tbuckley/cabot-search huggingface dataset:
Abstract 5409: Asymmetric interdependency among the CDK8 module subunits
Authors: Tzu-Hao Liu, Xiao Li, Fu-Ning Hsu, Mengmeng Liu, Rajitha-Udakara-Sampath Hemba-Waduge, Jun-Yuan Ji
Journal: Cancer Research (2025)

Abstract The CDK8 kinase module (CKM) of the transcriptional cofactor Mediator complex plays a pivotal role in regulating RNA polymerase II-dependent transcription. Dysregulation of the CKM has been implicated in various diseases, as CDK8 overexpression promotes tumorigenesis in colorectal cancer and melanoma, CKM subunits are mutated or amplified in other types of cancers and cardiovascular diseases. Understanding the in vivo functions and regulatory mechanisms of the CKM and Mediator complexes is essential for uncovering their contributions to tumorigenesis. Previous studies showed that the loss of CKM subunits in Drosophila resulted in distinct phenotypes, particularly in the eyes and wings. In this study, we observed that loss of Med13 and Med12 caused more significant reductions in multiple biological functions compared to the effects observed with CDK8 and CycC. Depleting individual CKM subunits revealed that Med13 has the strongest influence on cell growth and cell proliferation, likely due to differences in the rate of nascent protein synthesis. This hierarchy is followed by Med12 and then the CDK8-CycC complex, suggesting a differential impact of these CKM subunits at the cellular level. Immunoblot analyses further revealed that the stability of CDK8 and Med12 depends on the presence of Med13 in Drosophila. These findings support the hypothesis that CKM subunits are asymmetrically interdependent. Furthermore, knockdown of CKM subunits via lentiviral transduction in human LnCaP cells confirmed this asymmetric interdependency in mammalian systems. ​Taken together, our results suggest the stability and asymmetrical dependence of CKM subunits play a critical role in regulating nascent protein synthesis, cellular growth, and proliferation, with Med13 serving a critical role within the CKM module. Citation Format: Tzu-Hao Liu, Xiao Li, Fu-Ning Hsu, Mengmeng Liu, Rajitha-Udakara-Sampath Hemba-Waduge, Jun-Yuan Ji. Asymmetric interdependency among the CDK8 module subunits [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 5409.
Abstract 4736: A highly selective CDK4/9 dual inhibitor reverses tumor resistance to CDK4/6 inhibitors
Authors: Jinwen Huang, Zhongyuan Li, Zeng Song, Yunli Liu, Steve Shen
Journal: Cancer Research (2025)

Abstract Background: CDK4/6 inhibitors have been approved for the treatment of metastatic ER+ and HER2- breast cancer. However, patients will become resistance due to various mechanisms, resulting in high unmet need. Literature suggests that CDK9 activity may be involved in the mechanism of resistance to CDK4/6 inhibitors, and targeting CDK9 could be an effective strategy to overcome breast cancer resistance. Methods and Materials: Using the Convalife "Right 6D+AI" molecular design platform, AI-based screening and multi-angle evaluation were conducted on over 8, 000 virtual molecules, ultimately yielding candidate molecule N049 with selectivity for CDK4 and CDK9 that were &amp;gt;30-fold and &amp;gt;80-fold higher than for CDK6, respectively. To explore the therapeutic potential of N049 in palbociclib-resistant tumors, effects on cell viability were evaluated in both palbociclib-sensitive and -resistant cell lines. Additionally, patient-derived organoids (PDOs) and PDX models were used to assess the impact of CDK4/9 inhibitors on cell viability. Results: The CDK4/9 inhibitor N049 targeting CDK9 significantly impaired the viability of both palbociclib-sensitive and palbociclib-resistant LTED cell lines. Furthermore, in patient-derived organoids (PDOs) and PDX models, the CDK9 inhibitor drove tumor regression in palbociclib-resistant PDXs. Conclusion: Our findings suggest that simultaneous inhibition of CDK4 and CDK9 may exert potential synergistic effects to overcome CDK4/6 inhibitor resistance. The use of CDK4/9 inhibitors N049 could be an effective strategy to address resistance to endocrine therapy and CDK4/6 inhibitors in ER+ breast cancer. CDK4/9 inhibitors N049 represent a promising therapeutic approach for overcoming breast cancer resistance. Citation Format: Jinwen Huang, Zhongyuan Li, Zeng Song, Yunli Liu, Steve Shen. A highly selective CDK4/9 dual inhibitor reverses tumor resistance to CDK4/6 inhibitors [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 4736.
Abstract 5414: The RNA-binding protein HNRNPH1 regulates the expression of cell cycle-related genes to promote glioblastoma progression
Authors: Genaro Villa, Paolo Alimonti, Joseph Toker, Raziye Piranlioglu, Andrew Chiocca, Alexa Lauinger, E. Antonio Chiocca, Marco Mineo
Journal: Cancer Research (2025)

Abstract Heterogeneous nuclear ribonucleoprotein H1 (HNRNPH1) is a critical regulator of several aspects of RNA metabolism, including RNA stability and splicing. Alteration of the expression of RNA-binding proteins, such as HNRNPH1, has been shown to affect the RNA life cycle. This, in turn, results in the production of abnormal proteins that may promote the development of cancer. While aberrant expression of HNRNPH1 has been linked to several neuronal-related disorders, its role in the progression of glioblastoma (GBM), the most frequent and aggressive primary brain tumor, is still poorly understood. Given our previous findings that HNRNPH1 binds the RNA of several genes involved in cell-cycle regulation and cell proliferation, we hypothesized that HNRNPH1 regulates cell division and glioblastoma growth. Analyses of GBM patient data from The Cancer Genome Atlas database, combined with tissue microarray immunostaining and qPCR analyses of patient-derived tumors and patient-derived glioblastoma cells (PDGCs), revealed that HNRNPH1 was upregulated in GBM compared to normal brain. Single-cell RNAseq data showed that HNRNPH1 was more expressed in malignant cells than in other cells within the tumor microenvironment, and its expression was associated with specific cellular states. Knocking out HNRNPH1 in both U87 cells and PDGCs using the CRISPR/Cas9 system caused the downregulation of several genes involved in cell division, such as AURKB, ESPL1, PRC1, and UBE2S. This was associated with an increased number of cells stuck in G2M, reduced cell proliferation, abnormal cell morphology, and an increase in polynucleated cells. Silencing HNRNPH1 in vivo suppressed the tumor growth of PDGC-originated intracranial xenografts and had significant survival benefits. Together, our results showed the critical importance of HNRNPH1 in cell cycle progression and tumor growth, with a potential impact on developing novel strategies to overcome the current limitations of GBM therapies. Citation Format: Genaro Villa, Paolo Alimonti, Joseph Toker, Raziye Piranlioglu, Andrew Chiocca, Alexa Lauinger, E. Antonio Chiocca, Marco Mineo. The RNA-binding protein HNRNPH1 regulates the expression of cell cycle-related genes to promote glioblastoma progression [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 5414.
Abstract 4305: Targeting the exonuclease domain of POLE to induce synthetic lethality in highly aneuploidic tumor cells
Authors: Meng He, Eun Jung Kim, Yangmeng Wang, Alejandro Chibly, Kristel Dorighi
Journal: Cancer Research (2025)

Abstract Aneuploidy is a hallmark of cancer evolution, it is associated with fast disease progression and drug resistance across many tumor types. The underlying molecular aberration that causes aneuploidy remains largely unknown. Currently, there are no established therapeutics for tumors with high levels of aneuploidy. We propose that inhibition of the exonuclease domain of the DNA polymerase, POLE, could induce synthetic lethality in tumor cells with high levels of aneuploidy. We observed that loss of function mutations in the exonuclease domain of POLE are mutually exclusive with high levels of aneuploidy in the Foundation Medicine database, the Cancer Genome Atlas (TCGA) as well as the cancer Dependency Map (DepMap). Our analysis and statistical modeling showed that the number and unique spectrum of mutations induced by loss of POLE’s exonuclease activity have a high probability of hitting an essential gene with hemizygous loss in aneuploidic tumor cells, therefore leading to a synthetic lethality phenotype. Experimentally, we showed that specific inhibition of the exonuclease domain through genetic mutations can cause strong cellular fitness effects in highly aneuploidic cell lines. In summary, our data suggest that a specific inhibitor targeting the exonuclease domain of POLE might bring therapeutic benefits to patients with highly aneuploidic tumors. Citation Format: Meng He, Eun Jung Kim, Yangmeng Wang, Alejandro Chibly, Kristel Dorighi. Targeting the exonuclease domain of POLE to induce synthetic lethality in highly aneuploidic tumor cells [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 4305.
Abstract 3318: Serum Insulin-Like Growth Factor-1 levels predict outcomes in patients with advanced hepatocellular carcinoma receiving immunotherapy
Authors: Tsung-Che Wu, Ching-Tso Chen, Chien-Huai Chuang, Ann-Lii Cheng, Chih-Hung Hsu, Yu-Yun Shao
Journal: Cancer Research (2025)

Abstract Background: The combination of immune checkpoint inhibitors (ICIs) with antiangiogenesis agents or another ICI has become the standard of care for advanced hepatocellular carcinoma (HCC). Elevated serum levels of insulin-like growth factor-1(IGF-1) levels have been previously associated with better outcomes of patients with advanced HCC treated with sorafenib or atezolizumab plus bevacizumab. However, the prognostic value of serum IGF-1 level for other immunotherapy regimens remains unexplored. Methods: Patients with advanced HCC who received anti-PD-1/anti-PD-L1 monoclonal antibody monotherapy or combinations were enrolled. Serum samples were collected prior to initiating immunotherapy, and serum IGF-1 levels were quantified using enzyme-linked immunosorbent assay (ELISA). Based on prior findings from our group, a cutoff value of 63.6 ng/mL was used to stratify patients into high and low serum IGF-1 groups. Patient demographics, tumor characteristics, treatment responses, and survival outcomes were analyzed. Results: From August 2015 to July 2024, 111 patients were enrolled. Baseline characteristics were as follows: 90% male, 71% HBsAg-positive, 18% anti-HCV-positive, Child-Pugh scores: 72% (5 points)/23% (6 points)/5% (7 points), 43% with macrovascular invasion (MVI), 72% with extrahepatic involvement (EHI), and 46% treated with antiangiogenic-containing regimens. Patients with higher serum IGF-1 levels demonstrated fewer adverse clinical features, including lower Child-Pugh scores, ALBI grades, and MVI rates. Patients who achieved an objective response to therapy had significantly higher IGF-1 levels compared to those who did not (57.2 vs. 46.2 ng/mL, p = 0.037). Additionally, patients with high IGF-1 levels exhibited improved overall survival (OS) compared to those with low IGF-1 levels (p = 0.024). When stratified by regimen types, the prognostic value of high IGF-1 levels was maintained in patients treated with antiangiogenic-containing regimens (p = 0.001) but was not observed in patients treated without antiangiogenic agents (p = 0.967). Conclusions: High serum IGF-1 levels are associated with improved OS in patients with advanced HCC, but this prognostic value is confined to regimens containing antiangiogenic agents. These findings underscore the potential of IGF-1 as a biomarker for optimizing immunotherapy strategies in advanced HCC. Citation Format: Tsung-Che Wu, Ching-Tso Chen, Chien-Huai Chuang, Ann-Lii Cheng, Chih-Hung Hsu, Yu-Yun Shao. Serum Insulin-Like Growth Factor-1 levels predict outcomes in patients with advanced hepatocellular carcinoma receiving immunotherapy [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 3318.
Abstract 5662: Deep-mining the antibody repertoires of transgenic mouse models with high-throughput single cell BCR and whole transcriptome sequencing
Authors: Ajay Sapre, Alec Salvino, Guillermo Gallareta-Olivares, Efi Papalexi, Jose Jacob, Ashwath Kumar, Charles Roco, Alexander Rosenberg
Journal: Cancer Research (2025)

Abstract Transgenic mouse models are excellent tools to model human antibody response against antigens or disease of choice, given their ability to undergo diversification, in vivo affinity maturation, clonal selection and clonal expansion in their natural immune environment. Current antibody discovery methods lack the scale required to fully screen the antibody repertoire of transgenic mouse models to uncover maximum desirable antibody hits per discovery campaign. Here, we demonstrate our novel combinatorial barcoding approach to enable high-throughput single cell BCR and whole transcriptome profiling of transgenic mouse samples with unprecedented sensitivity, scalability, and flexibility. As a proof of concept, we profiled over 1 million cells from multiple transgenic mice that were either naive or immunized with antigens of interest to obtain hundreds of thousands of paired BCR clonotypes. Using the whole transcriptome data, we detected all B cell subpopulations including plasma cells at single cell resolution. We then used the paired heavy and light chain BCR data to detect productive chains in the majority of B cells revealing both unique and expanded clonotypes. In the expanded clonotype pool we found specific patterns of VDJ utilization and amino acid motifs compared to the naive pool. This method paves the way for high throughput screening of antibody repertoires from transgenic mice to allow for deep mining of repertoires for antibody discovery and therapeutic outcomes. Citation Format: Ajay Sapre, Alec Salvino, Guillermo Gallareta-Olivares, Efi Papalexi, Jose Jacob, Ashwath Kumar, Charles Roco, Alexander Rosenberg. Deep-mining the antibody repertoires of transgenic mouse models with high-throughput single cell BCR and whole transcriptome sequencing [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 5662.
Abstract 5866: Role of inflammatory cytokines and matrix metalloproteinases in colorectal cancer in a Hispanic population
Authors: Elba V. Caraballo, Sheila Natalie López Acevedo, Camille Zenón-Meléndez, Josué Pérez Santiago, Marcia R. Cruz-Correa
Journal: Cancer Research (2025)

Background: Colorectal cancer (CRC) is a leading cause of cancer-related deaths in Puerto Rico and the United States. Puerto Rican Hispanics (PRH) experience disproportionately higher CRC incidence and mortality rates compared to the general Hispanic population in the U.S. Biological processes, such as cytokine dysregulation and extracellular matrix remodeling, may contribute to these disparities. However, the molecular mechanisms driving CRC disease progression in PRH remain poorly understood. This study investigates the roles of inflammatory cytokines and matrix metalloproteinases (MMPs) in CRC disease progression. Methods: We conducted a case-case study using tumor (n=15) and adjacent mucosa (n=15) tissue samples collected from early (n=7) and advanced-stage (n=8) CRC archived cases recruited through the Puerto Rico Familial Colorectal Cancer Registry (PURIFICAR). RNA-seq was performed and analyzed for differential gene expression and fold changes (FC) for key immune-related pathways, including MMPs, interleukin IL-17(IL17), associated cytokines, and chemokines. STRING database was used to identify protein-protein interaction networks and functional associations (≥5 gene connections). Results: Transcriptomic analysis revealed stage-specific expression patterns. IL-13 was differentially expressed in early-stage tumors, while advanced-stage tumors were characterized by CXCL10 expression Both IL-17A and IL-8 were upregulated in early and advanced stages. Elevated expression levels of IL-17A (log2 FC: 2.72 vs 3.11) and IL-8 (log2 FC: 5.73 vs 3.44) were observed in tumor tissues compared to adjacent mucosa (adj. p&amp;lt;0.05). Advanced-stage tumors also showed increased expression of MMP13 and MMP3, indicating extracellular matrix remodeling and invasion. IL-17A-related pathways were consistently upregulated, suggesting their involvement in chronic inflammation, tumor growth, and immune escape. Conclusions: Our results show that differential expression of IL-17A and IL-8 at early-stage CRC may contribute to immune dysregulation and a tumor-promoting microenvironment. In advanced stages, elevated MMP expression could promote extracellular matrix remodeling, metastasis, and immune evasion. These findings suggest that IL-17A, IL-8, and MMPs are potential therapeutic targets for addressing CRC disease progression and reducing health disparities among PRH. Citation Format: Elba V. Caraballo, Sheila Natalie López Acevedo, Camille Zenón-Meléndez, Josué Pérez Santiago, Marcia R. Cruz-Correa. Role of inflammatory cytokines and matrix metalloproteinases in colorectal cancer in a Hispanic population [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 5866.
Abstract 3901: Charting copy number gain histories from mutational divergence among multi-samples
Authors: Yunong Xia, Ruping Sun
Journal: Cancer Research (2025)

Abstract In cancer, a somatic copy number gain (SCNG) on a tumor chromosomal region is often assumed to result from a series of minimum number of copy number events, but this parsimonious-trajectory assumption may be violated in reality. For example, an SCNG could develop through a complex trajectory involving a combination of gain and loss events, rather than exclusively through gains. While prior efforts have been made to infer the SCNG trajectories from patient data, the presence of complex trajectories remains to be validated. Furthermore, these methods are limited by either only utilizing SCNG profiles, or inferring trajectories from only a single sample. Here, we hypothesize that SCNG trajectories can be reflected by somatic single nucleotide variants (SSNVs) shared between samples from the same patient. By analyzing multi-regional whole genome sequencing data of tumor specimens, we found evidence where the multiplicities of shared SSNVs between samples pinpoint complex SCNG trajectories. Here, the SSNV multiplicity refers to the number of alleles harboring the corresponding SSNV in the dominating clone of a tumor sample. We also define the joint multiplicity distribution as the proportion of shared SSNVs that occur at different allelic states (multiplicities) across distinct tumor samples. We developed a probabilistic computational pipeline to automate the identification of non-parsimonious multi-sample SCNG trajectories utilizing shared SSNV multiplicities. Extending an existing method GRITIC from single sample to multi-sample setting, this pipeline enumerates all trajectories leading to SCNGs states in multiple samples, and characterizes the probability of observing the joint multiplicity distribution in the real patient data given each possible trajectory. We applied the method on prostate cancer and breast cancer datasets, and identified conclusive cases of complex trajectories on genomic regions affected by SCNGs. On regions showing different copy number states in multiple samples, we identified cases experiencing both gains and losses. On regions showing the same copy number states in multiple samples, we also identified a few of them experiencing independent acquisition of SCNGs in different samples. Our findings call for a stochastic modeling of SCNGs dynamics during tumor evolution. Citation Format: Yunong Xia, Ruping Sun. Charting copy number gain histories from mutational divergence among multi-samples [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 3901.
Abstract 3335: Non-tumor-bearing tissue: A prognostic biomarker for cancer
Authors: Ji Hye Choi, Yeong Hak Bang, YeonJu Lee, Woong-Yang Park
Journal: Cancer Research (2025)

Abstract Background: We hypothesized that distinct microenvironments either support or inhibit the growth of cancer cells, and that the non-tumor bearing tissue (NBT) reflects these microenvironments. Additionally, we assumed that the more closely the characteristics of the NBT resemble those of the tumor, the greater the likelihood of supporting cancer cell progression and promoting disease recurrence. Method: We investigated TCGA dataset with more than 20 samples of NBT and paired tumors. We employed a scoring system using the top 10-50 DEGs with high fold-change values in tumors. We scored the expression of the tumor-supportive signature genes in the NBT using single-sample gene set enrichment analysis (ssGSEA). We evaluated the mean score derived from the top 10-50 in the NBT to categorize the patients into two groups that most effectively facilitated prognostic differentiation. The groups were defined as follows: patients showing relatively high tumor supportive signatures in NBT (patients with tumor-supportive microenvironment in NBT; TSM), and patients showing relatively low supportive signatures in NBT (patients with healthy microenvironment in NBT; HM). Results: Among the 12 cancers, the significantly poorer overall survival (OS) in TSM were identified in head and neck cancer squamous cell carcinoma (HNSC; hazard ratio [HR]: 2.06 [1.03 - 4.10]), lung squamous cell carcinoma (LUSC; hazard ratio [HR]: 3.87 [1.69 - 8.90]), kidney renal cell carcinoma (KIRC; hazard ratio [HR]: 2.85 [1.31 - 6.21]). In other cancer types, there are no prognostic differentiations. The 3-year overall survival in the TSM group compared to the HM group were markedly lower: HNSC (0.569 vs. 0.813), LUSC (0.242 vs. 0.492), and KIRC (0.250 vs. 0.689). Pathway analysis suggested that leukocyte-mediated immunity and inflammatory pathways were upregulated, whereas the maintenance of epithelial barriers was decreased in the NBT of the TSM group in HNSC, LUSC and KIRC. Immune cell deconvolution analysis revealed that the TSM group had a significantly higher proportion of neutrophils compared to that of the HM group in HNSC and LUSC. In KIRC, significantly higher proportion of CD8+ T cells and memory CD4+ T cells were observed in the NBT of the TSM group. Conclusions: Our findings suggest that NBT serves as a prognostic biomarker that effectively predicts cancer invasiveness and tumor-promoting inflammation, particularly in HNSC, LUSC, and KIRC. This also highlights the importance of maintaining a healthy microenvironment. Citation Format: Ji Hye Choi Yeong Hak Bang YeonJu Lee Woong-Yang Park. Non-tumor-bearing tissue: A prognostic biomarker for 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 3335.