tbuckley/cabot-search huggingface dataset:
Abstract 7501: APOBEC3A drives chromosomal instabilityand tumor evolution in pancreatic cancer
Authors: Zhihui Zhang, Chunxu Gao, Sonja Wörmann, Peter Van Loo
Journal: Cancer Research (2025)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer characterized by extensive genomic complexity, rapid metastasis, and resistance to therapy. Our research focuses on the role of APOBEC3A (A3A), a cytidine deaminase enzyme, in promoting chromosomal instability (CIN) and intratumoral heterogeneity (ITH) as mechanisms driving PDAC progression and metastasis. Preliminary findings reveal that A3A drives CIN in a deaminase-independent manner, as demonstrated by dose-dependent increases in structural variants, micronuclei formation, and chromosomal aberrations. Furthermore, A3A expression significantly correlates with early tumor dissemination, enhanced metastatic colonization, and reduced survival, as shown in both human and murine models. While previous studies have highlighted A3A's molecular effects, they lack copy number signature analysis to systematically characterize CIN. Addressing this gap, our study aims to define A3A-driven copy number signatures in PDAC, providing critical insights into its role in tumor evolution and vulnerability to therapeutic interventions. Using a multi-modal approach, we integrate data from genetically engineered mouse models, human PDAC tissues, and cancer cell lines, employing bulk whole-genome sequencing (WGS) and advanced bioinformatics pipelines to uncover the full scope of A3A’s contributions to tumor evolution. We aim to demonstrate how A3A-mediated genomic instability accelerates the transition from pre-neoplastic lesions to advanced PDAC. Our findings will elucidate how A3A-mediated genomic instability accelerates the progression from pre-neoplastic lesions to advanced PDAC. By addressing critical gaps in the understanding of CIN and ITH, this study positions A3A as a compelling therapeutic target to mitigate genomic instability, reduce tumor heterogeneity, and ultimately improve clinical outcomes for patients with pancreatic cancer. Citation Format: Zhihui Zhang, Chunxu Gao, Sonja Wörmann, Peter Van Loo. APOBEC3A drives chromosomal instabilityand tumor evolution 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 7501.
Abstract 7380: Association of weight loss promoting medications with male breast cancer incidence, tumor grade, and stage: a SEER-Medicare nested case-control study
Authors: Aniruddha B. Rathod, Biai Dominique Elmir Digbeu, Jenil R. Patel, David S. Lopez
Journal: Cancer Research (2025)

Abstract Background: Obesity has been associated with an increased incidence of male breast cancer (MBC), including the high-grade and advance-stage of the disease. With the rising use of weight loss-promoting medications (WLPMs), including the use of metformin, there is a growing interest in their potential to positively influence cancer outcomes. Yet, there is a poor understanding about the impact of WLPMs and metformin on the incidence of MBC, stage and grade, presenting a significant gap in research. Methods: We conducted a nested case-control study using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database. The cohort included 2, 444 MBC cases and 12, 068 matched controls (1:5 by birth year and diagnosis date), all of whom had continuous Medicare Part A/B enrollment for at least one year between 2008 and 2019. Pre-diagnostic exposure to WLPMs and metformin was determined through prescription records. Multivariable weighted conditional logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for MBC incidence, advanced-stage cancer (stage 4), and high tumor grade (grade 3). Results: Among MBC cases, 83% were Non-Hispanic White, 34% were &amp;gt;=80 years, 75% had hypertension, 56% had hyperlipidemia, 36% had diabetes and 16% used metformin over 6 months prior to index date. Metformin use was associated with a reduced risk of MBC incidence (OR 0.64, 95% CI 0.54-0.74), and high tumor grade (OR 0.57, 95% CI 0.41-0.78). However, it was linked to an increased likelihood of advanced-stage cancer (OR 1.79, 95% CI 1.26-2.56). WLPMs did not significantly affect the incidence, tumor grade and stage of MBC. Conclusion: Our findings suggest that metformin may reduce the risk of MBC incidence but could be associated with advanced-stage disease at diagnosis. Further research is needed to explore the effects of WLPMs on MBC outcomes. Citation Format: Aniruddha B. Rathod, Biai Dominique Elmir Digbeu, Jenil R. Patel, David S. Lopez. Association of weight loss promoting medications with male breast cancer incidence, tumor grade, and stage: a SEER-Medicare nested case-control study [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 7380.
Abstract 4121: Correlation, interaction, and prognostic impact of SMC4 and NIPBL phosphorylation in endometrial carcinoma
Authors: Jie Zhang, Qin Yang, Feilong Zhao, Ding Zhang, Yantao Li
Journal: Cancer Research (2025)

Background: Uterine Corpus Endometrial Carcinoma (UCEC) poses treatment challenges due to limited options. Protein phosphorylation, a dynamic reversible process, emerges as optimal targets. Methods: We analyzed phosphoprotein, protein, and mRNA data of UCEC in the CPTAC dataset (PDC000126). Correlation network and hierarchical clustering were employed to identify core phosphoproteins and proteins. Protein-Protein Interaction network was constructed using the STRING database. Results:Data from 95 UCEC patients, mainly FIGO stage I, included 73,212 phosphoprotein sites (8,450 genes) and 9,099 protein expressions. Only genes expressed in ≥80% of samples were included. Generally, protein-mRNA expression correlation was high (median 0.51), while phosphoprotein-protein and mRNA correlations were weaker (median: 0). Using a correlation coefficient &amp;gt;0.4, we identified 259 phosphorylation sites that correlated with 91 proteins. Clustering identified 11 core phosphorylation sites that universally correlated with proteins and 15 core genes that universally correlated with phosphorylation sites. Further analysis found the phosphorylation sites that strongly associated with these core genes located at 72 genes. The interaction networks between the 14 core genes and 72 co-expressed genes revealed RFC4, TPX2, SMC4, and NCAPD2 as central nodes regulating at least 10 co-expressed genes. Survival analysis linked the 4 core genes to UCEC patient PFS and OS. By setting experimentally determined interactions &amp;gt;0.5, we identified previous confirmed phosphorylation counterparts of core genes: NCAPD2-NCAPG, RFC4-RFC1, SMC4-NCAPG, SMC4-NCAPD3, and SMC4-NIPBL. Notably, NIPBL harbored two phosphorylation sites (NIPBL_T599 and NIPBL_T592). Intriguingly, SMC4, NCAPG, and NCAPD3 are condensin complex subunits, while NIPBL is a cohesin-loading factor, suggesting coordinated regulation between the two protein complexes. Conclusion: The gene expression and protein phosphorylation network offer potential UCEC treatment targets. The SMC4-NIPBL interaction implies a harmonization between cohesin and condensin complexes, potentially impacting UCEC prognosis. Citation Format: Jie Zhang, Qin Yang, Feilong Zhao, Ding Zhang, Yantao Li. Correlation, interaction, and prognostic impact of SMC4 and NIPBL phosphorylation in endometrial carcinoma [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 4121.
Abstract 7490: Uncovering rare cellular populations in esophageal preneoplasia through genetic perturbation tracking and scRNA-seq
Authors: Jinho Jang, Kyung-Pil Ko, Jie Zhang, Jae-Il Park
Journal: Cancer Research (2025)

Abstract The early detection and characterization of rare cellular populations in preneoplastic lesions are crucial for understanding cancer initiation and progression, as well as for identifying novel therapeutic targets. Rare cell populations, often overlooked due to their low abundance, play pivotal roles in shaping the tumor microenvironment and driving disease development. In this study, we employed a lineage tracing system based on tracing vectors introduced into a 2D cell line model of esophageal preneoplasia. This approach allowed us to track genetic perturbations that accumulate during cell proliferation, enabling precise identification of distinct cellular lineages. By coupling this lineage tracing method with single-cell RNA sequencing (scRNA-seq), we achieved high-resolution transcriptomic profiling, uncovering rare cellular populations with unique molecular and lineage-specific characteristics. The rare populations identified through this integrated approach exhibited a quiescent phenotype, suggesting their involvement in lesion persistence and resistance to therapies targeting proliferative cells. Transcriptomic analysis revealed distinct genetic signatures and key pathways associated with these populations, offering potential avenues for therapeutic intervention and biomarker development. Our findings demonstrate the value of combining genetic perturbation-based lineage tracing with scRNA-seq to uncover rare and functionally significant cellular populations. This study provides new insights into the cellular dynamics underlying esophageal cancer initiation and progression, laying the groundwork for future research aimed at understanding the roles of these populations and developing targeted therapies. Citation Format: Jinho Jang, Kyung-Pil Ko, Jie Zhang, Jae-Il Park. Uncovering rare cellular populations in esophageal preneoplasia through genetic perturbation tracking and scRNA-seq [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 7490.
Abstract 7508: Transcriptomic analysis of polyisoprenylated cysteinyl amide inhibitors treatment of pancreatic and breast cancer reveals changes in apoptotic and angiogenic factors
Authors: Kweku Ofosu-Asante, Amarender Burra, Jahnissi Odoom, Joshua Ablordeppey, Nazarius S. Lamango
Journal: Cancer Research (2025)

Abstract The aggressive nature of KRAS-driven cancers and the lack of effective targeted therapies makes them extremely challenging to manage. The polyisoprenylated cysteinyl amide inhibitors (PCAIs) were designed to mimic the polybasic C-terminal hypervariable (HVR) region of KRAS and related proteins. The HVR and polyisoprene modifications are essential for their functional localization. Disrupting the polyisoprenylation-dependent interactions abrogates RAS signaling interactions, affording opportunities for controlling hyperactive G-proteins in cancers. Previous studies have demonstrated the effectiveness of PCAIs against cancer-progression phenomena various cancer cell lines. Hence, we determined the effect of the PCAIs on the gene expression in PANC-1, MIA PaCa-2 and MDA-MB-231 cells, to better understand biological responses elicited by cancer cells on exposure to PCAIs at gene level. Following 3 µM NSL-YHJ-2-27 treatment of MIA PaCa-2 cells, total RNA was extracted, sequenced and analyzed using Partek Flow. DESeq2 tool was used to analyze a total of 88 genes that were significantly differentially expressed. Out of the 88 genes, 85 were upregulated and 3 downregulated. Notable genes such as tumor suppressor gene, suppressor of cytokine signaling 1 (SOCS1) and autophagy-related protein 9 (ATG9L) were significantly upregulated by 2-fold and 3-fold, respectively. Moreover, treatment with 3 µM NSL-AB-51 of both PANC-1 and MDA-MB-231 cells resulted in 9 and 28 genes, respectively, being differentially expressed. The gene endothelin-1 (EDN1) which promotes cell proliferation, survival and neovascularization was significantly downregulated by one-fold in PANC-1 cells. Genes such as BCL-2 binding component 3 (BBC3) that has been shown to promote apoptosis and angiopoietin-like 4 (ANGPTL4) that inhibits tumor angiogenesis were significantly upregulated by 2-fold and 4-fold, respectively. These effects on the transcriptome strongly corroborate the phenotypic characteristics of the PCAIs against cell viability and proliferation, migration, invasion and angiogenesis and offers more opportunities to further understand and develop the PCAIs as potential agents to treat KRAS-driven cancers. Citation Format: Kweku Ofosu-Asante, Amarender Burra, Jahnissi Odoom, Joshua Ablordeppey, Nazarius S. Lamango. Transcriptomic analysis of polyisoprenylated cysteinyl amide inhibitors treatment of pancreatic and breast cancer reveals changes in apoptotic and angiogenic factors [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 7508.
Abstract 7220: Zongertinib demonstrates potent efficacy against cancer cells harboring HER2 non-tyrosine kinase domain mutations
Authors: Yuji Shibata, Monique B. Nilsson, Hibiki Udagawa, Jacqulyne P. Robichaux, Junqin He, Xiaoxing Yu, John V. Heymach
Journal: Cancer Research (2025)

Abstract Activating mutations in HER2 are found in approximately 2-4% of non-small cell lung cancer (NSCLC). Recurrent activating mutations most commonly occur in the tyrosine kinase domain (TKD) encoded by exons 18-21, with exon 20 insertions being the most frequent, followed by non-TKD mutations in the transmembrane domain (TMD) and juxtamembrane domain (JMD). While tyrosine kinase inhibitors (TKIs) such as the HER2-selective inhibitor zongertinib and the pan-HER inhibitors poziotinib, pyrotinib, and afatinib have been tested primarily in patients harboring TKD mutations, their efficacy against non-TKD mutations has been less well characterized. To systematically evaluate HER2 TKI activity against HER2 non-TKD mutations, we established a panel of Ba/F3 cell lines expressing various HER2 mutations including common TKD mutations (e.g. exon 20 insertions YVMA, GSP, and VC), TMD mutations such as V659E, and JMD mutations such as R678Q and evaluated drug sensitivity by Cell Titer Glo assay. Among HER2 TMD mutations, zongertinib showed potent activity with an average IC50 value of 8.72 nM. For HER2 JMD mutations, zongertinib demonstrated an IC50 value of 0.35 nM, and among HER2 TKD mutations, zongertinib treatment yielded an average IC50 value of 6.14 nM. Moreover, calculation of the relative IC50 value, representing the ratio of IC50 values between HER2 mutations and wild-type EGFR, revealed that zongertinib which had an average log IC50 mutant HER2/wild-type EGFR ratio of -2.31, -3.71, -2.46, for TMD, JMD, and TKD HER2 mutations, respectively, exhibited superior selectivity compared to pyrotinib (TMD -1.00, JMD -4.85, TKD -0.55) and poziotinib (TMD 0.09, JMD -3.13, TKD 0.48). This suggests zongertinib has high efficacy and a potentially lower risk of EGFR inhibition-associated toxicity. In addition, we generated a HER2 TMD mutant NSCLC cell line model by expressing HER2 V659E in HCC4006 cells and knocking out endogenous mutant EGFR. Consistent with our results obtained using Ba/F3 models, HCC4006 HER2 V659E cells were sensitive to HER2 inhibition with zongertinib. Our findings indicate that zongertinib demonstrates comparable or more potent inhibitory activity for HER2 non-TKD mutants (e.g TMD and JMD) as HER2 TKD mutations, providing a potential therapeutic option for patients with these HER2 non-TKD mutant cancers. Citation Format: Yuji Shibata, Monique B. Nilsson, Hibiki Udagawa, Jacqulyne P. Robichaux, Junqin He, Xiaoxing Yu, John V. Heymach. Zongertinib demonstrates potent efficacy against cancer cells harboring HER2 non-tyrosine kinase domain mutations [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 7220.
Abstract 6451: Tocilizumab in fibrolamellar carcinoma
Authors: Paul M. Kent, Jennifer Hamm, Tom Stockwell, Jordan Tasse
Journal: Cancer Research (2025)

Abstract Background: Fibrolamellar Carcinoma (FLC) is a rare liver cancer of young people. Interleukin-6 (IL-6), is overexpressed in many cancers, including FLC, drives inflammation, angiogenesis, and activation of the JAK-STAT signaling pathway associated with progression, a worse prognosis, and inhibition of T-cell tumor attack. Check-point inhibitor (CPI) drugs induce T-cell tumor attack, but also induce immune-related adverse effects (irAEs), often with elevated IL-6 and eosinophilia. Tocilizumab (TOC), an IL-6 receptor blocker, approved for inflammatory diseases and steroid-refractory CPI irAEs, has been shown in the lab to both mitigate CPI toxicity and promote tumor immunity, while avoiding the toxicity, immune suppression, and tumor promoting effects of steroids, and allowing patients to restart CPIs. We prospectively collected data over 18 months on all FLC TOC patients seen and report on those with irAEs. This is the first report of TOC use in FLC. Methods: With IRB approval and consent (NCT03793088), data was collected prospectively on all FLC TOC subjects from Apr. 1, 2023 to Dec. 1, 2024. Results: Overall, 83% of 24 FLC patients with irAEs responded to TOC (13F, median age 24, 50% recent CPI, 92% AE grade 3-4, 1/3 with concurrent steroids). The most common irAEs were ascites, hepatitis, pneumonitis and colitis, with a median serum IL-6 of 163 [&amp;lt;5 pg/ml], median tumor IL-6 overexpression at the 96Th percentile, and median 9% eosinophilia [&amp;lt;2%]. The median tumor volume and circulating tumor DNA response was -20% and -78%, respectively. Proximal follow-up scans showed CR/PR/SD/PD rates of 5%/40%/40%/15%. Most (74%) resumed CPI after TOC treatment and 41% continued TOC as maintenance [Table 1]. Best tumor responses corresponded with CR for irAE, higher IL-6, CPI continuation, and no steroids. No side effects were attributed to TOC (total 174 doses). Conclusions: TOC used for inflammatory conditions in FLC showed reliable responses, with many patients restarting CPI, and a majority with tumor burden reduction, suggesting a double benefit. Citation Format: Paul M. Kent, Jennifer Hamm, Tom Stockwell, Jordan Tasse. Tocilizumab in fibrolamellar carcinoma [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 6451.
Abstract 6454: Extracellular matrix topography drives adrenergic to mesenchymal transition in neuroblastoma
Authors: Antonios Chronopolous, Chandra Vemula, Vic Zamloot, Ivan Chavez, Rebekah Kennedy, Shahab Asgharzadeh, JinSeok Park
Journal: Cancer Research (2025)

Abstract Neuroblastoma (NB), the most common extracranial solid tumor in children, exhibits intra-tumoral heterogeneity with two interconvertible identities: adrenergic (ADRN) and mesenchymal (MES). MES cells display phenotypes associated with metastasis and resistance to therapies compared to ADRN. Thus, the reprogramming of ADRN to MES may contribute to poor NB outcomes, and the process requires further elucidation to improve NB clinical outcomes. The extracellular matrix (ECM), a critical component of the tumor microenvironment (TME), provides structural support and delivers mechanical signals that modulate oncogenic regulation. We demonstrate that high-risk NB contains more topographically aligned ECM fibers than low-risk NB. By using nano-fabricated biomaterials that mimic ECM alignment, we reveal that ECM topography drives the transition from ADRN to MES. This transition involves transcriptional and epigenetic changes, accompanied by the enhanced phenotypic features of MES cells. We also reveal that the Rho-associated kinase and YAP signaling pathways, stimulated by the ECM topography, mediate ECM-driven reprogramming. In summary, ECM-driven transition of NB cells toward MES offers new insights into TME-targeted therapeutic strategies to suppress MES cells and improve NB outcomes. Citation Format: Antonios Chronopolous, Chandra Vemula, Vic Zamloot, Ivan Chavez, Rebekah Kennedy, Shahab Asgharzadeh, JinSeok Park. Extracellular matrix topography drives adrenergic to mesenchymal transition in neuroblastoma [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 6454.
Abstract 6282: Age-related shifts in the immune system revealed from single-cell RNA-seq using non-negative matrix factorization
Authors: Ragnhild Laursen, David Martin-Pestana, Nicolai J. Birkbak
Journal: Cancer Research (2025)

Abstract Unraveling the molecular mechanisms driving aging and identifying potential therapeutic targets for age-related diseases are essential to increase healthspan. The aging immune system undergoes significant alterations, contributing to immune dysfunction and increased susceptibility to diseases. Identifying gene programs associated with immune aging is key to understanding these changes and developing strategies to counteract their effects. In this study, we leverage non-negative matrix factorization (NMF), an interpretable and powerful dimensionality reduction technique, to identify gene expression programs in the immune system that shift with age. We analyze single-cell RNA sequencing (scRNA-seq) data from the large OneK1K cohort, which includes 981 participants aged 19 to 97 years and encompasses 1.27 million peripheral blood mononuclear cells. We reveal two distinct age-related transitions in the immune system composition and function occurring with an average peak around 39.3 and 71.8 years of age. These transitions are characterized by the activation or suppression of particular gene programs, reflecting changes in immune cell types, their interactions, and signaling pathways. Our findings provide a clearer understanding of the molecular underpinnings of immune aging by uncovering gene programs associated with it. These potential biomarkers of immune aging could enhance therapeutic strategies aimed at rejuvenating immune function in aging populations. Citation Format: Ragnhild Laursen, David Martin-Pestana, Nicolai J. Birkbak. Age-related shifts in the immune system revealed from single-cell RNA-seq using non-negative matrix factorization [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 6282.