tbuckley/cabot-search huggingface dataset:
Abstract 3077: Integrin expression during ovarian cancer progression
Authors: Nazia Bano, Eva M. Schmelz
Journal: Cancer Research (2024)

Abstract During peritoneal dissemination, ovarian cancer cells exfoliate from the primary tumor and aggregate in the peritoneal fluid. This elicits survival signals via changes in mitochondrial morphology and function. As spheroids adhere to secondary sites, mitochondrial function is restored in the form of recovery of mitochondrial morphology, increased mitochondrial membrane potential, glucose uptake and increased proliferation. These findings suggested a mitochondrial phenotypic switch from mitophagy in spheroids to upregulation of mitobiogenesis upon spheroids adhesion to secondary sites. Hence, our objective was to identify critical receptors that facilitate the adhesion of spheroids to secondary sites, focusing on integrins that facilitate cell-extracellular matrix (ECM) attachment and activate downstream signaling cascades. To investigate changes in integrin expression, we mimicked three major stages of ovarian cancer progression by developing adherent stage, spheroid stage and adherent spheroid stage using our mouse ovarian surface epithelial (MOSE) cell lines representing benign (MOSE-E) stage as well as slow-developing (MOSE-L) and fast-developing disease (MOSE-LTICv) in biologically relevant conditions. Using RT qPCR and Western blotting, we determined gene and protein expression levels of integrins and adhesion related genes. Confocal microscopy was used to determine protein localization during ovarian cancer progression. RT qPCR result indicated differential up-regulated expression of integrins in both spheroid and adherent spheroid stage, suggesting the role of different integrins during the stages of ovarian cancer progression. Specifically, we observed a decrease (integrin ɑ5, ɑ6) or increase (ɑ2𝛃;1) of integrins after aggregation and an upregulation of 𝛃;1, α2, αV, α3, α5 and immunomodulatory integrins such as αE and αM in adherent spheroids, indicating their role in mediating specific steps during progression of ovarian cancer from tumorigenesis to metastatic implantation. We also observed increased expression levels of extracellular matrix proteins and their modulators, and cell-to-cell adhesion genes during ovarian cancer progression that was more pronounced in the MOSE-LTICv cells which suggests their association with an aggressive cancer phenotype. Overall, this project will aid in the identification of adhesion targets to develop new anti-metastatic treatments that will reduce mortality in women with ovarian cancer. Citation Format: Nazia Bano, Eva M. Schmelz. Integrin expression during ovarian cancer progression [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 3077.
Abstract 7238: Exploring the potential of targeted DNA Nanobot delivery systems for gene delivery
Authors: Melika Shahhoessini, Jeffrey R. Spitzner, Christopher R. Lucas, Carlos E. Castro, Patrick D. Halley
Journal: Cancer Research (2024)

Abstract Gene therapy is a cornerstone of modern medicine's quest for precision treatment to cure human disease including cancer. The current approach to gene delivery technology employs viral vector delivery systems. While effective, these vectors present significant challenges including immunogenicity, safety concerns due to off-target non-tissue specific delivery, payload limitations, and significant cost ultimately diluting their therapeutic potential. Thus, novel approaches to gene delivery are necessary. One such approach to address these critical limitations involves DNA Nanobots, a DNA-based nanotechnology that allows for a tissue-/target-cell specific gene delivery system. Utilizing DNA origami molecular assembly techniques, our DNA Nanobots offer a customizable and highly precise delivery platform, free from viral vector constraints. This innovative approach has the potential to transform the landscape of gene therapy by providing a safer, more efficient, and targeted alternative. Key technical advancements with our DNA Nanobots Gene Delivery Platform include: •CRISPR Cas-9 Integration: By incorporating CRISPR Cas-9 functional proteins, our nanobots were shown to enhance gene editing precision in primary human T cells, broadening therapeutic applications across various genetic conditions. •Targeted mRNA Delivery: Our nanobots revealed promising results in the targeted delivery of mRNA, vital for vaccine development and personalized treatments. •Efficient antisense/siRNA Delivery: Prior studies have overcome traditional challenges including endosomal escape and cytoplasmic entry, demonstrating effective siRNA delivery critical for gene silencing therapeutic development. In summary, DNA Nanobots mark a paradigm shift in gene therapy. Their ability to deliver various nucleic acids with high specificity and efficiency addresses many of the current methodological limitations especially off-target safety concerns and high cost. This advancement not only enhances the therapeutic index of existing treatments but also opens avenues for novel therapeutic strategies, potentially reshaping the future of molecular medicine and gene therapy. Citation Format: Melika Shahhoessini, Jeffrey R. Spitzner, Christopher R. Lucas, Carlos E. Castro, Patrick D. Halley. Exploring the potential of targeted DNA Nanobot delivery systems for gene delivery [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 7238.
Abstract 3075: Different roles of EPAC1 and EPAC2 in ovarian cancer: Implications for precision targeting in cancer therapy
Authors: Zhengyin Gao, Wanjun Yuan, Leo T.O. Lee
Journal: Cancer Research (2024)

Abstract There are two distinct functional isoforms of Exchange proteins directly activated by cAMP (EPACs), EPAC1 and EPAC2, which exhibit fundamental distinctions in structure, expression patterns, signaling specificity, and subcellular localization. This diversity suggests that EPAC1 and EPAC2 can operate independently, synergistically, or antagonistically, contributing to the wide range of reported functions and impacts in different cancers and studies. We compared the function of EPAC1 and EPAC2 in ovarian cancer using in vitro and in vivo models and further explored the underlying mechanism in the regulation of metabolism reprogramming. Selective inhibition of EPAC1 and EPAC2 markedly reduced proliferation in ovarian cancer cell lines, leading to cell death and cycle arrest. RNA-seq analysis indicated different downstream signaling pathways triggered by EPAC1 and EPAC2, with EPAC2 specifically linked to functions in energy metabolism. Treatment with an antagonist or knockdown of EPAC2 resulted in attenuation of both glycolysis and oxidative phosphorylation (OXPHOS), while EPAC1 did not induce such effects. Furthermore, inhibition of EPAC2 induced mitochondrial dysfunction, manifested by reduced ATP production, decreased mitochondrial membrane potential, and increased burden of reactive oxygen species (ROS). Our data also revealed that EPAC2 governs the MAPK pathway and mediates the mitochondrial unfolded protein response (UPRmt) in ovarian cancer cells. By delineating the distinctions between EPAC1 and EPAC2 within ovarian cancer cells, this project revised the prevailing understanding of EPACs and suggests the potential for precise targeting of EPAC isoforms as a viable strategy in cancer therapy. Citation Format: Zhengyin Gao, Wanjun Yuan, Leo T.O. Lee. Different roles of EPAC1 and EPAC2 in ovarian cancer: Implications for precision targeting in cancer therapy [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 3075.
Abstract 3053: PTEN as a double-edged sword regulates EGFRL858R-induced lung cancer progression
Authors: Jan-Jong Hung
Journal: Cancer Research (2024)

Abstract Lung cancer is the major cause of death worldwide. Activation of oncogenes or inhibition of tumor suppressors causes cancer formation. Previous studies have indicated that Pten, as a tumor suppressor, inhibits cancer formation. In this study, we studied the role of Pten in EGFRL858R-induced lung cancer in vivo. Interestingly, loss of Pten increased bronchial cell hyperplasia but decreased alveolar cell hyperplasia in EGFRL858R*Pten−/−-induced lung cancer. Syatematic analysis of gene expression by RNA-seq showed that a number of genes related to ciliogenesis were upregulated in EGFRL858R*Pten−/−-induced lung cancer and subsequently showed that bronchial ciliated cells were hyperplastic. Several critical ciliogenesis-related genes, such as mucin5a, DNAI2 and DNAI3, were found to be regulated by NR2F1. Next, NR2F1 was found to be inhibited by overexpression of Pten, indicating that Pten negatively regulates NR2F1, thereby inhibiting the expression of ciliogenesis-related genes and leading to the inhibition of bronchial cell hyperplasia during EGFRL858R-induced lung cancer progression. In addition, we also found that Pten decreased Akt phosphorylation in A549, Kras mutant, and H1299 cells but increased Akt phosphorylation in PC9, EGFRL858R, and H1299L858R cells, suggesting that Pten may function as a tumor suppressor and an oncogene in lung cancers with Kras mutation and EGFR mutation, respectively. PTEN acts as a double-edged sword that differentially regulates EGFRL858R-induced lung cancer progression in different genomic backgrounds. Understanding the Pten in lung cancer with different genetic backgrounds will be beneficial for therapy in the future. Citation Format: Jan-Jong Hung. PTEN as a double-edged sword regulates EGFRL858R-induced lung cancer progression [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 3053.
Abstract 205: Adaptive membrane trafficking activated by epithelial-to-mesenchymal transition drives lung adenocarcinoma progression
Authors: Oluwafunminiyi E. Obaleye, Kevin L. Fulp, Guan-Yu Xiao
Journal: Cancer Research (2024)

Abstract Cancer cells can become metastatic and develop resistance to targeted therapies through epithelial-to-mesenchymal transition (EMT), which is regulated by epigenetic factors. Our ultimate objective is to understand the molecular mechanisms behind EMT-driven cancer progression and identify potential targets for preventing cancer metastasis. Recently, we made groundbreaking discoveries indicating that EMT can modify membrane trafficking machinery to coordinate cancer cell invasion and immunosuppression in the tumor microenvironment (TME) of lung adenocarcinoma (LUAD). To dissect the “adaptive” membrane trafficking program, we initiated a CRISPRi in vivo screen to assess more than 2000 trafficking-related genes in syngeneic mouse LUAD models for their requirements for tumorigenesis both with and without immune selective pressure. We identified a panel of membrane trafficking regulators that specifically “dropped out” in immunocompetent mice, suggesting their essential roles in the immunosuppressive TME. Of particular interest is REEP2. REEPs are an evolutionarily conserved protein family that is critical to the endoplasmic reticulum (ER) function and potentially regulates secretory trafficking. We discovered that REEP2 is specifically linked to poor prognosis in LUAD patients and is highly correlated with a z-normalized, 16-gene EMT score (P = 1.32e-27) that was previously reported. Our previous studies demonstrated that the EMT activator, ZEB1, accelerates membrane trafficking dynamics by silencing a microRNA network that targets multiple membrane trafficking components. Analysis of REEP2 3’-untranslated regions (3’-UTRs) identified predicted binding sites for several microRNAs, which are silenced by ZEB1. Thus, we hypothesize that ZEB1 coordinates a microRNA network to activate REEP2-driven ER trafficking. We show that REEP2 depletion significantly reduces the invasion of cancer cells but does not affect their migration and proliferation. These findings suggest that REEP2 plays a significant role in extracellular matrix (ECM) modification to enhance the invasion of metastatic cells, conferring a vulnerability in EMT-driven LUAD metastasis. Citation Format: Oluwafunminiyi E. Obaleye, Kevin L. Fulp, Guan-Yu Xiao. Adaptive membrane trafficking activated by epithelial-to-mesenchymal transition drives lung adenocarcinoma progression [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 205.
Abstract 4692: A novel ceramide synthase 2 agonist and its implication in triple-negative breast cancer therapy
Authors: Hissah Alatawi, Nayeong Koo, Iqbal Mahmud, Haritha Nair, Amandeep Singh, Timothy J. Garrett, Arun K. Sharma, Sukwon Hong, Satya Narayan
Journal: Cancer Research (2024)

Abstract Based on the biological/molecular markers, breast cancer can be classified into five subgroups: Luminal A (ER+/PR+/HER2-), Luminal B (ER+/PR-/HER2- or ER+/PR+/HER2+, triple-positive), ER-/PR-/HER2+, and ER-/PR-/HER2- (triple-negative). Significant progress has been made in treating hormone-responsive and HER2-expressing breast cancer. However, the targeted therapies are limited for triple-negative breast cancer (TNBC) due to lack of well-defined druggable targets. Additionally, all breast cancer subtypes can quickly develop resistance to current treatments. Thus, there is an urgent need for therapeutic strategies targeting pathways common to all subtypes, irrespective of receptor status. In this effort, we have synthesized a novel biisoquinoline-derivative, DH20931 (US Patent ID: US9914733B2) that induces cytotoxicity in breast cancer cells, including TNBC cells. The spatial molecular modeling and enzymatic assays show that DH20931 interacts with and stimulates ceramide synthase 2 (CerS2) activity, reduces the growth of hormone-responsive, HER2-expressing, and TNBC cells in monolayer and 3D spheroid culture models. DH20931 treatment increases the level of very long chain fatty acid (VLCFA) containing ceramides, induces lipotoxic endoplasmic reticulum (ER) stress, and ATF4/CHOP/PUMA pathway of apoptosis. Based on Swiss-ADME analysis, DH20931 possess all the properties of a druggable molecule and obeys the Lipinski-rule-of-five. Thus, DH20931 can be developed as a novel targeted therapeutic agent independent of ER, PR and HER2 status that potentially may reduce the morbidity and mortality for women with breast cancer. Citation Format: Hissah Alatawi, Nayeong Koo, Iqbal Mahmud, Haritha Nair, Amandeep Singh, Timothy J. Garrett, Arun K. Sharma, Sukwon Hong, Satya Narayan. A novel ceramide synthase 2 agonist and its implication in triple-negative breast cancer therapy [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 4692.
Abstract 4687: Primary study on the anticancer role of BAM15 in lung cancer cells
Authors: Mei-yin Zhang, Yue-Ning Wang, Yu-Feng Zhou, Shuo-Cheng Wang, Shi-Juan Mai, Hui-Yun Wang
Journal: Cancer Research (2024)

Abstract Background: Lung cancer remains the leading cause of cancer-related death worldwide. Non-small cell lung cancer (NSCLC) accounts for about 80-85% of all lung cancer cases. BAM15, a mitochondrial uncoupler, is a potential therapeutic agent for many diseases, including obesity, diabetes, nonalcoholic fatty liver disease, Sepsis and cancers. However, there is no report on the anti-tumor role of BAM15 in NSCLC. Methods: To investigate the direct anti-cancer effects of BAM15 in NSCLC, we examined its inhibitory role on cell proliferation of NSCLC cells using the Cell Counting Kit-8(CCK8), colony forming assays and EdU staining assays. The impact of BAM15 on the cell cycle and cell apoptosis of NSCLC cells was analyzed by flow cytometric. A xenotransplanted NSCLC model in mice were used to test the anticancer role of BAM15. Result: Using the CCK8 assay, we found that the inhibitory role of BAM15 on the proliferation and colony formation of NSCLC cells is dose-dependent. The half maximal inhibitory concentration (IC50) values for cell proliferation were 2.71, 4.74, and 9.50 μM for A549, PC9, and H1299 NSCLC cells, respectively. The EdU staining assay demonstrated that BAM15 treatment significantly inhibited DNA synthesis in NSCLC cells. Flow cytometric analysis revealed that BAM15 arrested cell cycle at G2 phase in NSCLC cells and caused a striking increase in the percentage of apoptotic cells in NSCLC cells. The xenotransplanted NSCLC experiment indicated that BAM15 could significantly suppressed the growth of NSCLC tumors compared with the control tumors. Conclusions: Our study demonstrates that BAM15 significantly inhibits cell proliferation and promotes apoptosis in NSCLC cells, indicating that BAM15 is a potential therapeutic candidate for the treatment of NSCLC. Citation Format: Mei-yin Zhang, Yue-Ning Wang, Yu-Feng Zhou, Shuo-Cheng Wang, Shi-Juan Mai, Hui-Yun Wang. Primary study on the anticancer role of BAM15 in lung 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 4687.
Abstract 5615: Functional analysis of variants of uncertain significance in the <i>MSH6</i> mismatch repair gene
Authors: Elizabeth Szabo, Emily Blackburn, Alexander Radecki, Abhijit Rath, Christopher Heinen
Journal: Cancer Research (2024)

Abstract Lynch syndrome (LS) is a hereditary condition that increases patients’ lifetime risk of cancer, primarily colorectal cancer. LS is caused by germline mutations in mismatch repair (MMR) genes, MLH1, MSH2, MSH6, and PMS2. Identification and classification of these mutations is important in LS diagnosis for guiding treatment plans and preventative care for patients’ and their families. However, the consequences of some variants in these genes are not immediately obvious, granting them classification as variants of uncertain significance (VUS). Laboratory functional analysis to determine whether these variants disrupt MMR function in human cells can provide important evidence for understanding the pathogenicity of VUS and reclassifying them. Half of known variants in the MMR gene MSH6 are VUS and, thus, the goal of my project is to provide evidence for a subset of these variants to help provide evidence for reclassification for these variants. We are calibrating and validating functional assays for MSH6 variants, using known MSH6 pathogenic and benign controls. We will then test MSH6 VUS identified in patients as reported in the InSiGHT database, ClinVar database, and current literature. We are using CRISPR gene editing to recreate these variants in the endogenous MSH6 loci in human embryonic stem cells (hESC). Using these edited hESC lines we are examining the impact of the variants on RNA and protein stability, repair of DNA microsatellites, which is a hallmark of normal MMR function, and induction of the MMR-dependent DNA damage response. With this compilation of data, we will convert the results into a quantitative Odds of Pathogenicity value. This Odds of Pathogenicity score can be used by expert variant interpretation committees to help readily reclassify these variants and provide a clearer diagnosis for these suspected Lynch syndrome patients. Citation Format: Elizabeth Szabo, Emily Blackburn, Alexander Radecki, Abhijit Rath, Christopher Heinen. Functional analysis of variants of uncertain significance in the MSH6 mismatch repair gene [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 5615.
Abstract 2187: Influences of high-fat diet on tumor biology in a mouse model of colorectal cancer
Authors: Anindita Mahanty, Cara Wallingford, Revan Hammontree, Muturi Njoka, Zachary Clark, Michaella Rekowski, Michael Washburn, Jennifer S. Davis
Journal: Cancer Research (2024)

Abstract Purpose: To test the influence of high-fat diet on tumor biology in the inducible Kras, Apc and p53 (iKAP) model (Boutin, et al Genes &amp; Development 2017, 31:370). Methods: At weening, both male and female mice were fed either a high-fat (60%) or low-fat (10%) diet for 5-6 weeks prior to tumor induction. Mutant Kras expression was controlled using a tet-on system. Expression of mutant Kras was activated by the addition of doxycycline hyclate in the drinking water. Tumor growth was monitored by bi-weekly endoscopy and calculated as percent luminal occlusion. Tumor biology was assessed with proteomics and phospho-proteomics with comparisons by sex and diet. Results: In the absence of mutant Kras expression (no doxycycline in drinking water), tumors were larger in females on high-fat diet compared to low-fat diet. Tumor sizes were not significantly different in males or in the presence of mutant Kras expression. Proteomics analyses of tumor tissue identified significantly different patterns by diet in female mice, including altered levels of KIF4, DAB2iP, JNK cascade and JUN kinase activity (Table). Conclusion: Based on our preliminary data, high-fat diet may alter tumor kinase activities, even in a genetically engineered mouse model. Replication and validation studies are ongoing. Table of significantly upregulated biologic processes in female mice on high-fat diet compared to lo XXXXXXXXXXXXXXXX XXXXXXXXXXXXXXX Citation Format: Anindita Mahanty, Cara Wallingford, Revan Hammontree, Muturi Njoka, Zachary Clark, Michaella Rekowski, Michael Washburn, Jennifer S. Davis. Influences of high-fat diet on tumor biology in a mouse model of 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 2187.