tbuckley/cabot-search huggingface dataset:
Abstract 4845: The MLL3/GRHL2 complex modulates early malignant development and anti-tumor immunity in upper aerodigestive squamous cell carcinoma
Authors: Chehyun Nam, Guowei Huang, Yueyuan Zheng, Hua Zhao, Ethan Pan, Boyan Hu, Talia Wenger, Hieu Van, Liyan Xu, En-min Li, H.Phillip Koeffler, Kai Ge, Yali Dou, Uttam K. Sinha, Young Min Park, De-Chen Lin
Journal: Cancer Research (2025)

Abstract Upper aerodigestive squamous cell carcinoma (UASCC), including head and neck squamous cell carcinoma (HNSCC) and esophageal squamous cell carcinoma (ESCC), poses substantial challenges in clinical care due to its aggressive behavior and poorly understood mechanisms of early malignant transformation. This study investigates the role of MLL3 mutations as critical, clonal genomic events driving UASCC tumorigenesis. Using CRISPR-edited organoid models across species, we demonstrate that MLL3 loss facilitates early squamous neoplastic evolution. Additionally, we uncover an MLL3/GRHL2 protein complex that orchestrates epigenomic regulation, particularly influencing immune-related pathways. Strikingly, we identify a novel MLL3/GRHL2-IRF1 axis that induces the expression of Th1 chemokines, such as CXCL9 and CXCL10, enhancing anti-tumor immunity by promoting T cell infiltration within the tumor microenvironment. In syngeneic mouse models, including both subcutaneous and orthotopic settings, MLL3 was shown to modulate the efficacy of immune checkpoint blockade (ICB) therapy. Consistently, clinical data from human patients demonstrate a robust correlation between MLL3 expression and responsiveness to ICB therapy. This study underscores the pivotal role of MLL3 in UASCC pathogenesis and highlights the therapeutic potential of targeting the MLL3/GRHL2-mediated immune response pathways to improve outcomes in UASCC treatment. Citation Format: Chehyun Nam, Guowei Huang, Yueyuan Zheng, Hua Zhao, Ethan Pan, Boyan Hu, Talia Wenger, Hieu Van, Liyan Xu, En-min Li, H.Phillip Koeffler, Kai Ge, Yali Dou, Uttam K. Sinha, Young Min Park, De-Chen Lin. The MLL3/GRHL2 complex modulates early malignant development and anti-tumor immunity in upper aerodigestive squamous cell 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 4845.
Abstract 4506: Plasma proteomics reveals biomarkers of lung cancer in non-smoking women
Authors: Guojin Si, Zhangyan Lyu, Ximin Gao, Fengju Song
Journal: Cancer Research (2025)

Abstract Background: Lung cancer is the most prevalent cancer among women in China. The incidence of lung cancer in women is increasing, despite the fact that traditional risk factors such as smoking have decreased. The investigation of new protein markers may enhance the etiological network and further elucidate the pathogenesis of lung cancer in non-smoking women. Methods: We selected three non-smoking female lung cancer patients from the Chinese Colorectal, Breast, Lung, Liver, And Stomach Cancer Screening Trial (C-BLAST) cohort. Three healthy controls were matched based on age (±3 years), sex, year of screening, and smoking status. The proteomic assays were conducted on the Somascan Assay 11k platform, utilizing plasma that had been collected at baseline. The differential proteins between lung cancer patients and healthy controls were analyzed using paired t-tests (P &amp;lt; 0.05). The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) platforms were employed to investigate the functions and pathways enriched by differential proteins. The STRING platform was utilized to develop the protein-protein interaction (PPI) network of these proteins, and the core proteins were determined based on their degree. Results: The average age of the participants in the study was 55.8 years. Through the comparison of plasma proteomics between lung cancer patients and healthy controls, 224 differential proteins were discovered, including 116 up-regulated and 108 down-regulated proteins. GO analysis revealed these proteins were associated with some biological functions, including the response to hydrogen peroxide, nuclear-transcribed mRNA catabolic process, exonucleolytic, fatty acid homeostasis, immune effector processes, and T-helper 2 cell differentiation. KEGG analysis revealed that these proteins are enriched in pathways such as glycerolipid metabolism, aldosterone-regulated sodium reabsorption, transcriptional dysregulation in cancer, and NOD-like receptor signaling pathway. We constructed the PPI network based on these 224 proteins and identified the top ten core proteins: CD4, INS, MYD88, IFNA1, APOE, BECN1, CD86, MPHOSPH10, NLRP3, and C3. These core proteins are involved in biological processes, including immunology, inflammation, and antiviral responses, and may contribute to the development of lung cancer. Conclusions: We found several plasma proteins by plasma proteomics that may assist in identifying lung cancer patients and offer new insights into the etiological network of non-smoking lung cancer in women. Citation Format: Guojin Si, Zhangyan Lyu, Ximin Gao, Fengju Song. Plasma proteomics reveals biomarkers of lung cancer in non-smoking women [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 4506.
Abstract 1547: CXCL17 targets macrophage efferocytosis to modulate cutaneous squamous cell carcinoma (cSCC)
Authors: Alok R. Khandelwal, Dhananjay Kumar, Arif Yurdagul, Cherie-Ann O. Nathan
Journal: Cancer Research (2025)

Abstract Cutaneous squamous cell carcinoma (cSCC) is a keratinocyte-derived invasive and metastatic tumor of the skin. It is the second-most commonly diagnosed form of skin cancer, striking 200, 000 Americans annually. Excision of cSCC of the head and neck area results in significant facial disfigurement. An increased understanding of the mechanisms involved in the pathogenesis of cSCC could identify means to prevent, inhibit, and reverse this process. Chemokine (C-X-C motif) ligand 17 (CXCL17) is the latest chemokine family member, and an increased CXCL17 protein expression was observed in both mouse and human cSCC cell lines. Further, deletion of CXCL17 was associated with significant inhibition of tumor cell-intrinsic properties such as proliferation, migration, and motility. CXCL17 is identified as a potent chemoattractant for macrophages, dendritic cells and myeloid-derived suppressive cells. Accordingly, utilizing a syngeneic, tumor-cell xenograft cSCC mouse model, we evaluated the effect of CXCL17 deletion on cSCC tumor-immune evasion and elucidated the underlying mechanism. Deletion of CXCL17 was associated with a significant reduction in tumor volume compared to the wild-type counterparts. Further, CXCL17 deleted cSCC tumor cell xenografts exhibited a significant increase in CD8+, cytotoxic T cells in the tumor microenvironment, suggesting an important role of CXCL17 in mediating tumor-immune evasion. Interestingly, treatment with CXCL17 induced macrophage M2 polarization, increased oxidative phosphorylation and promoted macrophage efferocytosis via modulating efferocytotic machinery proteins such as MERTK, TIM4, GAS6 and AXL. Our studies have established substantial evidence for the role of CXCL17 in modulating tumor-cell extrinsic properties to affect the progression of cSCC. Citation Format: Alok R. Khandelwal, Dhananjay Kumar, Arif Yurdagul, Cherie-Ann O. Nathan. CXCL17 targets macrophage efferocytosis to modulate cutaneous squamous cell carcinoma (cSCC) [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 1547.
Abstract 6408: Stromal cell PD-L1 potentiates epitope spreading in the germinal center
Authors: Elliot Akama-Garren, Yingying Zhang, Balthasar Heesters, Padraic Fallon, Michael Carroll
Journal: Cancer Research (2025)

Abstract Background: Although immune checkpoint therapy targeting PD-1/PD-L1 can induce durable responses in cancer patients, it is also associated with epitope spreading and adverse events that can limit cancer treatment. Epitope spreading may occur in the germinal center (GC), where T follicular helper (TFH) and T follicular regulatory (TFR) cells interact with B cells to generate humoral immunity. Despite high expression of PD-1 by TFH and TFR cells, the function of its ligand PD-L1 in the GC remains unknown. Methods: We characterized the stromal cell compartment in secondary lymphoid organs by performing single cell RNA sequencing on human tonsils and mouse Peyer’s Patches and integrating these data with publicly available datasets. To investigate the functional significance of follicular dendritic cell (FDC) expression of PD-L1, we crossed Cxcl13Cre mice with Pdl1fl/fl mice to generate mice with conditional deletion of PD-L1 in FDCs. To visualize and quantify cellular dynamics in vivo, we adoptively transferred fluorescently labeled lymphocytes into mice and performed intravital multiphoton microscopy on skin draining lymph nodes. Results: Integrated analyses of human and mouse secondary lymphoid organs revealed that FDCs are heterogenous across tissues and species. FDCs also express PD-L1 and this expression is increased in autoantibody disease, although is not correlated with other changes in FDC gene expression. FDC specific deletion of PD-L1 decreases GC formation and prevents loss of B cell tolerance measured by entry of naïve B cells into autoreactive GCs. Autoreactive B cells also express increased PD-L1 and B cell specific deletion of PD-L1 similarly hinders GC responses. Intravital multiphoton microscopy demonstrated that FDC PD-L1 controls TFH and GC B cells by promoting stable T-B contacts. Single cell analyses of TFH cells revealed that PD-1 expression is highly correlated with Sostdc1 expression, which has been shown to promote TFR formation. Mechanistically, PD-L1 limits TFH production of Sostdc1, thereby suppressing TFR differentiation and enabling the GC response. Conclusion: We show that PD-L1 tunes T-B collaboration in the GC to promote humoral immunity. These findings uncover an immunogenic non-cell autonomous role of PD-L1 that is orthogonal to its well-established role in suppression of cell mediated immunity. We propose a model in which levels of PD-L1 on FDCs and bystander B cells tune the GC response by manipulating the follicular T cell compartment. Citation Format: Elliot Akama-Garren, Yingying Zhang, Balthasar Heesters, Padraic Fallon, Michael Carroll. Stromal cell PD-L1 potentiates epitope spreading in the germinal center [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 6408.
Abstract 7460: Unveiling NEPC vulnerabilities through single-cell analysis and drug screening
Authors: Ziyu Zeng, Yan Liu, Aktar Ali, Xin Lu
Journal: Cancer Research (2025)

Abstract Neuroendocrine prostate cancer (NEPC) represents an aggressive, treatment-resistant disease that emerges following androgen deprivation therapy. Despite growing evidence supporting transdifferentiation from luminal cells, the cellular origins and developmental trajectories remain poorly understood. Through comprehensive integration of single-cell RNA sequencing data from 318 human prostate cancer samples and 179 mouse models, analyzing over one million cells, we identified distinct neuroendocrine subpopulations as well as both convergence and diversity among non-neoplastic cells (especially fibroblasts and immune cells). These ongoing efforts are expected to provide an unprecedented comprehensive view of prostate cancer heterogeneity and unravel critical cellular and molecular differences between treatment-induced and de novo NEPC. Using our established dual-luciferase reporter system in NEPC cells, we screened 290 compounds and identified 19 AR-inducing compounds and 44 NEPC-selective compounds. Among these, several promising candidates showed significant therapeutic windows, including compounds targeting inflammatory pathways and epigenetic regulators, with one compound demonstrating 100-fold selectivity for NEPC cells compared to AR-positive prostate cancer cells. Additionally, we found that while NEPC cells retain basic AR signaling machinery, AR expression alone was insufficient to restore sensitivity to AR pathway inhibitors, highlighting the complexity of targeting cellular plasticity in NEPC. This integrative approach combining computational analysis with experimental validation provides new insights into NEPC development and presents novel therapeutic opportunities for this aggressive disease. Our ongoing work aims to validate these findings through cross-species comparative analyses and detailed mechanistic studies. Citation Format: Ziyu Zeng, Yan Liu, Aktar Ali, Xin Lu. Unveiling NEPC vulnerabilities through single-cell analysis and drug screening [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 7460.
Abstract 7465: Clustered macrophages cooperate to eliminate tumors via coordinated intrudopodia
Authors: Dennis E. Discher, Lawrence Dooling
Journal: Cancer Research (2025)

Abstract Macrophages often pervade solid tumors, but observations that macrophage clusters might associate with patient survival have remained largely unexplored. We observe dynamic macrophage clusters in tumors under conditions that maximize cancer cell phagocytosis, and our reductionist approaches to cluster formation reveal pathways and roles for tumor-intrusive pseudopodia. Aggregates form over hours on low-adhesion substrates after ‘M1’ polarization of macrophages with interferons, including Tcell-derived cytokines, and yet clusters prove fluid on timescales of minutes. Clusters also sort from M2 macrophages which are induced by an interleukin and that disperse on the same substrates. M1’s upregulate cell-cell adhesion receptors but suppress actomyosin contractility, and while both pathways contribute to cluster formation, decreased cortical tension was predicted to unleash pseudopodia. Macrophage neighbors in tumor spheroids indeed extend intrusive pseudopodia or ‘intrudopodia’ in between adjacent cancer cell junctions - at least when phagocytosis conditions are maximized, and coordinated intrudopodia help detach and individualize cancer cells for rapid engulfment. Macrophage clusters thereby provide a cooperative advantage for phagocytosis to overcome solid tumor cohesion. Citation Format: Dennis E. Discher, Lawrence Dooling. Clustered macrophages cooperate to eliminate tumors via coordinated intrudopodia [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 7465.
Abstract 7467: Unveiling racial disparities in prostate cancer using an integrative genomic and transcriptomic analysis
Authors: Ahmed Fadiel, Abdalla Elbialy, Akshay Sood, Shang-Jui Wang, Peng Wang, Anil V. Parwani, Gennady Shvets, Nagireddy Putluri, Jenny Li, Xuefeng Liu
Journal: Cancer Research (2025)

Abstract Significant racial disparities are found in prostate cancer patients. African American (AA) individuals have a ∼64% higher incidence and 2.3 times increased mortality rate compared to Caucasian (CA) counterparts. This study integrates RNA and exome sequencing from prostate cancer tissue in both populations to uncover genetic and transcriptomic differences driving these disparities. We analyzed 52 prostate cancer samples (27 AA, 25 CA) using RNA-seq and exome sequencing. RNA-seq analysis revealed 1003 upregulated and 1589 downregulated genes in AA samples compared to CA samples. Pathway analysis showed enhanced activity in immune response and cellular interactions in AA samples, with notable regulation by histone-associated transcription factors (HIST1H1A, HIST1H1D, and HIST1H1B). X2K analysis identified enrichment of EZH2 and SUZ12 transcription factors, core components of the PRC2 complex, suggesting epigenetic regulation involvement in AA prostate cancer. Exome sequencing identified 5419 mutations unique to AA samples and 1146 unique to CA samples. After filtering race-specific variants, we identified 266 unique mutations affecting 20 genes in AA samples and 415 unique mutations impacting 21 genes in CA samples. Key genes with high-impact mutations in AA samples included TP73 (tumor suppression), XYLB (metabolism), ALDH4A1 (oxidative stress), PTPRB (cellular signaling), and HLA-DRB5 (immune response), potentially contributing to disease progression and therapy response disparities. The distinct molecular profiles identified between AA and CA prostate cancers, particularly in immune response pathways and epigenetic regulation, suggest potential therapeutic targets. These findings highlight the importance of considering genetic and epigenetic variations in developing tailored therapeutic approaches to improve treatment efficacy and reduce mortality rates across diverse populations. Citation Format: Ahmed Fadiel, Abdalla Elbialy, Akshay Sood, Shang-Jui Wang, Peng Wang, Anil V. Parwani, Gennady Shvets, Nagireddy Putluri, Jenny Li, Xuefeng Liu. Unveiling racial disparities in prostate cancer using an integrative genomic and transcriptomic analysis [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 7467.
Abstract 6288: Precise characterization of complex repeats in cancer genomes
Authors: Khi Pin Chua, Egor Dolzhenko, Zev N. Kronenberg, Seiya Imoto, Seiichi Mori, Michael A. Eberle
Journal: Cancer Research (2025)

The characterization of somatic variation, especially in complex genomic regions, is crucial for understanding the molecular drivers of cancer progression. Accurate PacBio long-read sequencing (HiFi) enables detection of all variant classes, from simple SNVs and INDELs up to complex structural variation, tandem repeats, and changes in epigenetic signatures. Complex and repetitive regions, while fully sequenced by HiFi reads, remain bioinformatically challenging, requiring tailored solutions. Here, we describe new tools to genotype understudied repetitive regions in cancer genomes, a task that has historically posed significant challenges to short-read sequencing.Our software tool, TRGT, resolves the sequence and methylation patterns of complex repetitive regions at a single-nucleotide resolution. A recent algorithmic improvement (vclust module) enables us to type expanded hyper-polymorphic regions, termed variation clusters. Variation clusters usually result in many incorrect variant calls in computational pipelines. By analyzing a variation cluster as a single region, rather than many small variants, we can accurately measure genetic variation. To demonstrate the importance of variation clusters in cancer, we comprehensively resolved repeat regions in five cell lines and 50 clinical tumor samples (with matched healthy tissue). We identified 5,500 new variation clusters across the tumors and an average of 46,220 (out of 4 million, 1%) loci that are contracted or expanded in a tumor compared to its matched normal tissue. We find 3% of these loci can be located within genes found in the Compendium of Cancer Genes, suggesting potentially oncogenic significance. In addition, using TRGT, we were able to detect microsatellite instability (MSI) in a tumor with a compound heterozygous coding mutation in MSH2. Lastly, we further analyzed haplotypes in selected variation clusters to detect and resolve sequences in somatic mosaicism. By incorporating this new class of variants—complex repeats—into our analysis, we significantly enhanced the capability of HiFi reads to detect a comprehensive spectrum of genomic variations. The inclusion of complex repeat genotyping with PacBio HiFi reads will enable a more detailed understanding of cancer genetics and open new avenues for research and clinical applications. Citation Format: Khi Pin Chua, Egor Dolzhenko, Zev N. Kronenberg, Seiya Imoto, Seiichi Mori, Michael A. Eberle. Precise characterization of complex repeats in cancer genomes [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 6288.
Abstract 5328: p16 confers sensitivity to CDK2 inhibitors in CCNE1-amplified ovarian cancers
Authors: Chance Sine, Lotte Watts, Brianna Fernandez, Jianxin Wang, Erik S. Knudsen, Agnieszka K. Witkiewicz, Sabrina L. Spencer
Journal: Cancer Research (2025)

Abstract Blocking the cell cycle is a promising avenue for cancer therapy, with Cyclin-Dependent Kinase 2 (CDK2) emerging as a key target. However, in multiple cell types, CDK4/6 activity compensates for CDK2 inhibition and sustains the proliferative program, enabling CDK2 reactivation. Thus, we hypothesized that sensitivity to CDK2 inhibition is linked to the absence of this CDK4/6-mediated compensatory mechanism. Here we show that Cyclin E1-driven ovarian cancers often co-express the tumor suppressor p16, which inhibits CDK4/6. We show that ovarian cancer cells expressing p16 exhibit heightened sensitivity to CDK2 inhibitors and that depletion of p16 renders them significantly more resistant. Multiplexed immunofluorescence of 225 ovarian patient tumors reveals that at least 18% of tumors express high Cyclin E1 and high p16, a group that we expect to be particularly sensitive to CDK2 inhibition. Thus, p16 may be a useful biomarker for identifying the patients most likely to benefit from CDK2 inhibitors. Citation Format: Chance Sine, Lotte Watts, Brianna Fernandez, Jianxin Wang, Erik S. Knudsen, Agnieszka K. Witkiewicz, Sabrina L. Spencer. p16 confers sensitivity to CDK2 inhibitors in CCNE1-amplified ovarian cancers [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 5328.