tbuckley/cabot-search huggingface dataset:
Abstract 1242: Foxa1/2-dependent epigenomic reprogramming drives lineage switching in lung adenocarcinoma
Authors: Katherine Gillis, Walter Orellana, Emily Wilson, Gabriela Fort, Headtlove Essel Dadzie, Timothy Parnell, Xiaoyang Zhang, Eric Snyder
Journal: Cancer Research (2024)

Abstract The ability of cancer cells to alter their identity is essential for tumor survival and progression. Loss of the pulmonary lineage specifier NKX2-1 within KRAS-driven lung adenocarcinoma (LUAD) enhances tumor progression and results in a pulmonary-to-gastric lineage switch that is dependent upon the activity of pioneer factors FoxA1 and FoxA2; however, the underlying mechanism remains largely unknown. Here, we perform transcriptional and epigenetic assays to show that FoxA1/2 reprogram the chromatin landscape of NKX2-1-negative LUAD to facilitate a gastric differentiation program. Using sequential recombination models, we find that FoxA1/2 are required for demethylation of gastric-defining genes after Nkx2-1 deletion. FoxA1 colocalizes with TET3, an enzyme that mediates DNA demethylation, in NKX2-1-negative tumors. Deletion of Foxa1/2 results in loss of TET3 occupancy at key gastric marker genes, indicating that FoxA1/2 recruit TET3 to lineage-specific sites. H3K27ac ChIP-seq and HiChIP show that FoxA1/2 also control the activity of enhancers and promoters as well as their 3D interactions at gastric target genes following NKX2-1 loss. Furthermore, oncogenic KRAS is required for the FoxA1/2-dependent epigenetic reprogramming in NKX2-1-negative LUAD. This work demonstrates the role of FoxA1/2 in rewiring the methylation and histone landscape and cis-regulatory dynamics of NKX2-1-negative LUAD to drive cancer cell lineage switching. Citation Format: Katherine Gillis, Walter Orellana, Emily Wilson, Gabriela Fort, Headtlove Essel Dadzie, Timothy Parnell, Xiaoyang Zhang, Eric Snyder. Foxa1/2-dependent epigenomic reprogramming drives lineage switching in lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1242.
Abstract 1195: Prospective study for the identification of nivolumab biomarkers via analyses of pre-treatment plasma exosome mRNAs from head and neck cancer patients (BIONEXT)
Authors: Muneyuki Masuda, Satoshi Toh, Mioko Matsuo, Masashi Sugasawa, Keisuke Yamazaki, Ueki Yushi, Torahiko Nakashima, Hideoki Uryu, Takeharu Ono, Tsutomu Ueda, Hirohito Umeno, Satoshi Kano, Kiyoaki Tsukahara
Journal: Cancer Research (2024)

Abstract Nivolumab paved a new way in the treatment of recurrent or metastatic (RM) head and neck squamous cell carcinoma of (HNSCC). However, the limited rates of long-term survivors (&amp;lt; 20%) demand a robust prognostic biomarker. This nationwide multi-centric prospective study aimed to identify a plasma exosome (PEX) mRNA signature, which serves as a companion diagnostic of nivolumab and as well provides a biological clue to develop effective therapies for a majority of non-survivors. Pre-treatment plasmas (N = 104) were subjected to comprehensive PEX mRNA analyses for prognostic marker discovery and validation. In parallel, paired treatment naïve tumor and plasma samples (N = 20) were assayed to elucidate biological implications of the PEX mRNA signature. A combination of 6 candidate PEX mRNAs plus neutrophil-to-lymphocyte ratio precisely (P = 0.000124) distinguished non-survivors from &amp;gt;2-yr survivor (0% vs 57.7%) with a high hazard ratio (2.878; 95% confidence interval 1.639-5.055; P = 0.0002348). In paired samples, high PEX HLA-E mRNA (a non-survivor-predicting marker) reflected the increased HLA-E protein expression (P = 0.0191) and the dense population of tumor-infiltrating NK cells (P = 0.024) in the corresponding tumor. It is estimated that the effects of PD-1blockade is canceled by the HLA-E-NKG2A immune checkpoint in patients with high PEX HLA-E mRNA. The combination of NKG2A antibody (i.e., monalizumab) and nivolumab may be a promising strategy for non-survivors predicted by a RT-qPCR-based pre-treatment measurement of PEX mRNAs. A candidate companion diagnostic of nivolumab that indicates a possible treatment option is identified. Citation Format: Muneyuki Masuda, Satoshi Toh, Mioko Matsuo, Masashi Sugasawa, Keisuke Yamazaki, Ueki Yushi, Torahiko Nakashima, Hideoki Uryu, Takeharu Ono, Tsutomu Ueda, Hirohito Umeno, Satoshi Kano, Kiyoaki Tsukahara. Prospective study for the identification of nivolumab biomarkers via analyses of pre-treatment plasma exosome mRNAs from head and neck cancer patients (BIONEXT) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1195.
Abstract 3176: Otopetrin 3 promotes cell proliferation and regulates glycolysis via interaction with MYC in colorectal cancer
Authors: Hyeung-Jin Jang, Wona Jee, So-Mi Park, Ye-rin Park, Seok Woo Kim, Ji Hoon Jung
Journal: Cancer Research (2024)

Abstract Otopetrin 3 (OTOP3) stands out as a pivotal regulator of intracellular pH through its control over proton transportation into cells, affecting fundamental cellular processes. Previous studies have shown that OTOP3 is associated with the prognosis of colorectal cancer (CRC) patients. However, the mechanism underlying OTOP3 regulation remains unclear in cancer. Our investigation reveals OTOP3 as a potent oncogene in CRC, with higher OTOP3 levels correlating with diminished overall survival rates in CRC patients. Comparative analysis between cancerous and normal colon cells highlights a pronounced overexpression of OTOP3 in cancer cells. Suppression of OTOP3 expression significantly curtailed CRC cell proliferation, colony formation, migration, and invasion, concurrently inducing apoptosis and cell cycle arrest, ultimately leading to cancer cell death. Moreover, through CHX, FBS inactivation, and MG132 treatment experiments, it was confirmed that OTOP3 regulates c-Myc expression and stability through ubiquitination and has a critical impact on CRC cell proliferation and growth. Additionally, OTOP3's modulation of HK2, PKM2, and LDHA, underscores its role in impacting cancer cell behavior via glycolytic pathways. In summary, the overexpression of OTOP3 in CRC cells drives cell proliferation and growth through the regulation of c-Myc, impacting crucial cellular processes. Additionally, it promotes these processes by influencing glycolysis. These findings provide valuable insights into potential therapeutic targets for CRC treatment, possibly involving OTOP3 and its associated pathways. Citation Format: Hyeung-Jin Jang, Wona Jee, So-Mi Park, Ye-rin Park, Seok Woo Kim, Ji Hoon Jung. Otopetrin 3 promotes cell proliferation and regulates glycolysis via interaction with MYC in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3176.
Abstract 2907: Therapeutic targeting miR-146a and miR-21 induce malignant cell death and regulate CD8+ T-cell function in mycosis fungoides with large-cell transformation
Authors: Zhen Han, Piotr Swiderski, Xiwei Wu, Yate-Ching Yuan, Jun Wu, Chingyu Su, Hanjun Qin, Steven Rosen, Christiane Querfeld
Journal: Cancer Research (2024)

Abstract Large cell transformation of mycosis fungoides (LCT-MF) occurs in 20-50% of advanced MF and is associated with an aggressive clinical course and poor survival not to overcome by any standard treatment regimen. We have previously identified a distinct miRNA expression profile in LCT-MF from that of non-transformed MF with significant upregulation of miR-21 and miR-146a. Our analyses demonstrated the involvement of genes for immune checkpoint pathways such as ICOS-ICOSL and PD1-PDL1 signaling (Di Raimondo C et al. Cancers 2021). Here, we aimed to investigate the efficacy of antagomiR-146a and -21 (amiR-146a, and -21) on the tumor growth and CD8+ tumor infiltrating lymphocyte exhaustion in LCT-MF. The amiR-146a, and -21 were synthesized in our DNA/RNA Synthesis Core by linking CpG-D19. In vitro, CTCL cell lines (Myla and HH) were treated with amiR-146a and -21, the cell viability was assessed by the 2,5-diphenyl-2H-tetrazolium bromide assay and cell apoptosis was evaluated using apoptosis assay. We found that amiR-146a, and -21 synergistically inhibited the proliferation of MyLa and HH cells due to the activation of apoptosis through Caspase3/7 pathways and inducing cell cycle arrest by blocking STAT3/CDK1/Cyclin B1 pathway. Our RNA-seq data indicated that the exhausted CD8+ T cells express elevated amounts of STAT3, IRF4, and BATF in LCT-MF compared with non-LCT MF. To evaluate the functional importance of amiR-146a, and -21 on CD8+ T cell exhaustion, we induced an exhausted state of CD8+ T cells with high level of immune checkpoints and dysfunctional cytokine production by continues anti-CD3/DC28 beads and culture supernatant (MyLa or HH cell) exposure. Our data revealed that amiR-146a and -21 attenuated the CD8+ T cell exhaustion by blockade of immune checkpoints and STAT3/IRF4/BATF pathway to trigger the cytotoxic immune response. Collectively, the findings of our study suggest that targeting miR-146a and -21 is a promising and novel therapeutic strategy for LCT-MF. Citation Format: Zhen Han, Piotr Swiderski, Xiwei Wu, Yate-Ching Yuan, Jun Wu, Chingyu Su, Hanjun Qin, Steven Rosen, Christiane Querfeld. Therapeutic targeting miR-146a and miR-21 induce malignant cell death and regulate CD8+ T-cell function in mycosis fungoides with large-cell transformation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2907.
Abstract 5969: VRK1 can be a therapeutic target in small cell neuroendocrine carcinoma of the uterine cervix
Authors: Mariya Kobayashi, Satoshi Nakagawa, Mizuki Kanda, Yuji Kamei, Masuda Tatsuo, Mamoru Kakuda, Kosuke Hiramatsu, Toshihiro Kimura, Yutaka Ueda, Takayuki Enomoto, Masahiro Inoue, Tadashi Kimura
Journal: Cancer Research (2024)

Abstract Objective: Small cell neuroendocrine carcinoma of the uterine cervix (SCNEC) is extremely rare but highly aggressive and its prognosis is usually poor. Vaccinia-related kinase (VRK)1 is a serine/threonine protein kinase that is involved in cell proliferation by regulating cell-cycle progression and inducing cell-cycle arrest in response to stress signals. VRK2 belongs to the same family as VRK1, and they are paralogs. VRK1 has been reported as a potential therapeutic target in nervous system tumors with low VRK2 expression. Previously, we identified high expression of VRK1 in SCNEC through proteomic analysis of isolated organoids. The objective of the present study is to investigate the effect of VRK1 on the proliferation of SCNEC and its potential as a therapeutic target. Methods: The mRNA and protein expression of VRK1 and VRK2 in ten organoids and two cell lines derived from SCNEC were examined and compared with cervical cancer of other histological subtypes by RNA microarray and western blot analysis. The effect of VRK1 on tumor growth in vitro and in vivo (xenograft model) were evaluated by shRNA-mediated knockdown of VRK1 (shVRK1). RNA-seq was performed from the xenograft tumors. The effects of shVRK1 on cell proliferation were evaluated under various levels of oxidative stress induced by H2O2. Results: VRK1 expression was higher in organoids and cell lines derived from SCNEC than those derived from squamous cell carcinoma and adenocarcinoma, while VRK2 expression was lower in SCNEC. Tumor growth was suppressed significantly by shVRK1 in vivo (mean weight: cell line 1: 0.62 vs 0.06g, p&amp;lt;0.05, 2: 1.79 vs 0.58g, p&amp;lt;0.01). Gene ontology analysis of RNA-seq data suggested that VRK1 is related to cellular responses to stress. Proliferation was slightly suppressed by shVRK1 under normal conditions; however, it was significantly enhanced under oxidative stress (Cell line 1: in shVRK1, -14.0% without oxidative stress vs -54.9% under H2O2 750μM, p&amp;lt;0.01, Cell line 2: similar to Cell line 1). Conclusion: SCNEC exhibited high VRK1 and low VRK2 expression, and the tumor suppressive effect of shVRK1 was more significant in vivo than in vitro. VRK1 may play a role in the tumor microenvironment, including oxidative stress, and is a potential therapeutic target for SCNEC. Citation Format: Mariya Kobayashi, Satoshi Nakagawa, Mizuki Kanda, Yuji Kamei, Masuda Tatsuo, Mamoru Kakuda, Kosuke Hiramatsu, Toshihiro Kimura, Yutaka Ueda, Takayuki Enomoto, Masahiro Inoue, Tadashi Kimura. VRK1 can be a therapeutic target in small cell neuroendocrine carcinoma of the uterine cervix [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5969.
Abstract 2272: Unlocking the potential of miRNA sequencing for early detection and monitoring of pancreatic cancer progression and recurrence
Authors: Ryan N. Fuller, Ann Morcos, Desirae Escalera, Nathan R. Wall
Journal: Cancer Research (2024)

Abstract Pancreatic cancer (PC) is an elusive and deadly disease. Many patients with PC are diagnosed with metastatic or locally advanced tumors, limiting surgical resection, and increasing the risk of relapse after treatment. Relapse is recorded to be as high as 75% in the first 2 years after clinical intervention, resulting in a mean 5-year survival of 12% in the US, and as low as 2% worldwide. It is vital to develop diagnostic and monitoring techniques for PC. MicroRNAs (miRNAs) are robustly expressed in patient tumors and provide a rich source of biomarkers for disease detection and status. miRNA are short nucleic acid strands that bind to catalytic proteins to guide the regulation of large RNAs within the cellular space. This system is altered in tumors, leading to abhorrent expression of miRNA. Due to significant advancements in sequencing technology, miRNA-seq has become more accurate and affordable in detecting profile changes. To identify biomarkers for PC progression, we developed from the Gemcitabine-sensitive MIA-PaCa-2 (MP2) cell line the Gemcitabine and FOLFIRINOX resistant MP2-GR cell line. MiRNA-seq was conducted on the parental MP2 and resistant MP2-GR cells to identify those miRNAs that were differentially expressed between the cell lines. These miRNAs were analyzed via pathway analysis and gene ontology to find predicted functions followed by annotations from the miRNA Enrichment Analysis and Annotation tool (miEAA) to identify differentially expressed miRNAs associated with PC progression. This comparison indicated several miRNAs related to PC resistance. This dataset was then compared to The Cancer Genome Atlas (TCGA), which contains data from over 300 PC patients. The miRNA set was used to predict both PC progression after treatment, and recurrence. We are currently refining this data set to increase its predictive sensitivity and widen our patient data set comparison to further elucidate this approach in a clinical setting. Citation Format: Ryan N. Fuller, Ann Morcos, Desirae Escalera, Nathan R. Wall. Unlocking the potential of miRNA sequencing for early detection and monitoring of pancreatic cancer progression and recurrence [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2272.
Abstract 7175: Web-based cross-database exploration of molecular pharmacology data from cancer cell lines and patient genomics
Authors: William C. Reinhold, Augustin Luna, Fathi Elloumi, Sudhir Varma, Daiki Taniyama, Makito Mizunuma, Jaydira del Rivero, Anish Thomas, Karyyne Reilly, Karel Pacak, Mirit Aladjem, Yves Pommier
Journal: Cancer Research (2024)

Abstract CellMiner Cross-Database (CellMinerCDB, discover.nci.nih.gov/cellminercdb) allows integration and analysis of molecular and pharmacological data within and across cancer cell line datasets from the National Cancer Institute (NCI), Broad Institute, Sanger/MGH, MD Anderson Cancer Center (MDACC), and the National Center for Advancing Translational Sciences (NCATS, discover.nci.nih.gov/rsconnect/cellminercdb_ncats/). Altogether, our database spans over 1,700 distinct cell lines, over 1,000 clinically relevant drugs, ~25,000 experimental compounds, and molecular profiling data, such as gene/protein expression, molecular signatures including epithelial mesenchymal transition (EMT), replication stress (RepStress), neuroendocrine evaluation (NE), DNA copy, methylation, mutational status, and gene dependencies (Broad DepMap). This rich and growing set of cell lines and tested drugs allows for novel avenues for response determinant discovery and clinical translation that is facilitated by 1) common annotations (e.g., tissues of origin and matched drug names) across pharmacogenomic datasets and 2) various univariate and multivariate analyses tools. A major challenge to clinical translation occurs in relating pre-clinical models to patient samples. As part of this work, we show how the CellMinerCDB infrastructure additionally supports annotated patient multi-omics data to aid researchers to relate findings from cancer cell lines with patient data; we use data from small cell lung cancer (SCLC) and neuroendocrine tumors as illustrative examples. This work provides significant pharmacogenomic integration that allows exploration within a comprehensive dataset of cancer cell lines and to inter-relationships with patient-derived datasets; this is being developed to display and mine patient samples as part of the complementary web-based tool (PatientTumorMiner). Citation Format: William C. Reinhold, Augustin Luna, Fathi Elloumi, Sudhir Varma, Daiki Taniyama, Makito Mizunuma, Jaydira del Rivero, Anish Thomas, Karyyne Reilly, Karel Pacak, Mirit Aladjem, Yves Pommier. Web-based cross-database exploration of molecular pharmacology data from cancer cell lines and patient genomics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7175.
Abstract 943: Identification and validation of unusual drug combinations identified from combination databases
Authors: Rainer Grant, Marco Pinheiro, Rachel Weller Roska, Robert Felix
Journal: Cancer Research (2024)

Abstract There is a noted trend in the identification and subsequent approval of rational drug combinations to treat various diseases, particularly cancer. When applied in a clinical setting, synergistic combinations can have significant benefits including improved patient response and avoiding or overcoming drug resistance. Although multiple strategies have been successfully implemented to identify rational drug combinations, extensive validation is initially required to confirm a combination as synergistic. The existence and growing use of web-based repositories containing comprehensive drug combination data is a key resource and can be a valuable starting point for identifying synergistic combinations. However, are synergistic combinations from these datasets expected or rational and can they be validated experimentally? By mining available drug combinations from the DrugCombo database, we wanted to identify unusual drug combinations reported as synergistic and experimentally validate these with dose-response assays. In addition, we set out to establish if cytokines could be used as an inhibition biomarker to easily assess synergy. We found multiple unexpected synergies including a predicted synergy between the JAK1/2 inhibitor Ruxolitinib with Maraviroc, a CCR5 antagonist, or Levetiracetam, an SV2A binding anti-epileptic reported in the lymphoma cell line, L-1236. Experimentally, these predicted synergies could not be validated. In the context of synergistic drug combinations, this work shows that experimental validation is crucial, particularly for combinations with uncertain biological mechanisms. Citation Format: Rainer Grant, Marco Pinheiro, Rachel Weller Roska, Robert Felix. Identification and validation of unusual drug combinations identified from combination databases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 943.
Abstract 140: Distinct pathways regulated by activated β-Catenin and YAP in hepatoblastoma pathogenesis
Authors: Weiting Liao, Xin Chen
Journal: Cancer Research (2024)

Abstract Hepatoblastoma (HB) is a rare, yet the most common primary malignant hepatic liver in children. A significantly portion of children with HB have tumors that are not resected at diagnosis, leading to the dismal prognosis in these patients. Concomitant YAP and β-catenin activation could be seen 80% of HB. The signaling pathways regulated by YAP and β-catenin in HB pathogenesis remain unclear. Here, we engineered a inducible HB murine model using hydrodynamic injection to deliver transposon plasmids encoding constitutive YAP and doxycycline (Dox) inducible ΔN90-β-Catenin (Yap/TRE-β-Catenin). When fed with Dox, HB formed rapidly in the mice. Upon Dox withdraw, HB regressed over the long term. We analyzed gene expression patterns in mouse HB lesions upon short term Dox withdrawal, i.e, tumors still existed yet ΔN90-β-Catenin was turned off. This approach assisted to identify genes regulated by the activated β-Catenin in HB tumors. We compared these genes with the previously identified YAP regulated genes and found the distinct gene expression programs regulated by YAP and β-Catenin in HB. Specifically, YAP off down-regulated Hippo pathway and up-regulated metabolism-related pathways, whereas β-Catenin off down-regulated protein export, DNA replication pathway and up-regulated immune-related pathways. Finally, we identified ONECUT1 as a gene down-regulated by activated β-Catenin in HB. ONECUT1 expression was down-regulated in human HBs, and co-expression of ONECUT1 strongly suppressed Yap/β-Catenin HB formation in mice. Mechanically, ONECUT1 could regulate proliferation-related downstream signaling. Altogether our studies demonstrated that suppression of activated CTNNB1 mutations could repress HB progression in vivo, and we identified distinct pathways regulated by activated β-catenin and YAP in HB. Suppression of ONECUT1 expression by β-catenin is a key genetic event leading to HB formation. Citation Format: Weiting Liao, Xin Chen. Distinct pathways regulated by activated β-Catenin and YAP in hepatoblastoma pathogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 140.