tbuckley/cabot-search huggingface dataset:
Abstract 5674: Characterizing Cellular Heterogeneity and Identifying Potential Biomarkers in Esophageal Squamous Cell Carcinoma (ESCC) Using Single-Cell RNA Sequencing
Authors: Tzu-Hung Hsiao, Chih-Hung Lin, Ting-Shuan Wu, Li-Wen Lee, Chung-Ping Hsu
Journal: Cancer Research (2024)

Abstract Esophageal squamous cell carcinoma (ESCC) exhibits significant cellular heterogeneity, rendering it susceptible to developing radioresistance and recurring tumors. Single-cell RNA sequencing (scRNA-seq) is an advanced technique that allows for the exploration of distinct gene expression profiles in individual cells. To investigate cellular heterogeneity in ESCC, scRNA-seq analysis was performed on tumor tissues from ten ESCC patients, as well as adjacent non-malignant esophageal tissues. The cellular composition revealed 19 distinct cell clusters, further categorized into seven cell populations: 69.31% Fibroblast, 15.36% T cell, 5.30% Monocytes, 5.26% Endothelial cells, 2.68% plasma cell, 1.91% Epithelial cells, and 0.18% ambiguous. Notably, Fibroblast and Endothelial cells were more prevalent in non-malignant tissues, while the remaining cell types were enriched in tumor tissues. Differential gene expression analysis identified 49 genes with higher expression in tumor cells and 37 genes with lower expression. Gene Set Enrichment Analysis (GSEA) revealed the top three most relevant GO Biological Processes pathways: positive regulation of immune response, regulation of T cell activation, and positive regulation of cell migration. Furthermore, in post-treatment follow-up, four patients were observed to develop metastasis within one year. Comparative analysis between metastatic and non-metastatic patients unveiled 9 Differentially Expressed Genes (DEGs), including KRT6A and AKR1B10, which exhibited specific expression in Epithelial cells and were highly expressed in tumor tissues. Additionally, IGLC2, IGHG4, and IGHG1 demonstrated specific expression in plasma cells, with elevated expression in tumor tissues. These findings suggest that KRT6A, AKR1B10, IGLC2, IGHG4, and IGHG1 may serve as potential biomarkers for predicting post-chemotherapy metastasis in ESCC patients. Citation Format: Tzu-Hung Hsiao, Chih-Hung Lin, Ting-Shuan Wu, Li-Wen Lee, Chung-Ping Hsu. Characterizing Cellular Heterogeneity and Identifying Potential Biomarkers in Esophageal Squamous Cell Carcinoma (ESCC) Using Single-Cell RNA Sequencing [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 5674.
Abstract 3364: PELO is a synthetic lethal target in chromosome 9p21-deleted or MSI cancers
Authors: Edmond M. Chan, Patricia Borck, Nolan Bick, Kristina Jankovic, Isabella Boyle, Lucy Parker-Burns, Kyla Foster, Anthony Lau, Ashir Borah, Joshua Dempster, Francisca Vazquez
Journal: Cancer Research (2024)

Abstract Homozygous deletion of chromosomal region 9p21.3 is one of the most frequently observed somatic copy number alterations in cancers, occurring in approximately 15% of all cancers. Many of the 9p21.3-deleted cancers are further characterized by poor clinical outcomes including subsets of glioblastoma, pancreatic, esophageal, and urothelial cancers. Large deletions of chromosomal regions may also provide unique therapeutic opportunities. Specifically, cancer-specific therapeutic opportunities can arise from co-deletions of passenger genes neighboring tumor suppressors. As such, we sought to identify novel therapeutic targets associated with Ch9p21.3 loss in cancers and identified the pelota mRNA surveillance and ribosome rescue factor (PELO) as the top preferential dependency in 9p21.3-deleted cancers. Intriguingly in another analysis, we identified PELO to be amongst the top preferential dependencies in cancers with microsatellite instability (MSI), which accounts for subsets of colorectal, endometrial, gastric, and ovarian cancers. Given the strength of PELO as a candidate synthetic lethal target in two distinct cancer subsets, we performed focused validation with CRISPR interference across multiple cell lines. Knockdown of PELO preferentially impaired the viability of MSI or 9p21-deleted as compared to control (9p21-proficient and microsatellite stable) cells. Further validation with patient-derived organoid and in vivo xenograft models confirmed these findings. We next sought to refine the predictive biomarkers for PELO dependency and identified loss of FOCAD (a 9p21.3 gene and an interactor of the SKI mRNA surveillance pathway) as necessary and sufficient for PELO dependency in the 9p21.3-deleted context. Our findings implicate splicing alterations involving TTC37, a key protein in the SKI mRNA surveillance complex, as the underlying cause of PELO dependency in MSI cancers. Together, we found that loss of large deletions of 9p21.3 and MSI independently impair the SKI complex, uncovering a dependency upon PELO and highlighting a novel functional interaction between PELO and the SKI complex. Furthermore, the strength of this synthetic lethal interaction in a broad range of cancers with poor outcomes underscores the potential of PELO as a promising drug target for patients with 9p21.3-deleted or MSI cancers. Citation Format: Edmond M. Chan, Patricia Borck, Nolan Bick, Kristina Jankovic, Isabella Boyle, Lucy Parker-Burns, Kyla Foster, Anthony Lau, Ashir Borah, Joshua Dempster, Francisca Vazquez. PELO is a synthetic lethal target in chromosome 9p21-deleted or MSI cancers [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 3364.
Abstract 2839: The mouse models of human cancer database (MMHCdb)
Authors: Dale A. Begley, Debra M. Krupke, Emily Jocoy, Steven B. Neuhauser, Carol J. Bult
Journal: Cancer Research (2024)

Abstract The laboratory mouse plays a pivotal role as an experimental system for investigations into the genetic and genomic basis of cancer susceptibility, initiation, and progression and for preclinical research on novel treatment strategies for cancer. Advances in mouse models include humanized mice, transplant compliant mouse strains, and panels of genetically diverse mice (e.g., Diversity Outbred and Collaborative Cross). The distributed and heterogenous nature of information about these model systems presents a significant challenge to finding and aggregating information about mouse models and to identifying the most relevant models for a particular research question. The Mouse Models of Human Cancer database (http://tumor.informatics.jax.org) is an expertly curated FAIR-compliant knowledgebase that applies community annotation standards and nomenclature standards for genes, alleles, and strains to support accurate and comprehensive search results for mouse models of human cancer. The data in MMHCdb are curated from peer-reviewed scientific publications and direct data submissions from individual investigators and large-scale programs. A primary focus of the resource is to reflect the impact that genetic background has on the cancer-related characteristics of mouse models. The database includes information on spontaneous and genetically engineered cancer models as well as Patient Derived Xenografts and diversity panels. The database supports faceted searching for models by multiple criteria including, tumor type, genetic background of the mouse model, somatic mutations, and publication. Model descriptions include summaries of observed frequencies of tumors observed in the model and histopathology images. Information in MMHCdb is linked to cancer model data from other bioinformatics resources including the Patient Derived Cancer Models database (PDCM), PathBase, the Gene Expression Omnibus (GEO), and ArrayExpress. MMHCdb is supported by NCI R01 CA089713 Citation Format: Dale A. Begley, Debra M. Krupke, Emily Jocoy, Steven B. Neuhauser, Carol J. Bult. The mouse models of human cancer database (MMHCdb) [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 2839.
Abstract 5490: Spatial profiling of inflamed tumor microenvironment of clear cell renal cell carcinoma
Authors: Teijo Pellinen, Lassi Luomala, Kalle Mattila, Jenni Säilä, Annabrita Hemmes, Katja Valimaki, Oscar Bruck, Lassi Paavolainen, Harry Nisen, Petrus Järvinen, Olli Kallioniemi, Paula Vainio, Panu Jaakkola, Tuomas Mirtti
Journal: Cancer Research (2024)

Abstract Clear cell renal cell carcinoma (ccRCC) presents a distinctive tumor microenvironment (TME) characterized by extensive vascularization and immune infiltration. This unique TME makes ccRCC an attractive target for anti-angiogenesis and immune checkpoint blockade (ICB). To better understand the complexity of ccRCC and the associated cell types and states involved in disease progression, we conducted high-throughput single-cell immunofluorescence imaging on tissue sections from 437 localized tumors that were surgically resected. These samples included regions from the tumor center, tumor edge, and adjacent benign areas (TMA cores, n=1859). Our primary focus was on tumors with elevated immune cell enrichment (CD45high), as these tumors are known to be aggressive and may respond well to immunotherapy. Our study reveals the intricate interactions between tumor, vascular, stromal, and immune cells within ccRCC. We find that CD45high tumors, upon losing epithelial marker expression, acquire tumor cell PD-L1 and mesenchymal markers such as Fibroblast activation protein (FAP). This shift is indicative of the epithelial-mesenchymal transition (EMT) process. These CD45high and EMThigh tumors are enriched with changes in TME, including elevated FAP+ cancer-associated fibroblasts (CAFs) and subsets of immune suppressive T cells and macrophages. We report that ccRCC patients with high tumor PD-L1 expression or abundant FAP+ CAFs are associated with earlier metastasis and, in sunitinib-treated patients, shorter progression-free survival. This study illuminates the intricate connection between immune cell infiltration, stromal biology, and EMT in ccRCC, offering a deeper understanding of the disease's complex biology and potentially guiding future therapeutic approaches and strategies. Citation Format: Teijo Pellinen, Lassi Luomala, Kalle Mattila, Jenni Säilä, Annabrita Hemmes, Katja Valimaki, Oscar Bruck, Lassi Paavolainen, Harry Nisen, Petrus Järvinen, Olli Kallioniemi, Paula Vainio, Panu Jaakkola, Tuomas Mirtti. Spatial profiling of inflamed tumor microenvironment of clear cell renal cell carcinoma [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 5490.
Abstract 4831: Racialized economic segregation and disparities in late-stage diagnosis, treatment and mortality among patients with non-small cell lung cancer
Authors: Pratibha Shrestha, Min Lian, Ying Liu
Journal: Cancer Research (2024)

Abstract Importance: Little is known about the impact of residential segregation on early detection, treatment, and prognosis among patients with non-small cell lung cancer (NSCLC), a predominant type of lung cancers. Objective: To examine the associations of racialized economic segregation with the risks of late-stage diagnosis, non-adherence to guideline-recommended treatment, and mortality among non-Hispanic White (NHW) patients and non-Hispanic Black (NHB) patients with NSCLC. Methods: This population-based retrospective cohort study included patients with NSCLC as a first primary malignancy diagnosed at age 20 and older between January 2007 and December 2015, followed through December 2016, and identified from the Surveillance, Epidemiology, and End Results (SEER) dataset released in April 2019. County-level racialized economic segregation was estimated using the Index of Concentration at the Extremes (ICE). We used multilevel logistic regression and multilevel Cox regression accounting for county-level clustering to estimate odds ratios (ORs) for late-stage diagnosis and non-adherence to guideline-recommended treatment, and hazard ratios (HRs) for overall mortality and lung cancer-specific mortality. Results: Of 203, 441 patients, 85.8% were NHW and 14.2% were NHB. Compared with patients living in the most privileged (lowest ICE quintile―segregated, high-income NHW) counties, patients living in the least privileged (highest ICE quintile―segregated, low-income NHB) counties had higher risks of late-stage diagnosis (OR=1.09, 95% CI: 1.02-1.16; Ptrend &amp;lt;.001), non-adherence to guideline-recommended treatment (OR=1.28, 95% CI: 1.16-1.41; Ptrend &amp;lt;.0001), lung cancer-specific mortality (HR=1.10, 95% CI: 1.07-1.14; Ptrend &amp;lt;.0001), and overall mortality (HR=1.12, 95% CI: 1.09-1.16; Ptrend &amp;lt;.0001). The association of segregation with treatment underutilization was stronger in NHW patients than NHB patients (Pinteraction =0.02). There was no significant difference in the segregation-related risk of late-stage diagnosis, lung cancer-specific mortality, or overall mortality between NHW and NHB patients. Conclusions: Living in segregated, low-income NHB counties was associated with increased risks of late-stage diagnosis, suboptimal treatment, and mortality among patients with NSCLC. Future research should investigate contributors to the adverse impact of residential segregation on lung cancer care and outcomes. Citation Format: Pratibha Shrestha, Min Lian, Ying Liu. Racialized economic segregation and disparities in late-stage diagnosis, treatment and mortality among patients with non-small cell lung 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 4831.
Abstract 4378: Identification of novel TXNIP-dependent antitumor pathways in breast cancer
Authors: Jasvinder Singh, Bindeshwar Sah, Robert Clarke, Liang Liu
Journal: Cancer Research (2024)

Abstract Thioredoxin-interacting protein (TXNIP) plays a critical role in glucose metabolism and redox signaling. TXNIP has recently emerged as a potent tumor suppressor in various cancer models. In previous studies, we found TXNIP was activated by UNC0642, an inhibitor of histone methyltransferase, in MDA-MB-231 breast cancer cells. TXNIP activation was coupled with significant suppression of cell proliferation and tumor growth. In contrast, TXNIP knockdown increased MDA-MB-231 cell proliferation and in tumor growth and metastasis in vivo. TXNIP-reconstitution in TXNIP-deficient HCC1954 cells reduced cell proliferation and migration coupled with increased reactive oxygen species production. TXNIP-reconstitution also significantly decreased mitochondrial respiration, mitochondrial membrane potential and glycolysis in HCC1954 cells. To understand the mechanisms underlying TXNIP’s antitumor activity, we performed co-immunoprecipitation and proteomic analyses to uncover TXNIP-interacting proteins. We identified calpastatin (CAST) as a novel TXNIP-interacting protein in breast cancer cells. CAST is an endogenous inhibitor of calpains, a family of calcium-activated cysteine proteases. Intriguingly, CAST association with TXNIP was readily detectable in TXNIP-low, but not in TXNIP-high breast cancer cells. The disassociation of CAST from TXNIP in TXNIP-high cells might allow CAST to inhibit calpain activity to augment TXNIP’s antitumor function. Through RNAseq analysis, we identified a positive correlation between TXNIP expression and IL-24 activation in various breast cancer cells, which were also confirmed by western blotting. IL-24 has emerged as an important cancer therapy target because of its role in promoting cancer-specific apoptosis. Our data also demonstrated that TXNIP upregulated the level of IL-24 and downregulated STAT-3. Moreover, TXNIP exerts multifaceted effects on BC development through the IL24-STAT3 signaling axis, deepening our understanding of its complex role in the disease. Taken together, these studies identified novel TNXIP-dependent pathways and their potential new mechanisms in breast cancer pathogenesis with significant clinical implications. Citation Format: Jasvinder Singh, Bindeshwar Sah, Robert Clarke, Liang Liu. Identification of novel TXNIP-dependent antitumor pathways in breast 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 4378.
Abstract 7192: Teriflunomide overcomes gemcitabine resistance by inhibiting the GSK3β/mTOR pathway in pancreatic cancer
Authors: Caiming Xu, Yuan Li, Silei Sui, Meiling Chen, Laleh Melstorm, Haiyong Han, Steven T. Rosen, Ajay Goel
Journal: Cancer Research (2024)

Abstract Background: Pancreatic cancer (PC) is a lethal malignancy that is partly attributable to the acquisition of chemoresistance to conventional chemotherapies. Hence, developing strategies to overcome such chemoresistance is essential. Teriflunomide, an active metabolite of leflunomide, has been widely utilized in managing autoimmune disorders, and emerging evidence suggests that it can augment the efficacy of chemotherapy in cancer. We investigated the therapeutic effect of teriflunomide in overcoming resistance to Gemcitabine-based therapy in PC. Methods: We performed docking and genomewide transcriptomic profiling analyses to identify therapeutic targets of Teriflunomide associated with Gemcitabine resistance (Gem-R) in PC. Subsequently, we analyzed the TCGA dataset to determine the prognostic significance of candidate genes in PC patients. A series of experiments were performed in PC cells, and the key findings were validated in patient-derived 3D organoids and a Gem-R Mia-PaCa2 xenograft model. Results: Docking and transcriptomic profiling studies identified GSK3β, MAPK8, and MAPK9 as potential targets of Teriflunomide, which were significantly upregulated in Gem-R cell lines (P &amp;lt; 0.05). GSK3β was independently associated with poor overall and disease-free survival in PC patients. Combined Teriflunomide and Gemcitabine treatment exhibited superior synergistic anti-tumor potential, as evidenced by reducing PC cell proliferation, clonogenicity, invasion, and migration. The combined treatment with Teriflunomide and Gemcitabine primarily inhibited GSK3β phosphorylation, resulting in the silencing of the downstream AKT/mTOR pathway. Lentiviral-based silencing of GSK3β inhibited the AKT/mTOR pathway and reduced the IC50s of Gemcitabine in PC cells. Furthermore, co-administrating both drugs to Gem-R Mia-PaCa-2 xenograft mice significantly reduced tumor growth rates and volumes. These findings were recapitulated in patient-derived 3D-organoids, where the combined treatment resulted in fewer and smaller organoids vs. each drug individually (P &amp;lt; 0.05). Conclusions: We provide novel evidence that Teriflunomide helps overcome resistance to Gemcitabine by inhibiting the GSK3β/AKT/mTOR pathway, which could improve treatment outcomes in PC. Citation Format: Caiming Xu, Yuan Li, Silei Sui, Meiling Chen, Laleh Melstorm, Haiyong Han, Steven T. Rosen, Ajay Goel. Teriflunomide overcomes gemcitabine resistance by inhibiting the GSK3β/mTOR pathway in pancreatic 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 7192.
Abstract 7079: The Wnt/β-catenin signaling pathway regulates cellular metabolism through the suppression of HAL and ARG1 in liver cancer cells
Authors: Saya Nakagawa, Kiyoshi Yamaguchi, Kiyoko Takane, Sho Tabata, Tsuneo Ikenoue, Yoichi Furukawa
Journal: Cancer Research (2024)

Abstract Aberrant activation of the Wnt/β-catenin signaling pathway plays a crucial role in a wide range of human tumors including colorectal and liver cancer. The activated signaling causes nuclear accumulation of β-catenin, which leads to the elevated expression of target genes of TCF/LEF (T-cell factor/lymphoid enhancer factor) transcription factors through their interaction with nuclear β-catenin. Recent studies have identified a lot of genes induced by this pathway such as MYC, CCND1, AXIN2, and LGR5, and clarified their roles in tumorigenesis. However, the roles of the genes down-regulated by the pathway remain to be elucidated. Our previous study revealed that the histidine ammonia-lyase gene (HAL) encoding an enzyme involved in the catabolism of histidine was down-regulated by the signaling pathway in liver cancer. In addition, we identified a region that is involved in the Wnt-dependent regulation of HAL. To clarify the regulatory mechanism of HAL by the pathway, we searched for transcription factors that are associated with the regulatory region, and identified CEBPA and FOXA1, two liver-enriched transcription factors. It is of note that the expression of these factors was reduced by the TCF/β-catenin complex. Further investigation identified arginase 1 (ARG1) encoding an enzyme that catalyzes the hydrolysis of arginine as another target gene of CEBPA and FOXA1. Consistent with these data, inhibition of the Wnt signaling increased the expression of ARG1 as well as HAL in liver cancer cells. Furthermore, the up-regulation of HAL and ARG1 by the inhibition of this pathway decreased intracellular concentrations of histidine and arginine, suggesting that the Wnt signaling plays an important role in cellular metabolism through the regulation of the two transcription factors. These findings shed light on the role of the Wnt/β-catenin signaling pathway in the metabolism of amino acids in liver cancer cells. Citation Format: Saya Nakagawa, Kiyoshi Yamaguchi, Kiyoko Takane, Sho Tabata, Tsuneo Ikenoue, Yoichi Furukawa. The Wnt/β-catenin signaling pathway regulates cellular metabolism through the suppression of HAL and ARG1 in liver cancer cells [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 7079.