tbuckley/cabot-search huggingface dataset:
Abstract 1054: Reciprocal circRNA-miRNA expression axes indicative of early tumor initiation in breast
Authors: Nour Abbas Maatouk, Sarah Hussein Marei, Abdallah Bilal Kurdi, Nadim Shady Hamade, Rihab Raif Nasr, Rabih Shakib Talhouk
Journal: Cancer Research (2024)

Abstract Cancer prevention and early detection are the most effective tools for cancer control. In this study, we adopt a novel approach of identifying a network of proteins/mRNA-circRNA-miRNA axes. We hypothesize that mutation of oncogenes or tumor suppressor genes during pre-oncogenic stage result in aligned change in levels of circular RNAs-derived genes, as well as, reciprocally, in corresponding sponged miRNAs. These epigenetic risk predictive proteins/mRNA-circRNA-miRNA axes serve as potential tool for early detection of changes leading to breast cancer (BC) and can be further used as non-invasive screening biomarkers of patients’ blood in populations susceptible to cancer. BC patients in GDC Data Portal, TCGA-BRCA project are selected based on several criteria such as their age at diagnosis (20-50 years old), early clinical stage of cancer (stage I) and disease type (ductal and lobular neoplasms). Differentially expressed genes are acquired from mRNA sequencing data by comparing Stage I Breast cancer versus normal primary tissues using R Studio. Then, mRNAs whose expression is aligned with the differentially expressed circRNAs and their host genes acquired from Gene Expression Omnibus (GEO) (GSE182471, Triple Negative Breast cancer tissues versus normal tissues) are selected. Differentially expressed miRNAs, in reciprocal expression with circRNAs, are defined using miRNA sequencing data of the same previously chosen TCGA BRCA patients. Selected miRNAs are hypothesized to be sponged with high confidence by selected circRNAs based on a context percentile binding score in CircInteractome. Using KM Plotter, the survival analysis of corresponding miRNAs in grade I BC patients is examined. The predicted miRNA expression was correlated with lower survival rates among stage I BC patients in KM Plotter. MiRNA-enrichment analysis is used to further validate the involvement of selected miRNAs in early tumorigenic events through exploring in which molecular pathways their downstream genes are enriched. We have constructed more than 20 potential proteins/mRNA-circRNA-miRNA axes for non-invasive screening of patients’ body fluid (i.e. Blood) in populations susceptible to BC using RNA and miRNA sequencing data available in online databases and further validate the proposed axes using in-silico tools. The described axes, once validated in clinical samples could provide a potential tool for early-stage BC prediction and prevention. Citation Format: Nour Abbas Maatouk, Sarah Hussein Marei, Abdallah Bilal Kurdi, Nadim Shady Hamade, Rihab Raif Nasr, Rabih Shakib Talhouk. Reciprocal circRNA-miRNA expression axes indicative of early tumor initiation in breast [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 1054.
Abstract 3635: Insulin-like growth factor receptor predicts poor prognosis in early-stage non-small cell lung cancer
Authors: Hiroaki nagamine, Masakazu Yashiro, Megumi Mizutani, Akira Sugimoto, Yoshiya Matsumoto, Yoko Tani, Kenji Sawa, Kazuhiro Yamada, Hiroyasu Kaneda, Tetsuya Watanabe, Kazuhisa Asai, Satoshi Suzuki, Tomoya Kawaguchi
Journal: Cancer Research (2024)

Abstract Introduction: Insulin like growth factor receptor (IGF1R) is involved in the proliferation and metastasis of various cancers. However, the clinical significance of IGF1R in non-small cell lung cancer (NSCLC) remains to be unclear. In this study, we retrospectively evaluated the correlation between IGF1R expression and clinicopathological features of NSCLC. Method: A total of 782 specimens of NSCLC patients who underwent surgical resection of primary lung cancer between 2010 and 2019 at Osaka Metropolitan University Hospital was enrolled in this study. Immunohistochemical staining of IGF1R were performed, and the correlation between IGF1R expression and clinicopathological features of NSCLC, especially in recurrence free survival (RFS) and overall survival (OS), was evaluated. We also evaluated an association between IGF1R and programmed death ligand 1 (PD-L1) expression. Results: IGF1R expression was positive in 279 (35.8%) patients. IGF1R-positive group had significantly longer smoking histories (median smoking index, 1,000 vs 600, p &amp;lt;0.01) and a higher proportion of squamous cell carcinomas (35.1% vs 14.1 %, p &amp;lt;0.01). IGF1R-positive group also significantly expressed PD-L1 (24.4% vs 6.4%, p&amp;lt;0.01). IGF1R-positive group had significantly worse RFS (10-year recurrence-free rate; 42.7% vs 53.7%, p &amp;lt;0.01) and OS (10-year survival rate; 54.4% vs 67.3%, p &amp;lt;0.01). RFS and OS were significantly worse in the IGF1R-positive NSCLC patients at stage 0 and stage I (10-year recurrence-free rate; 49.0% vs 62.9%, p &amp;lt;0.01, 10-year survival rate; 57.4% vs 74.2%, p&amp;lt;0.01), but not in stage II (10-year recurrence-free rate; 52.0% vs 43.8%, p=0.68, 10-year survival rate; 63.4% vs 47.5%, p=0.95) and III (10-year recurrence-free rate; 20.7% vs 20.8%, p=0.77, 10-year survival rate; 38.3% vs 54.6%, p=0.18). IGF1R expression was associated with poorer RFS and OS in early-stage NSCLC. Conclusion: IGF1R is a predictor of poor prognosis in resected early-stage NSCLC. Citation Format: Hiroaki nagamine, Masakazu Yashiro, Megumi Mizutani, Akira Sugimoto, Yoshiya Matsumoto, Yoko Tani, Kenji Sawa, Kazuhiro Yamada, Hiroyasu Kaneda, Tetsuya Watanabe, Kazuhisa Asai, Satoshi Suzuki, Tomoya Kawaguchi. Insulin-like growth factor receptor predicts poor prognosis in early-stage 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 3635.
Abstract 5052: Novel drug resistance mechanisms and drug targets in <i>BRAF</i> mutated peritoneal metastasis from colorectal cancer
Authors: Christin Lund-Andersen, Annette Torgunrud, Chakravarthi Kanduri, Vegar J. Dagenborg, Ida S. Frøysnes, Mette M. Larsen, Ben Davidson, Stein Larsen, Kjersti Flatmark
Journal: Cancer Research (2024)

Abstract Objective: Patients with peritoneal metastasis (PM) from colorectal cancer (CRC) have inferior prognosis and respond poorly to chemotherapy compared to other metastatic locations. This study aims to identify the molecular explanation for the observed clinical behavior and suggest novel treatment strategies in PM-CRC. Design: Tumor samples from a Norwegian national cohort of 230 patients undergoing surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) with mitomycin C (MMC) for PM-CRC were subjected to targeted DNA sequencing, and associations between molecular findings and clinical data were analyzed. mRNA sequencing was conducted on a subset of thirty samples to compare gene expression in tumors harboring mutations in the BRAF or KRAS oncogenes and wild-type tumors. Results: Almost one-third of the patients had mutations in the BRAF oncogene, which were associated with RNF43/R-Spondin aberrations and low expression of negative Wnt regulators (ligand dependent Wnt activation). This molecular profile, with high abundance in PM, could be an underlying mechanism promoting aggressive tumor biology that facilitates metastasis to the peritoneal cavity, and could contribute to the observed poor overall survival of this patient subgroup. BRAF mutations were also associated with gene expression changes in transport solute carrier proteins and drug metabolism enzymes that could influence the efficacy of MMC and irinotecan, commonly used in PM-CRC treatment. BRAF-mutated tumors exhibited increased expression of BTN immune checkpoint molecules, and targeting these checkpoints in addition to ligand dependent Wnt activation could be two novel targeted therapy approaches. Conclusion: BRAF mutations were associated with particularly poor survival in this cohort, possibly related to altered drug transport and metabolism conferring resistance to MMC and irinotecan. Two potential novel therapeutic approaches were identified, suggesting specific targeting of BTN immune checkpoint molecules and the use of inhibitors to target ligand-dependent Wnt activation. Citation Format: Christin Lund-Andersen, Annette Torgunrud, Chakravarthi Kanduri, Vegar J. Dagenborg, Ida S. Frøysnes, Mette M. Larsen, Ben Davidson, Stein Larsen, Kjersti Flatmark. Novel drug resistance mechanisms and drug targets in BRAF mutated peritoneal metastasis from 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 5052.
Abstract 5208: Dynamic changes in circulating tumor DNA and T cell receptor repertoire predict disease progression in patients with unresectable esophageal squamous cell carcinoma
Authors: Baidong Zhang, Xiang Zhan, Qiang Li, Chenxuan Wang, Jiaohui Pang, Yaru Zhang, Song Wang, Qiuxiang Ou, Haimeng Tang, Alei Feng, Zhe Yang
Journal: Cancer Research (2024)

Abstract Background: Patients with unresectable esophageal squamous cell carcinoma (ESCC) showed variations in their response to treatments and experienced inevitable disease progression. The development of non-invasive and clinically viable biomarkers is urgently needed. Therefore, this study aimed to investigate prognostic value of circulating tumor DNA (ctDNA) and T cell receptor (TCR) repertoire in these patients. Methods: A total of 21 ESCC patients who underwent definitive chemoradiotherapy, radiotherapy, or immune checkpoint inhibitor (ICI)-combined therapy from October 2020 to March 2022 were retrospectively evaluated. Baseline tumor samples were collected for genomic profiling using targeted NGS. Baseline and post-therapy plasma were collected for genomic and TCR profiling. Results: We found that ctDNA detection rates were significantly reduced after treatment (P&amp;lt;0.001). Post-treatment ctDNA positivity were associated with worse local recurrence-free survival (P=0.001) and progression-free survival (P=0.001), but not overall survival. Moreover, TCR clonality was significantly increased after treatment, including CDR3 diversity (P=0.003), TCR clonotype (P=0.004), and VJ pairs (P=0.010), indicating an increased T cell expansion and complexity. Specifically, we identified two increased and four reduced VJ rearrangements after treatment, and the four reduced VJ rearrangements (Vβ12-2Jβ2-4, Vβ6-9Jβ1-5, Vβ6-7Jβ1-5, and Vβ6-9Jβ1-1) were significantly associated with worse progression-free survival. Conclusion: Our findings suggest the prognostic implication of plasma ctDNA and TCR profiles in patients with unresectable ESCC receiving definitive therapy, supporting the future development of non-invasive monitoring of disease progression in these patients. Citation Format: Baidong Zhang, Xiang Zhan, Qiang Li, Chenxuan Wang, Jiaohui Pang, Yaru Zhang, Song Wang, Qiuxiang Ou, Haimeng Tang, Alei Feng, Zhe Yang. Dynamic changes in circulating tumor DNA and T cell receptor repertoire predict disease progression in patients with unresectable esophageal squamous 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 5208.
Abstract 2410: Comparative genomic profiling of unresectable NSCLC patients in the U.S. and China using a globally harmonized liquid biopsy assay platform
Authors: Haoran Tang, Cancan Jia, Feng Xie, Yue Zhang, Xiaoxi Dong, Yong Huang, Shading Jia
Journal: Cancer Research (2024)

Abstract Background: Non-Small Cell Lung Cancer (NSCLC), accounting for over 80% of all lung cancers, benefits from targeted therapies based on genetic tests like EGFR, KRAS, ALK, and ERBB2. While prior studies focused on molecular characteristics through tissue biopsies, limited research has explored NSCLC molecular profiles via liquid biopsy, especially across different human races. This study presents a comprehensive genomic profiling analysis of unresectable NSCLC patients in the U.S. and China, using a globally harmonized liquid biopsy assay. Methods: As part of Predicine's Phoenix Program, a global molecular biomarkers screening initiative, 61 patients in the U.S. and 352 patients in China with unresectable advanced NSCLC were enrolled. All were treatment-naïve or recurred after 1st-line targeted therapies. Blood samples (10ml) were tested using PredicineCARE, an NGS-based liquid biopsy assay, to profile somatic mutations, copy number variations, and gene fusions. Results: The assay, validated in both regions using the same reference materials, achieved a Limit of Detection (LOD) of 0.25% mutation allele frequency, with a positive predictive value exceeding 99%. Profiling NSCLC patients in the U.S. and China revealed common genes like TP53, CDKN2A, EGFR, KRAS, RB1, and PIK3CA. TP53 and PIK3CA variations showed equivalent prevalence. However, EGFR variations were significantly higher in China (p&amp;lt;0.05), while CDKN2A (p&amp;lt;0.001), KRAS (p&amp;lt;0.01), and RB1 (p&amp;lt;0.01) variations were notably higher in the U.S. Conclusions: This study unveils the mutational landscape of advanced NSCLC through liquid biopsy. Unique prevalence patterns between U.S. and China cohorts suggest novel biomarkers for clinical diagnosis and provide insights for targeted therapy mechanism studies. Citation Format: Haoran Tang, Cancan Jia, Feng Xie, Yue Zhang, Xiaoxi Dong, Yong Huang, Shading Jia. Comparative genomic profiling of unresectable NSCLC patients in the U.S. and China using a globally harmonized liquid biopsy assay platform [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 2410.
Abstract 2764: Ubiquitin-specific peptidase 22 controls integrin-dependent cancer cell stemness &amp; metastasis
Authors: Qiong Gao, Kun Liu, Yuzhi Jia, Juncheng Wei, Shuvam Mohan Chaudhuri, Shengnan Wang, Amy Tang, Nikita Lavanya Mani, Radhika Iyer, Yang Cheng, Beixue Gao, Weiyuan Lu, Zhaolin Sun, Huiping Liu, Deyu Fang
Journal: Cancer Research (2024)

Abstract Integrins play critical roles in connecting the extracellular matrix and actin skeleton for cell adhesion, migration, signal transduction, and gene transcription. While the upregulation of integrins is thought to promote cancer stemness and metastasis, the mechanisms underlying their upregulation in cancer stem cells (CSCs) remain poorly understood. Herein, we show that the death from cancer signature gene, USP22, is essential in maintaining breast cancer cell stemness by promoting the transcription of a group of integrin family members, in particular, integrin β1 (ITGB1). Both genetic and pharmacological inhibition of USP22 largely impaired breast cancer stem cell self-renewal and prevented their metastasis. Reconstitution of Integrin β1 partially rescued USP22-null breast cancer stemness and their metastasis. At the molecular level, USP22 functions as a bona fide deubiquitinase to protect the proteasomal degradation of the forkhead box M1 (FoxM1), a transcription factor for tumoral ITGB1 gene transcription. Importantly, unbiased analysis of the TCGA database revealed a strong positive correlation between USP22 and ITGB1 in more than 90% of human cancer types, implying that USP22 functions as a key factor in maintaining stemness across a broad spectrum of human cancer types possibly through regulating ITGB1. To support this notion, immunohistochemistry staining detected a positive correlation among USP22, FoxM1 and integrin β1 in human breast cancers. Collectively, our study identifies the USP22-FoxM1-integrin β1 signaling axis as critical for cancer stemness and offers a potential target for antitumor therapy. Citation Format: Qiong Gao, Kun Liu, Yuzhi Jia, Juncheng Wei, Shuvam Mohan Chaudhuri, Shengnan Wang, Amy Tang, Nikita Lavanya Mani, Radhika Iyer, Yang Cheng, Beixue Gao, Weiyuan Lu, Zhaolin Sun, Huiping Liu, Deyu Fang. Ubiquitin-specific peptidase 22 controls integrin-dependent cancer cell stemness &amp; metastasis [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 2764.
Abstract 1593: Intercellular network in immune suppressive microenvironment of pancreatic cancer
Authors: Kazunori Aoki, Hironori Fukuda, Yukihiro Mizoguchi, Kosuke Arai
Journal: Cancer Research (2024)

Abstract Despite constant efforts to improve treatment, the prognosis remains poor, with an overall survival rate of 6% (ranges from 2% to 9%) due to lack of efficient chemotherapy, radiotherapy, and targeted therapy. Immune checkpoint inhibitors (ICIs) has been reported to be effective in various solid cancers, such as melanoma, lung cancer, and renal cell carcinoma. However, pancreatic ductal adenocarcinoma (PDAC) is resistant against ICIs. The responsiveness of immune therapy is mainly determined by immune tumor microenvironment (TME) composed of tumor-infiltrating lymphocytes (TIL) and stromal cells. PDAC possesses unique TME, which is abundant of fibrosis, termed of desmoplasia, and the role of fibrosis in constructing immune suppressive TME remains unclear. First, in this study, to examine the immunological characteristics of TME, we constructed an integrated data base of TIL profiling, RNA-seq and whole exome seq using 31 fresh resected tissues of PDAC. An unsupervised clustering of based on numbers and percentages of 12 TIL types analyzed by flow cytometry showed that PDAC was divided into 2 types of cluster (myeloid cell-, T cell-dominant type), and the prognosis of myeloid type was significantly poorer than T cell-type. Myeloid type contained the high frequency of myeloid cell lineage including monocytes, macrophages and myeloid-derived suppressor cells (MDSC). Only MDSCs were significantly associated with poor prognosis among various immune cell types. Furthermore, gene enrichment analysis identified activated and suppressed pathways in each immune type, and in myeloid cell-dominant type, the immune-related pathways were significantly down-regulated. Then, to understand the characteristics of MDSCs infiltrated into pancreatic cancer tissues, single cell RNA-seq with surgical specimens was performed, and the analysis showed that a specific subtype of MDSCs infiltrated into cancer tissues. In addition, activation status of cancer-associated fibroblasts (CAFs) was related with MDSC recruitment and activation, indicating that the interaction between MDSCs and CAFs is crucial to create MDSC-rich TME. Inhibition of interaction between MDSCs and CAFs is expected to overcome immunosuppressive TME can be a therapy in PDAC. Citation Format: Kazunori Aoki, Hironori Fukuda, Yukihiro Mizoguchi, Kosuke Arai. Intercellular network in immune suppressive microenvironment of 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 1593.
Abstract 2767: Exploring ADAR1 dependencies in breast cancer brain-metastases
Authors: Teresa Sposito, Emma E. Klacking, Antonio W. Ruiz, Jessica Pham, Catriona Jamieson
Journal: Cancer Research (2024)

Abstract Background: Adenosine deaminase acting on double-stranded RNA (ADAR1) is a recognized driver of epitranscriptomic (post-transcriptional) remodeling and tumor progression. Changes in amino acid sequence, mRNA splicing, and/or polyadenylation sites are only some of the adenosine-to-inosine (A-to-I) RNA editing effects. Under physiological conditions, ADAR1 activity prevents autoinflammation by inhibiting the accumulation of endogenous immunostimulatory double-stranded RNA and by suppressing the Z-RNA sensor ZBP1. Such mechanisms are exploited by cancer cells to desensitize tumor response to therapies, therefore augmenting aggressiveness. Approximately 10 to 20% of patients diagnosed with breast cancer (BC) will develop metastatic disease, which remains the leading cause of death in individuals with BC. We have hypothesized that ADAR1 and its interferon-inducible p150 isoform, play a pivotal role in promoting BC metastases since high levels of ADAR1 are associated with a worse prognosis in patients with high grade BC, especially in the triple-negative BC subgroup (TNBC), which is the most likely to develop brain metastases. Methods: We established a humanized mouse model of breast cancer brain metastases (BC-BrM) using neonatal intracerebroventricular inoculation of MDA-MD-231 TNBC cells and primary patient derived metastatic cells in Rag2−/−γc−/− mice. Before implantation, MDA-MD-231 cells were transduced with a nanoluc-GFP reporter for tracing ADAR1 enzymatic activity in the brain metastatic niche. Lentiviral shRNA knockdown vectors targeting ADAR1, combined with over-expression vectors of full-length ADAR1 or the p150 deleted isoform were adopted to detect editing changes in the metastatic model through RNA-sequencing of BC-BrM. Results: BrM derived from MDA-MD-231 implants display upregulation of ADAR1 p150 and activation of the WNT/β-catenin pathway compared to the non-implanted cell lines. Upon shRNA knockdown of ADAR1, decreased expression of BC stem cell markers was detected via FACS in MDA-MD-231 ADAR1 knocked-down versus control BC-BrM isolated cells. We are now exploring molecular pathways affected by ADAR1 loss/overexpression in establishing BrM. Future Directions: We have developed a biorepository of primary patient-derived metastatic breast cancer samples and have begun the process of tracking metastatic kinetics and ADAR1 activation with the ADAR1 reporter in an orthotopic mouse model. Overall, this study will provide new insights into the molecular role of ADAR1 deaminase activity in establishing and maintaining metastatic niches. Citation Format: Teresa Sposito, Emma E. Klacking, Antonio W. Ruiz, Jessica Pham, Catriona Jamieson. Exploring ADAR1 dependencies in breast cancer brain-metastases [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 2767.