tbuckley/cabot-search huggingface dataset:
Abstract 5092: Characterization of mismatch repair status in colorectal cancer using single cell and spatial transcriptomics
Authors: Dimitri Joseph, Alexandra Guillaume
Journal: Cancer Research (2025)

Abstract Background: Mismatch repair (MMR) status plays a critical role in colorectal cancer (CRC), influencing tumor biology and response to therapies. MMR-deficient (MMR-d) tumors, characterized by microsatellite instability (MSI), exhibit high mutation burdens and increased T cell infiltration, whereas MMR-proficient (MMR-p) tumors typically demonstrate low T cell density and poor immune checkpoint inhibitor response. Despite well-documented clinical implications, the molecular and cellular differences of T cells in the tumor microenvironment between MMR-d and MMR-p CRC remain incompletely understood. Methods: Single-cell RNA sequencing (scRNA-seq) data were analyzed using the CellChat R package to identify ligand-receptor interactions enriched in MMR-p colorectal cancer. Differentially enriched pathways involving T cells were identified and subjected to Gene Ontology (GO) enrichment analysis to uncover biological processes specific to these interactions. Validation was performed using spatial transcriptomic data from the Human Tumor Atlas Network (HTAN) to confirm ligand-receptor co-expression in a spatial context. Results: CellChat analysis revealed significant enrichment of TNFRSF14-associated signaling pathways (BTLA-TNFRSF14, LTA-TNFRSF14, and TNFS14-TNFRSF14) in MMR-p CRC. Functional analysis of TNFRSF14+ T cells in MMR-p tumors demonstrated upregulation of pathways related to leukocyte migration, negative regulation of T cell activation, and immune effector process regulation, as identified through GO enrichment analysis. Validation using spatial transcriptomic data confirmed co-expression of the BTLA-TNFRSF14 ligand-receptor pair in a single MSS sample but did not support broader enrichment across MMR-p samples. Conclusion: These findings highlight distinct ligand-receptor interactions and immune regulatory processes in MMR-p CRC, particularly involving TNFRSF14 signaling. While functional analysis underscores the role of these interactions in shaping T cell activity, spatial transcriptomic validation suggests heterogeneity in their enrichment across samples. This underscores the complexity of immune microenvironment regulation in MMR-p CRC tumors. Citation Format: Dimitri Joseph, Alexandra Guillaume. Characterization of mismatch repair status in colorectal cancer using single cell and spatial transcriptomics [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 5092.
Abstract 4553: Evaluation of cfDNA release profiles in colorectal cancer patients during surgery
Authors: Mailson Alves Lopes, Maria Elvira Ribeiro Cordeiro, Flávio de Alencar Teles Barreto, Lara de Souza Moreno, André Araújo Silva, Mayra Veloso Soares, Mariana Braccialli de Loyola, Joao Batista de Sousa, Fabio Pittella-Silva
Journal: Cancer Research (2025)

Abstract Surgical intervention is one of the most employed treatments for colorectal cancer, especially in patients with localized disease. However, the dynamics of circulating cell-free DNA (cfDNA) release during surgical procedures remain poorly understood. This lack of understanding underscores a significant gap regarding the biological processes underlying tumor response to surgery. Here we examined surgical cfDNA release from 30 colorectal cancer patients. cfDNA was extracted from plasma samples at three key points: preoperative (just before surgery), intraoperative (during surgery), and postoperative (at the end of surgery). Automated electrophoresis was used to analyze cfDNA concentrations and fragment sizes, which were then correlated with different clinical variables. Our findings show a significant increase in cfDNA release during and after surgery in comparison to preoperative time (2.8- and 2.2-fold higher, respectively). cfDNA fragments of &amp;lt;400 bp were predominant at all surgical stages, with no significant release of genomic DNA detected in any stage. We found that cfDNA concentrations increase on an average of 2 to 3-folds during and after surgery in patients over 60 years old, in patients with comorbidities and in patients with CEA levels &amp;gt; 5 ng/mL. Importantly, cfDNA release during surgery was significantly higher in patients with adverse clinical characteristics. Patients with locally advanced tumors or metastasis had a 3.1-fold increase in cfDNA release intraoperatively and a 2.4-fold increase postoperatively (p &amp;lt; 0.01). cfDNA concentrations also increase intraoperatively in patients with high tumor bud scores (2.6-fold higher, p &amp;lt; 0.02), perineural invasion (3.4-fold higher, p &amp;lt; 0.02), and lymphovascular invasion (3.1-fold higher, p &amp;lt; 0.05). Overall, our findings indicate that factors such as advanced physiological age, existing comorbidities, adverse clinical characteristics, and extensive surgical manipulation may contribute to increased tissue damage and enhanced cfDNA release. Citation Format: Mailson Alves Lopes, Maria Elvira Ribeiro Cordeiro, Flávio de Alencar Teles Barreto, Lara de Souza Moreno, André Araújo Silva, Mayra Veloso Soares, Mariana Braccialli de Loyola, Joao Batista de Sousa, Fabio Pittella-Silva. Evaluation of cfDNA release profiles in colorectal cancer patients during surgery [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 4553.
Abstract 4040: p63 represses metabolic pathways in aggressive bladder cancer
Authors: Artem Smirnov, Mariacristina Franzese Canonico, Damiano Barnaba, Maurizio Fanciulli, Alessandro Mauriello, Gerry Melino, Eleonora Candi
Journal: Cancer Research (2025)

Abstract Over half a million of people get bladder cancer (BLCA) each year worldwide with a third of all cases leading to death. Recent breakthroughs significantly improved early detection of BLCA, however little progress has been done to manage advanced invasive cancers since 1980s. Regulation of gene expression by key transcription factors governs multiple molecular pathways determining tumour evolution and selection. Here, we screen the transcription factors based on changes of their essentiality throughout bladder cancer evolution and identify p63 is a key factor. p63 is an oncogene in multiple epithelial tumours, however its expression is dramatically reduced in advanced BLCA, furthermore the loss of p63 is associated with a worse prognosis. Yet, little is known about p63 targetome in bladder cancer. In this work, we use transcriptomics, genome occupancy and chromatin accessibility assays to characterise global p63 targetome in BLCA in vitro along with bioinformatic analyses of gene expression in BLCA patients. We identify metabolism as a key pathway repressed by p63 during BLCA evolution and we show that activation of this pathway is associated with poor prognosis. In vitro, targeting of specific metabolic pathways induces cell death. Altogether, we identify an unexpected tumour-suppressive role for p63 in bladder cancer and propose novel therapeutic strategies for treatment of invasive BLCA. Citation Format: Artem Smirnov, Mariacristina Franzese Canonico, Damiano Barnaba, Maurizio Fanciulli, Alessandro Mauriello, Gerry Melino, Eleonora Candi. p63 represses metabolic pathways in aggressive 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 4040.
Abstract 2375: Investigating airway epithelial TP53 somatic mutation prevalence as a common risk factor for COPD and lung cancer
Authors: Andrew Boring, Erin L. Crawford, Dan J. Craig, Heidi Chen, Rami Ahmad, Mohamed Omballi, Eric Grogan, Stephen Deppen, James C. Willey
Journal: Cancer Research (2025)

Abstract Background: Lung cancer (LC) and Chronic Obstructive Pulmonary Disease (COPD) are leading causes of morbidity and mortality both in the United States and worldwide. There is a high degree of association between COPD and LC, which is not well understood. Smoking is a risk factor for COPD, while both cigarette smoke and COPD are risk factors for LC. Approximately 10% of current smokers are at risk for developing COPD and every year an estimated 1% of COPD patients develop LC. We recently reported that in the airway epithelium of smokers, there is an increased prevalence of somatic TP53 mutations. Further, among heavy smokers TP53 mutation prevalence was associated with LC. Due to the known association between COPD and LC risk we investigated whether TP53 mutation prevalence in airway epithelium may be a common factor. Methods: Patients undergoing bronchoscopy were recruited into an IRB-approved research study wherein soft brushings of the large airways were collected. Bronchial brush specimens from 59 subjects were sequenced by PCR-amplicon library NGS. The TP53 biomarker was measured from 59 subjects, 30 LC and 29 non-LC. The non-LC group comprised 7 COPD and 22 non-COPD subjects. Using specialized internal standards to compensate for sequencing error, VAF was observable down to 0.01%. Results: The TP53 biomarker was associated (p&amp;lt;0.05) with COPD among all 59 subjects with 76% specificity, 62% sensitivity, positive predictive value (PPV) 59% and negative predictive value (NPV) 78%. When plotted on a receiver operator characteristic (ROC) curve the area under the curve (AUC) was 0.82. Notably, the TP53 biomarker was significantly associated with COPD among non-LC subjects, with 95% specificity, 57% sensitivity, PPV 80% and NPV 87.5%. When fit to an ROC curve, the AUC for the COPD cohort was 0.84 Conclusions: TP53 prevalence was associated with COPD diagnosis among both LC and non-LC patients in this small discovery set. We plan to validate the association in larger case-control studies. If validated, this biomarker may enable early detection of those at risk for COPD before the obstructive defect develops as well as those who should be prioritized for LC screening. We will also further investigate interindividual variation between which patients develop lung cancer and or without the background of COPD through the lens of the TP53 biomarker. Citation Format: Andrew Boring, Erin L. Crawford, Dan J. Craig, Heidi Chen, Rami Ahmad, Mohamed Omballi, Eric Grogan, Stephen Deppen, James C. Willey. Investigating airway epithelial TP53 somatic mutation prevalence as a common risk factor for COPD and lung 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 2375.
Abstract 4232: DW91170B: A novel potent EZH1/2 dual inhibitor for adrenocortical carcinoma treatment
Authors: Doc-Gyun Jeong, Yeonkyung Oh, Woon Heo, DongHyuk Shin, Jung Hee Kim, Emilia Moonkyung Youm, Jihyun Youm, Kiyoon Kim, Sangho Lee, Yun-Ha Hwang
Journal: Cancer Research (2025)

Abstract Adrenocortical carcinoma (ACC) is an aggressive cancer that occurs in the adrenal cortex with a poor prognosis, and its 5-year survival rate is less than 60%. Previous studies have characterized molecular and cellular alterations in ACC, including changes in p53, the WNT-β-catenin pathway, PKA, and chromatin remodeling pathways. EZH2 (Enhancer of zeste homolog 2), a catalytic subunit of PRC2 (polycomb repressive complex 2), also exhibits abnormal characteristics in ACC. EZH2 has been reported to be overexpressed in ACC patients and is associated with disease progression and survival rates. Here, we present DW91170B, a novel and potent dual inhibitor of EZH1/2, as a candidate for the treatment of adrenocortical carcinoma. DW91170B induces histone modification by reducing the trimethylation of H3K27, suppresses cell viability, and induces apoptosis in adrenal cancer cells. Additionally, DW91170B affects the molecular and cellular characteristics of adrenal cancer cells. Specifically, treatment with DW91170B reduces the expression of HSD3B2 and CYP11B1, genes involved in steroidogenic process. As a result, aldosterone and cortisol secretion induced by forskolin is inhibited by DW91170B. Long-term treatment with DW91170B decreases the expression of transcription regulators such as β-catenin and SF-1. These changes in transcriptional complex were confirmed through RNA sequencing, revealing alterations in gene expression. Among the differentially expressed genes, those related to epithelial-mesenchymal transition (EMT) and apical junctions were notably affected. Functional changes were further confirmed by EMT marker protein expression and a wound healing assay. The in vivo efficacy of DW91170B was assessed in two adrenal cancer models. NCI-H295R cells, which have high expression EZH2, and SW13 cells, which carry a SMARCA4 mutation that is susceptible to synthetic lethality from EZH2 inhibition, were used. DW91170B effectively inhibited tumor growth in both models. In summary, the novel EZH1/2 inhibitor DW91170B exhibits anti-tumor efficacy in adrenocortical carcinoma. These effects appear to be mediated by alterations in cancer cell characteristics and the inhibition of cell survival. Citation Format: Doc-Gyun Jeong, Yeonkyung Oh, Woon Heo, DongHyuk Shin, Jung Hee Kim, Emilia Moonkyung Youm, Jihyun Youm, Kiyoon Kim, Sangho Lee, Yun-Ha Hwang. DW91170B: A novel potent EZH1/2 dual inhibitor for adrenocortical carcinoma treatment [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 4232.
Abstract 4143: Analyzing BRAFV600E signaling complexes to better understand BRAF driven melanoma
Authors: Adamaris M. Martinez, Kayla T. O'Toole, Martin McMahon
Journal: Cancer Research (2025)

Abstract In approximately 8% of all cancers, mutational activation of BRAF is an oncogenic driver, with a particular prevalence in lung cancer, thyroid cancer, and melanoma. Mutations in BRAF account for about 50% of the cutaneous melanoma cases in patients. The most common mutational alteration is the BRAFT1799A encoding the BRAFV600E oncoprotein kinase. Combined inhibition of BRAFV600E and MEK 1/2 has been approved to treat BRAFV600E-driven melanoma and lung cancer. There are several mechanisms of resistance to inhibitors of BRAFV600E signaling, with one of the most intriguing being the emergence of tumors expressing p61-BRAFV600E that is encoded by a variant mRNA that is aberrantly spliced to remove exons 4-8. Consequently, p61-BRAFV600E is missing amino acid sequences that promote association with RAS.GTP (RBD) and the cysteine rich domain (CRD). Moreover, while full-length BRAFV600E is widely considered to signal as a monomer, p61-BRAFV600E is thought to require dimerization for activation. Here, we use gel-filtration chromatography and immunoblotting to show that both forms of BRAFV600E are detected in a large molecular weight complex of 450-500 kDa. However, p61-BRAFV600E containing complexes are smaller than those with full-length BRAFV600E, which may reflect the difference in size of the BRAFV600E proteins or subtle differences in the signaling complexes. Interestingly, the addition of a BRAFV600E inhibitor, vemurafenib, shifted the elution of complexes with full-length BRAFV600E into lower molecular weight fractions. In addition, we have utilized the proximity labeling technique, TurboID, to uncover more of the BRAF interactome. Citation Format: Adamaris M. Martinez, Kayla T. O'Toole, Martin McMahon. Analyzing BRAFV600E signaling complexes to better understand BRAF driven melanoma [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 4143.
Abstract 4749: Evaluating NUAK2 as a potential target in neuroendocrine prostate cancer
Authors: Umar Mehraj, Shaista Manzoor, Julie Parks, Emily Cordova, Everardo Macias
Journal: Cancer Research (2025)

Abstract Background: Neuroendocrine Prostate Cancer (NEPC) is an aggressive and lethal prostate cancer subtype. Due to Androgen Receptor-independence, NEPC lacks targeted therapeutics, with platinum-based chemotherapy serving as the primary treatment modality. This highlights the need for new molecular targets in NEPC. NUAK2, also known as sucrose non-fermenting (SNF1)-like AMPK-related kinase (SNARK) is an unstudied kinase. Yet, pan-cancer analysis shows increased expression of NUAK2 across several malignancies. Analysis of prostate cancer and NEPC datasets revealed a significant increase in NUAK2 expression levels correlating with disease progression. The objective of our study was to determine if NUAK2 is essential for NEPC tumor growth. Methods: To investigate the therapeutic potential of NUAK2 in NEPC, we conducted genetic and pharmacological modulation of NUAK2 both in vitro and in vivo. We conducted label-free quantitative phospho-proteomic and proximity ligation interactome analyses of NUAK2 using LC-MS/MS to elucidate its role in NEPC. Results: NUAK2 knockdown significantly decreased proliferation and 3D spheroid growth in NEPC preclinical models. CRISPR-Cas9-mediated knockout of NUAK2 in NCI-H600 cells led to reduced tumor growth in vivo. Furthermore, NUAK2 overexpression accelerated NEPC growth in a kinase-dependent manner. Pharmacological inhibition of NUAK2 significantly reduced the growth of NEPC cell-line and patient-derived xenografts. Phosphoproteome and interactome studies by LC-MS/MS and pathway enrichment analysis revealed the role of NUAK2 in chromatin remodeling, mRNA metabolic processes, and cytoskeleton organization. Conclusions: Collectively, our study highlights NUAK2 is essential for NEPC tumor growth and is an actionable target in NEPC. Citation Format: Umar Mehraj, Shaista Manzoor, Julie Parks, Emily Cordova, Everardo Macias. Evaluating NUAK2 as a potential target in neuroendocrine prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4749.
Abstract 5992: In vitro efficacy of novel USP1 inhibitors as a single agent and in combination with SOC in ovarian, prostate, and breast cancer cells independent of BRCA mutational status
Authors: Marina Curcic, Mohamed Eltokhy, Sanjay K. Srivastava, Partha Pratim Sarma, Prashant Kashinath Bhavar, Uday Kumar Surampudi
Journal: Cancer Research (2025)

Abstract Background: Ubiquitin-specific protease 1 (USP1) is a key regulator of DNA repair pathways and is implicated in the response to genotoxic stress. Targeting USP1 has emerged as a potential therapeutic strategy for cancer treatment. This study investigates the in vitro efficacy of a series of novel USP1 inhibitor both as a monotherapy and in combination with other treatment agents, in ovarian, prostate, and breast cancer cell lines. Methods: In vitro efficacy of three different series of USP1i in ovarian (OVCAR-3), prostate (DU-145), and breast (SUM149) cancer cell lines were accessed using cell viability and colony formation assays. Combination included co-treatment with standard chemotherapy agents and determining synergy using composite score. Results: Treatment with USP1i alone led to significant reductions in cell viability and colony formation irrespective of BRCA mutation status. Furthermore, in combination with USP1 inhibitors enhanced efficacy was seen, leading to a positive shift in IC50 in cell viability assay and a significant increase in apoptosis compared to either treatment alone. Conclusion: Our results demonstrate the potent in vitro anti-cancer activity of series of USP1 inhibitors, both as single agent and in combination with chemotherapeutic agents in ovarian, prostate, and breast cancer cell lines, irrespective of BRCA mutational status. These findings suggest that USP1 inhibition could provide a promising therapeutic approach for a broad range of cancers, warranting further investigation in preclinical models and clinical trials. Citation Format: Marina Curcic, Mohamed Eltokhy, Sanjay K. Srivastava, Partha Pratim Sarma, Prashant Kashinath Bhavar, Uday Kumar Surampudi. In vitro efficacy of novel USP1 inhibitors as a single agent and in combination with SOC in ovarian, prostate, and breast cancer cells independent of BRCA mutational status [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 5992.
Abstract 5082: Deep learning model for cancer diagnosis in frozen section sentinel lymph nodes with limited annotations
Authors: Joonho Lee, Joonyoung Cho, DoKyung Kim, Yoon-La Choi, Kyungsoo Jung, Tae-Yeong Kwak, Sun Woo Kim, Hyeyoon Chang
Journal: Cancer Research (2025)

Abstract Introduction: Frozen section (FS) rapidly examines suspected tumor tissue microscopically during surgery, aiding diagnosis and surgical decisions. However, when applying AI or digital pathology to FS examination, stain and scanner variations pose significant challenges in developing robust deep learning-based diagnostic models. This study proposes a method that reduces stain variation to detect cancer in H&amp;E-stained FS images of breast sentinel lymph nodes. Design: We utilized 19, 881 FS WSIs and 11, 985 FFPE WSIs. The dataset included FS and FFPE WSIs from 33 organs collected from The Cancer Genome Atlas (TCGA), additional FS and FFPE WSIs from a domestic hospital and the Camelyon16 dataset. We reserved 20% of the FS dataset for evaluation; the remaining data were split into training (75%) and validation (25%). We employed instance-based Multiple Instance Learning (MIL) to identify cancerous patches (512×512 pixels at 10× magnification) in each WSI. After achieving sufficient feature discrimination, we fixed the backbone network. We obtained rough annotations from pathologists on 12 lymph node FS WSIs and trained a classifier with various data augmentation. Result: Our method shows that the MIL plus classifier-only approach consistently outperforms MIL with full fine-tuning across diverse datasets (Camelyon16 FFPE and domestic FS). By reducing scanner variation, we significantly improved the model's generalization, which is a primary contribution of this study. Conclusion: These findings suggest that mitigating stain and scanner variations with limited annotations can substantially enhance the performance and generalizability of deep learning models in cancer diagnosis. Citation Format: Joonho Lee, Joonyoung Cho, DoKyung Kim, Yoon-La Choi, Kyungsoo Jung, Tae-Yeong Kwak, Sun Woo Kim, Hyeyoon Chang. Deep learning model for cancer diagnosis in frozen section sentinel lymph nodes with limited annotations [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 5082.