, Marion Classe, Cecile Badoual
Journal: Cancer Research (2025)

Abstract Introduction: In digital pathology, extracting comprehensive data from a single tissue sample is critical for enhancing diagnostic precision and therapeutic strategies. Techniques like multiplex imaging and spatial transcriptomics offer unprecedented depth of information. This study introduces a novel and innovative approach combining for the first time Phenocycler® (with a 34-marker panel) and Visium® spatial transcriptomics on the same tissue section of squamous cell carcinoma of the upper aerodigestive tract. A single tissue section was analyzed using Phenocycler® (PP) for proteomics with a 34-marker panel targeting microenvironment and structural proteins, followed by H&amp;E staining and Visium® spatial transcriptomics (ST) to map RNA expression. This approach allowed for the thorough assessment of immune cell spatial distribution and transcriptomic profiles, while evaluating the impact of proteomic treatment on RNA integrity and gene expression. Results: Despite initial concerns about RNA degradation due to multiplex staining treatments, RNA integrity in the PP+ST sample was comparable to ST-only samples, as indicated by similar total gene expression distributions. The PP+ST sample exhibited high-density feature points across the tissue, suggesting that proteomic pre-treatment did not impair subsequent transcriptomic analysis. Unsupervised UMAP visualization revealed similar clustering patterns between PP+ST and ST-only samples, indicating preserved cellular heterogeneity and molecular signatures. Consistent spatial distributions and clustering were observed between Phenocycler® pseudospots and Visium® data, with significant correlations in the spatial distribution of key cell types, including malignant clusters and immune cells. This study is a pioneering demonstration of the feasibility and efficiency of integrating spatial proteomics and transcriptomics on the same tissue section, guaranteeing high fidelity in molecular profiling. This combined method is crucial for deepening the understanding of the tumor microenvironment, with potential implications for improving diagnostics and personalized cancer therapies. The ability to analyze multiple data layers on the same cells enhances the development of precise AI-based diagnostic tools and personalized treatment strategies. Citation Format: yasmine adimi, clement Levin, Emilia Puig Lombardi, Marion Classe, Cecile Badoual. A new spatial multi-omics approach to deeply characterize human cancer tissue using a single slide: a new spatial muti-omics approach to deeply characterize human cancer tissue using a single slide [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 7483.
Abstract 4441: Specific OXPHOS inhibitors can overcome chemoresistance of triple negative breast cancer
Authors: Cemile Uslu, Eda Kapan, Etna Abad, Alex Lyakhovich
Journal: Cancer Research (2025)

Abstract Recently, we and others have shown that drug-resistant malignancies are characterized by higher levels of mitochondrial oxidative phosphorylation (OXPHOS) compared to chemotherapy-responsive tumors. Specifically, we used cisplatin- and cyclophosphamide-resistant triple-negative breast cancer cells and corresponding xenograft models to show that the chemoresistant phenotype is characterized by a higher oxygen consumption rate and higher metastatic potential compared to its chemosensitive counterpart. We hypothesized that OXPHOS inhibitors may resensitize chemoresistant cells to anticancer therapy. Given the endosymbiotic origin of mitochondria from alphaproteobacteria, we analyzed OXPHOS inhibitors among hundreds of antimicrobial agents and selected several that specifically target chemoresistant cancer cells. Experiments in nude mice confirmed the efficacy of these compounds against tumors derived from chemoresistant cells. In addition, we performed proteomic profiling and identified several mechanisms of action of these chemicals, including enhancement of oxidative stress, induced mitophagy, and suppression of metalloproteinase activity. Furthermore, we confirmed the synergistic effects of individual antibactericidal drugs and chemotherapeutic agents and suggest that this alternative approach should be considered for the treatment of OXPHOS-dependent chemoresistant tumors. Citation Format: Cemile Uslu, Eda Kapan, Etna Abad, Alex Lyakhovich. Specific OXPHOS inhibitors can overcome chemoresistance of 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 4441.
Abstract 7405: Temporal evolution of early signs and symptoms of early-onset colorectal cancer in diverse populations: Insights from the All of US Research Program
Authors: Ruiyi Tian, Chongliang Luo, Xiaoyu Zong, Cassandra D. Fritz, Philip R. Payne, Yin Cao
Journal: Cancer Research (2025)

Abstract Introduction: The incidence of early-onset colorectal cancer (EOCRC, diagnosed before age 50) has risen sharply over the past three decades. Current screening guidelines are inadequate for detecting EOCRC in individuals under the recommended screening age, emphasizing the urgent need for identifying pre-diagnostic signs and symptoms and their temporal evolution patterns to inform early detection. Methods: A total of 347 incident EOCRC cases within the NIH All of Us Research Program (1991-2022) with ≥1 year of pre-diagnostic electronic health record (EHR) were matched with up to four controls. Signs and symptoms were classified as chronic (vs non-chronic) based on whether required ongoing medical care or impacted daily functioning for ≥12 months. Poisson regression models and dynamic network analyses were used to identify signs and symptoms from 1 year to 3 months before diagnosis and characterize their co-occurrence network within 2 years to diagnosis. Longitudinal trajectory analysis was used to examine the evolution of symptom intensity over 3-month sliding windows from 2 years to diagnosis. Results: From 1 year to 3 months pre-diagnosis, 16 non-chronic signs and symptoms were significantly associated with increased EOCRC risk, with the highest incidence rate ratios (IRRs) for blood in stool (IRR 12.9, 95% CI 4.4-38.1) and hemorrhage of rectum and anus (11.4, 5.0-26.0). Network analysis identified three symptom clusters centered on abdominal pain: (1) hemorrhage of the rectum and anus, which connects to blood in stool, acute pain, and anal/rectal conditions; (2) benign neoplasm of the colon; and (3) nausea and vomiting, back pain, syncope and collapse, and urinary tract infection, which interconnect. Clusters 1 and 2 co-occurred increasingly from 2 years to 3 months pre-diagnosis, with connections between clusters 1 and 3 emerging in the final 3 months. Longitudinal trajectory analysis demonstrated a steady increase in symptom intensity, accelerating 9 months before diagnosis, for abdominal pain, hemorrhage of rectum and anus, blood in stool, benign neoplasm of colon and anal and rectal conditions. Conclusion: Mapping symptom networks and their temporal evolution offers a promising path to enhance EOCRC detection. Integrating these insights into precision diagnostics can align with advanced prevention frameworks, improving outcomes for younger at-risk populations. Citation Format: Ruiyi Tian, Chongliang Luo, Xiaoyu Zong, Cassandra D. Fritz, Philip R. Payne, Yin Cao. Temporal evolution of early signs and symptoms of early-onset colorectal cancer in diverse populations: Insights from the All of US Research Program [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 7405.
Abstract 5872: The gut microbiota from vasoactive intestinal peptide knock-out mice confers resistance to the growth of leukemia in wild-yype mice
Authors: Kayla Robinson, Shayna Jankowski, Jian Ming Li
Journal: Cancer Research (2025)

Mice Resistance to Leukemia via Gut Microbiota Transfer Vasoactive Intestinal Peptide (VIP) regulates adaptive immunity through receptors expressed in T lymphocytes, VPAC1andVPAC2. VIP over production in leukemia suppresses immune function, facilitating cancer progression. VIP-knockout (VIP-KO) mice show a survival advantage against leukemia, likely due to gut microbiota-mediated immune response regulation. Cohousing enables gut microbiota transfer from VIP-KO to wild-type (WT) mice via coprophagy, potentially enhancing WT mice's resistance to leukemia. This study investigates whether cohousing WT and VIP-KO mice alters WT gut microbiota and confers resistance to leukemia challenge. Eighty mice, 42VIP-KO 38WT, were cohoused across 10cages for six weeks. Blood and stool samples were collected pre- and post-cohousing for immune and microbiome analyses. Mice were injected with syngeneic CD1498leukemiacells post-cohousing and monitored for survival. Gender differences in survival outcomes were also assessed. WT mice cohoused with VIP-KO mice demonstrated significant colonization by VIP-KO-derived gut microbiota, including Ruminococcus gnavus and Lactobacillus murinus, characterized by lower gut pH. Cohousing improved WT survival rates after leukemia challenge(p&amp;lt;0.009), producing long-term survivors. VIP-KO mice showed the highest presence of R. gnavus after cohousing (p=0.017)Cohousing-induced microbiota transfer enhances leukemia resistance in WT mice through gut microbiota-mediated immune modulation. Survival improvements are independent of gender, underscoring the robustness of this therapeutic strategy. These findings highlight microbiota-targeted therapies, such as fecal microbiota transplantation, as promising approaches for leukemia treatment. Future studies will evaluate combined microbiota transfer and VIP antagonism therapies i.e. ANT308tooptimizeoutcomes. Wild Type cohousing had a significance of p&amp;lt;0.001. Knockout cohousing had a significance of p&amp;lt;0.009. Wild type mice had the highest median survival time at 27days. Citation Format: Kayla Robinson, Shayna Jankowski, Jian Ming Li. The gut microbiota from vasoactive intestinal peptide knock-out mice confers resistance to the growth of leukemia in wild-yype mice [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 5872.
Abstract 5870: Blocking cadherin-11 activates pyroptosis-mediated antitumor immunity via the PD-L1/GSDMD/CCL3 axis in bladder cancer
Authors: Thomas I-Sheng Hwang, An-Chen Chang
Journal: Cancer Research (2025)

Abstract Introduction: Pyroptosis, a form of programmed cell death driven by proinflammatory signals, plays a dual role in inflammation and cancer progression. Cadherin-11 (CDH-11), a type II cadherin, is known to mediate cell-cell and cell-extracellular matrix adhesion. Emerging evidence suggests that CDH-11 contributes to tumor progression and metastasis, making it a potential therapeutic target. In this study, we investigate whether targeting CDH-11 can suppress bladder cancer (BC) cell invasiveness and activate pyroptosis-mediated antitumor immunity. Materials &amp; Methods: Transwell assays were conducted to evaluate cell migration and invasion abilities. Pyroptosis was measured using lactate dehydrogenase (LDH) assays, while calcein AM staining-based cytotoxicity assays were employed to measure natural killer (NK) cell-mediated cytotoxicity. Inflammatory cytokine levels in BC tissues were determined using a human antibody array. To investigate the role of CDH-11 in tumor progression, a subcutaneous tumor model and a popliteal lymph node model were established to evaluate tumor growth and lymphatic metastasis in vivo. Immunohistochemistry staining was utilized to assess CDH-11 protein expression in human BC tissues. Results: Elevated CDH-11 expression was observed in BC patients compared to healthy individuals, with a positive correlation to advanced clinical stages, lymphatic metastasis, and poor overall survival. In vitro analyses demonstrated that blocking CDH-11 significantly reduced BC cell invasiveness. Notably, CDH-11 blockade induced bubble-like protrusions on the cell surface and increased LDH release, indicative of enhanced pyroptosis. Mechanistically, CDH-11 inhibition activated PD-L1-mediated GSDMD expression, with the GSDMD N-terminal domain forming membrane pores to initiate pyroptosis. Further analysis revealed that CDH-11-induced pyroptosis elevated the release of the proinflammatory cytokine CCL3 within the tumor microenvironment, thereby enhancing natural killer (NK) cell-mediated cytotoxicity against BC cells. In vivo, CDH-11 blockade effectively suppressed tumor growth, lymphatic metastasis, and lung metastasis, highlighting its therapeutic potential. Conclusions: These findings reveal a novel role of CDH-11, demonstrating that its inhibition suppresses cell invasion and enhances pyroptosis-mediated antitumor immunity through CCL3 in BC. Targeting CDH-11 represents a promising therapeutic strategy for the management of BC. Citation Format: Thomas I-Sheng Hwang, An-Chen Chang. Blocking cadherin-11 activates pyroptosis-mediated antitumor immunity via the PD-L1/GSDMD/CCL3 axis in bladder 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 5870.
Abstract 4445: Super-enhancers reorganization controls re-sensitization of oxaliplatin-resistant FBXW7-mutated colorectal cancer
Authors: Vanessa Tolotto, Nicolò Gualandi, Raffaella Picco, Ylenia Cortolezzis, Francesca D'Este, Monica Colitti, Wayne W. Hancock, Claudio Brancolini, Luigi Xodo, Eros Di Giorgio
Journal: Cancer Research (2025)

Abstract The resistance of cancer to therapies remains an unresolved issue. It may result from tumor evolution, which is characterized by epigenetic plasticity and large-scale chromatin remodeling. Catalytically inactive class IIa HDACs (HDAC4, HDAC5, HDAC7, HDAC9) control the targeted recruitment of chromatin remodeling complexes, making them attractive therapeutic targets in oncology. Recently, we have described the role of HDAC4 in monitoring the assembly of the end resection complex involved in homologous recombination (HR) repair. In cells defective for HR repair, HDAC4 is proteasomally degraded. Here, through in silico and in vitro screenings we identified FBXW7 as the E3 ligase involved in proteasomal degradation of HDAC4, and its role was confirmed by means of ubiquitin co-immunoprecipitation experiments and in vitro ubiquitylation assays. FBXW7 is a tumor suppressor gene encoding the substrate recognition component of an SCF ubiquitin ligase complex. It is one of the most frequently mutated genes in colorectal cancer (CRC), and loss of function of FBXW7 has been reported to induce resistance to chemotherapeutic agents such as oxaliplatin (OxPt), which is commonly used in adjuvant therapy for CRC. We confirmed that FBXW7-/- CRC cells were resistant to OxPt treatment and HDAC4 was not degraded under these conditions. Silencing or forced degradation of HDAC4 using a PROTAC-based compound restored OxPt sensitivity in FBXW7-mutated CRC cells, in patient-derived organoids (PDOs) and in a xenograft model in mice. By evaluating the transcriptomic landscape and super-enhancer (SE) repertoire status in FBXW7-mutated PDOs, we demonstrated the relevance of epigenetic resetting in controlling OxPt resistance. In particular, forced downregulation of HDAC4 resulted in dramatic loss of SEs in FBXW7-deficient tumors and restoration of certain SEs found in OxPt-sensitive tumors. Furthermore, patient profiling based on the epigenetic state of SEs controlled by HDAC4 identified a priori CRC patients resistant to OxPt. This study supports HDAC4 as a key mediator of OxPt resistance in FBXW7-mutated CRC and highlights the remodeling of a well-defined repertoire of SEs as part of the process of successful re-sensitization. Citation Format: Vanessa Tolotto, Nicolò Gualandi, Raffaella Picco, Ylenia Cortolezzis, Francesca D'Este, Monica Colitti, Wayne W. Hancock, Claudio Brancolini, Luigi Xodo, Eros Di Giorgio. Super-enhancers reorganization controls re-sensitization of oxaliplatin-resistant FBXW7-mutated 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 4445.