tbuckley/cabot-search huggingface dataset:
Abstract 1719: Targeting H3.3 serine 28 phosphorylation as a novel therapeutic strategy for diffuse midline glioma
Authors: Yuqian Yan
Journal: Cancer Research (2024)

Abstract Background: Diffuse midline glioma (DMG) is a highly aggressive pediatric brain cancer with a poor prognosis [1]. Mechanistically, DMG harbors a lysine-to-methionine substitution at position 27 of histone H3.3 (H3.3K27M), which leads to global hypomethylation and a dramatically altered epigenetic landscape [2, 3]. Aim: This study aims to explore the H3.3K27M mutation from a novel perspective by investigating its effects on H3.3 ubiquitination, with the goal of identifying effective, novel therapeutic targets. Methods: Mass spectrometry was used to identify potential E3 ligases for H3.3, while immunoprecipitation to verify this interaction. Cell viability and survival were determined by MTS and clonogenic survival assays, respectively. Nucleosome fractionation was performed to detect the distribution of wild-type (WT) or K27M mutant H3.3 histones. Results: Mass spectrometry identified UBR7, an E3 ligase, as exhibiting a stronger binding affinity with WT H3.3 than its K27M mutant counterpart. Further nucleosome fractionation assay revealed that K27M histones are more likely deposited in nucleosomes than WT H3.3. Further analysis demonstrated that a non-phosphorylation mimic mutation (serine to alanine) at amino acid 28 (S28A) restored the binding affinity of K27M mutant H3.3 with UBR7. Importantly, this mutation disrupted H3.3 phosphorylation and significantly diminished cell survival, whereas the constitutively activated phosphorylation mutation (S to glutamine (E)) on S28 (S28E) mimics K27M mutation in promoting cell proliferation and survival. Conclusion: These findings suggest that S28ph impairs UBR7-mediated K27M ubiquitination and promotes DMG cell growth, suggesting that targeting S28ph is an effective therapeutic strategy. However, the underlying mechanisms by which K27M interplays with S28ph in promoting tumorigenesis require further investigation. Citation Format: Yuqian Yan. Targeting H3.3 serine 28 phosphorylation as a novel therapeutic strategy for diffuse midline glioma [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 1719.
Abstract 1599: Metabolism as a key regulator of macrophage phenotype in pancreatic cancer
Authors: Cecily Anaraki, Christopher Halbrook
Journal: Cancer Research (2024)

Abstract Pancreatic Ductal Adenocarcinoma (PDAC) is the 3rd leading cause of cancer-related deaths in the US, with a five-year survival rate of 12%. Barriers to treatment include the highly fibrotic tumor microenvironment (TME), the high interstitial pressure which acts to collapse the blood vessels, and the influx of immunosuppressive immune cells. Within this immune milieu, we find that the most abundant are tumor-associated macrophages (TAMs). These TAMs display a phenotype similar to anti-inflammatory (M2-like) macrophages. Despite TAMs exerting an immunosuppressive function within the TME, there is not a complete overlap with the characteristics associated with M2 macrophages. Interestingly, TAMs still display many markers associated with the pro-inflammatory (M1-like) macrophages. This dichotomy suggests there may be a level of plasticity within the macrophage compartment that can be exploited to lead to better tumor control. Previous studies have shown a connection between arginine metabolism and macrophage effector function along the M1/M2 axis. In macrophages, arginine can be broken down in two ways: via iNOS into nitric oxide, which aids in effector function, or via Arginase 1 (Arg1) into ornithine and later proline, which is an essential component of the extracellular matrix (ECM). This study seeks to elucidate how metabolic perturbations influence macrophage function and phenotype. Here we observed that changes in oxygen availability and glucose abundance shifted macrophage expression of iNOS and Arg1. In vivo we found that conditionally knocking out Arg1 in the myeloid compartment leads to lower fibrosis when inducing inflammation in the pancreas. Furthermore, macrophages polarized with PDAC cancer-conditioned media display a sharp increase in Arg1 expression as compared to unpolarized macrophages, as well as increased resistance to both glycolytic inhibitors and mitochondrial inhibitors. This preliminary data demonstrates an important link between macrophage metabolism and function in the context of pancreatic disease. Citation Format: Cecily Anaraki, Christopher Halbrook. Metabolism as a key regulator of macrophage phenotype 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 1599.
Abstract 5412: In vitro plasticity profiling of metastatic cancer cells with an imaging-based pipeline
Authors: Saba Sameri, Durdam Das, Stefanie Michaelis, Joachim Wegener, Hedayatollah Hosseini, Martin Hoffmann
Journal: Cancer Research (2024)

Abstract Different types of cancer cells exhibit varying levels of invasiveness, migration behavior and ability to resume growth at distant sites. In order to classify cell lines for these fundamentally important traits of metastasis, we sought to generate an image-based in vitro assay that quantifies morphological and functional features of cancer cell plasticity. We developed an Imaging-Based Pipeline as an R Package for in vitro cell monitoring using the breast cancer cell lines MDA-MB-231 and MCF-7 that represent high-metastatic and low-metastatic cells in vivo, respectively, to identify relevant feature variables. Live cell imaging via the zenCELL owl system captured images for labeling and segmentation. Pre-trained neural network models from Cellpose, combined with user-calibrations, accurately segmented cells for tracking. The tracking pipeline calculated similarity coefficients, Jaccard index, between consecutive frames for cell trajectory analysis. Geometric and morphological features, speed, and distance measurements were derived for assessing structural motility and proliferation-associated changes. The analysis of two cell line models revealed significant variations in morphological changes, with MDA-MB-231 showing more rapid changes between round and elongated shape compared to MCF-7 cells. Moreover, the analysis of cell motility, consistent with the morphological changes, revealed that TGF-beta1 induced migration in MDA-MB-231 cells much stronger than in MCF-7 cells. Likewise, differences in proliferation induction upon addition of growth factor was monitored, showing that MCF-7 cells are more responsive to the growth stimulation than MDA-MB-231 cells. Consequently, the morphological plasticity of cancer cells, closely linked to the epithelial-to-mesenchymal transition (EMT) state, emerges as a defining factor for the in vitro plasticity of these cells. Quantified proliferation rate and migration speed of the cells was then used to establish an in vitro "plasticity index" that captures a cell line’s ability to switch between migration and proliferation. This index will undergo validation using cell lines with well-established metastatic propensities. In conclusion, we developed an Imaging-Based Pipeline that can effectively explore cancer cell plasticity in vitro and monitor the impact of genetic or pharmacologic perturbations on this critical characteristic of aggressive cancer cells. Citation Format: Saba Sameri, Durdam Das, Stefanie Michaelis, Joachim Wegener, Hedayatollah Hosseini, Martin Hoffmann. In vitro plasticity profiling of metastatic cancer cells with an imaging-based pipeline [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 5412.
Abstract 351: Quaratusugene ozeplasmid mediated TUSC2 upregulation in EML4-ALK bearing non-small cell lung carcinoma can induce cellular apoptosis
Authors: Ananya Banerjee, Neeke Busette, Mark S. Berger, Matthew B. Soellner, Angel Qin, Sofia D. Merajver, Nathan M. Merrill
Journal: Cancer Research (2024)

Abstract Anaplastic Lymphoma Kinase (ALK), a potent oncogenic driver in Non-Small Cell Lung Carcinoma (NSCLC), is found to be rearranged and fused to Echinoderm microtubule-associated protein-like 4 (EML4), contributing to approximately 5% of NSCLC as a distinct clinicopathological subset. Tumors bearing the EML4-ALK fusion are sensitive to ALK Tyrosine Kinase Inhibitors (TKIs), that form the first and second line of treatment for these patients. However, ALK+ lung cancers develop resistance to ALK inhibitors, creating the need for newer treatment strategies in ALK+ NSCLC. Tumor Suppressor Candidate 2 (TUSC2) is a tumor suppressor gene that is known to have low endogenous expression in NSCLC in general but data on TUSC2 in ALK+ lung cancers are not available. Quaratusugene ozeplasmid, developed by Genprex, is an immunogene therapy that upregulates TUSC2 expression in cancer cells by delivering the functional TUSC2 gene. It consists of the TUSC2 gene expressing plasmid encapsulated in non viral lipid nanoparticles. We evaluated TUSC2 expression in 3 ALK+ cell lines, both before and after exposure to quaratusugene ozeplasmid and to a TUSC2-containing plasmid. Controls were non-ALK+ cell lines and transfection with a plasmid containing no insert. Our studies in ALK+ lung cancer reveal that overexpressing TUSC2 using quaratusugene ozeplasmid treatment of ALK+ lung cancer cell lines is able to suppress colony formation by 50%, the effect being more significant than using a TUSC2-containing plasmid. Furthermore, we have observed a robust pro-apoptotic response to TUSC2 expression in ALK+ NSCLC, as both quaratusugene ozeplasmid and TUSC2-containing plasmid induced an increase in caspase 3/7 activity in the cancer cells, accompanied by an increase in cleaved PARP expression. Taken together, our data indicate that overexpression of TUSC2 in ALK+ NSCLC cell lines with quaratusugene ozeplasmid or with TUSC2-containing plasmid is effective in decreasing growth and proliferation through the activation of apoptotic pathways and warrants further investigation as an anti-ALK NSCLC strategy. Citation Format: Ananya Banerjee, Neeke Busette, Mark S. Berger, Matthew B. Soellner, Angel Qin, Sofia D. Merajver, Nathan M. Merrill. Quaratusugene ozeplasmid mediated TUSC2 upregulation in EML4-ALK bearing non-small cell lung carcinoma can induce cellular apoptosis [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 351.
Abstract 5433: Functional involvement of ribosomal protein L9 to colorectal cancer stemness
Authors: Eun-Hye Jeon, Keun Uk Park, Hun-Mo Ryoo, Ilseon Hwang, Yun-Han Lee
Journal: Cancer Research (2024)

Abstract We have previously demonstrated that targeting of ribosomal protein L9 (RPL9) suppresses the growth of colorectal cancer (CRC) via the inactivation of Id-1/NF-κB signaling axis which is known to augment tumor stemness. Thus we aimed in this study to investigate whether the function of RPL9 was associated with CRC stemness properties. It was initially evidenced that inhibition of RPL9 expression reduces the migration and invasion abilities of HT29 parental cell population. We have then sorted out CD133+ cancer stem cells (CSCs) from HT-29 parental cell culture and treated RPL9-specific siRNAs to the isolated CSCs to observe the effect of RPL9 targeting on stemness. As results, knockdown of RPL9 significantly suppressed the proliferation potential and sphere forming capacity of CD133+ HT29 CSCs accompanying with the reduction in CD133 and Id-1 levels. Reflecting these molecular alterations, targeting RPL9 also inhibited the abilities of migration and invasion in CD133+ HT29 CSCs population. Taken together, these findings suggest that RPL9 could be a therapeutic target for both primary CRC treatment and the prevention of metastasis and/or recurrence. Citation Format: Eun-Hye Jeon, Keun Uk Park, Hun-Mo Ryoo, Ilseon Hwang, Yun-Han Lee. Functional involvement of ribosomal protein L9 to colorectal cancer stemness [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 5433.
Abstract 5560: Role of SPARC and collagen in immunogenicity of cancer: A theoretical approach
Authors: Ramakrishna Prasad Are, Anju R Babu
Journal: Cancer Research (2024)

Abstract Secreted protein acidic and rich in cysteine (SPARC), is a multifunction protein that interacts with extracellular matrix (ECM), cell surface receptors, and signaling molecules. These interactions in cancer cells result in less susceptible of cells to the immune system, leading to poor prognosis. SPARC plays a crucial role in transporting collagen, a significant component of the ECM, from the site of synthesis to the basement membrane of the cells. Collagen mediated rigidity enhancement of cell microenvironment promotes cancer cell growth, proliferation, and angiogenesis. Collagen remodeling plays a complex and multifaceted role in cancer immunomodulation. Our current research focuses on exploring the cancer treatment mechanism by immunomodulation based on SPARC and collagen through theoretical and computational approaches. Our previous investigations identified SPARC and collagen as potential biomarkers for targeting cancer cells. Our current theoretical research identifies the role of SPARC and collagen in tuning the tumor microenvironment and altering the immune system cell surface receptors. This theoretical investigation is followed by computational study to formulate the pathway from secretions of both SPARC and collagen to reprogramming of tumor microenvironment. SPARC and collagen’s effects on the cell immune system are analyzed by performing molecular interaction and molecular dynamics studies for SPARC and collagen with the cell surface receptors. From our study, we identify the cellular mechanisms involved either actively or passively in the progression and prognosis of the cancer. Our study will provide insight into a novel pathway for targeting the cancer microenvironment, which will be helpful in the formation of low-dosage cancer drugs, resulting in the decreased adverse effects of drugs and increased patient quality of life. Citation Format: Ramakrishna Prasad Are, Anju R Babu. Role of SPARC and collagen in immunogenicity of cancer: A theoretical approach [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 5560.
Abstract 5874: Phenotypic plasticity of TKI resistance reprograms cytoskeleton organization through cadherin-catenin and integrin pathways
Authors: Chun Ma, Jerry Chieh-Yu Chen, Mong-Lien Wang
Journal: Cancer Research (2024)

Abstract The acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) restricts its clinical utility. Clinically, acquired resistance has been highly associated with epithelial-mesenchymal transition (EMT) traits. In this study, we characterized shared phenotypic plasticity features of TKI-resistant cells and aimed to find its key driver in three different cell lines harboring mutant EGFR. In vitro resistance cell lines were generated by dose-escalation exposure to osimertinib, a 3rd generation TKI, for more than 2 months. We employed canonical markers (E-cadherin, vimentin, pan-cytokeratin, and N-cadherin) along with additional markers (EpCAM and fibronectin) to define the EMT status of resistant cells. Moreover, cytoskeleton architecture (F-actin and Vimentin) was utilized to clarify the types of cell motility. Transcriptomics analysis illustrated enriched pathways at focal adhesion and adherens junction. Loss of adherens junction-related catenin (α-E-catenin, β-catenin, γ-catenin, p120 catenin) and aberrant activation of focal adhesion-related protein (p-FAK Y397 and Y576/57, p-Src Y416) confirmed the transcriptomics analysis of reduced contact inhibition and cell polarity. The resulting migration mode of resistant cells highly resembles ameboid movement. Mechanistically, we identified that YTHDF3, a metastasis-promoting regulator of mRNA methylation, destabilizes the mRNA of E-cadherin. Depletion of YTHDF3 in resistant cells reversed the cadherin-catenin pathway and distribution of vimentin and f-actin. In conclusion, resistant cells display ameboid-like movement resulting from loss of contact inhibition and aberrant activation of focal adhesion. Mechanistically, we identified that YTHDF3, a metastasis-promoting regulator of mRNA methylation, destabilizes the mRNA of E-cadherin. Depletion of YTHDF3 in resistant cells reversed the cadherin-catenin pathway and distribution of vimentin and f-actin. YTHDF3 serves as an RNA epitranscriptomic regulator that destabilizes CDH1 mRNA, thereby disrupting adherens junction formation and reducing integrin-mediated focal adhesion stabilization. Citation Format: Chun Ma, Jerry Chieh-Yu Chen, Mong-Lien Wang. Phenotypic plasticity of TKI resistance reprograms cytoskeleton organization through cadherin-catenin and integrin pathways [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 5874.
Abstract 1613: Evolution of mutations in the antigen presentation machinery across cancers
Authors: Wenjie Chen, Toby Baker, Zhihui Zhang, Peter Van Loo, Shengqing Stan Gu
Journal: Cancer Research (2024)

Abstract Immune escape is a critical hallmark of cancer progression. Under immunosurveillance, a subset of cancer-associated antigens or neoantigens are presented to the cancer cell surface via the antigen presentation machinery (APM) for recognition by antigen-specific T cells. During clonal evolution, cancer cells can evade such immunosurveillance by suppressing or ablating the APM. The defects in APM can further cause resistance to cancer immunotherapies and is associated with worse prognosis. Understanding how the defects in APM emerge and further shape the evolution of cancers is critical for devising strategies to overcome such immune escape mechanisms. However, it is not known when mutations in the APM occur along the history of cancer clonal evolution. We utilized a molecular archeology of cancer approach to reconstruct the evolution history of mutations in APM across 38 cancer types using whole-genome sequencing data from PCAWG. Genetic alterations in the APM occur in nearly 30% of patients, with varying frequencies and associations with immune infiltration across cancer types. Employing a League model to compare the timing of genetic events, we found that APM mutations can be early clonal, late clonal, or subclonal along cancer development. Further examination of individual tumors identified driver mutations that can happen before or after APM mutations along cancer development. Our study reveals the evolution of APM mutations in different cancers in a genetic context-aware manner. This information can contribute to optimizing personalized immunotherapy. Citation Format: Wenjie Chen, Toby Baker, Zhihui Zhang, Peter Van Loo, Shengqing Stan Gu. Evolution of mutations in the antigen presentation machinery across 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 1613.
Abstract 5435: CUEDC2 involved in the inhibitory effect of dandelion on triple-negative breast cancer stem cells
Authors: Xinxin Deng, Yanna Jiao, Huifeng Hao, Zhengwang Guo, Dong Xue, Shuyan Han
Journal: Cancer Research (2024)

Abstract Background: Cancer stem cells (CSCs) exert a substantial influence on the initiation, progression, and metastasis of triple-negative breast cancer (TNBC). Dandelion has exhibited encouraging outcomes in impeding the proliferation of TNBC cells. Nevertheless, the extent of investigation regarding the efficacy of dandelion in targeting CSCs remains restricted. Purpose: The aim of this study was to investigate the impact of dandelion extract (DE) on CSCs properties. Methods: In vitro experiments were conducted using TNBC cell lines. Mice bearing TNBC tumors were established for in vivo investigations. Biochemical analysis and cell biological assay were carried to evaluate the effect of dandelion and the underlying mechanisms. Results: DE treatment significantly decreased the proportion of ALDH+ cells, mammosphere formation ability, and CSCs-related markers. CUEDC2 is highly expressed in ALDH+ TNBC cells, and its overexpression increased the expression of markers related to CSCs. Conversely, the tumor growth was impeded in CUEDC2 KO mice and the markers related to CSCs also were also reduced. CUEDC2 overexpression reversed the inhibitory effect of DE on TNBC CSCs properties. Mechanistically, CUEDC2 related pathway involved in the inhibitory effect of DE on TNBC CSCs properties. Conclusion: CUEDC2 played a crucial role in maintaining the stem cell properties of TNBC. DE inhibit the self-renewal of TNBC stem cells by regulating the CUEDC2 related signaling pathway. Keywords: Dandelion; CUEDC2; Triple-negative breast cancer; Cancer stem cell. Citation Format: Xinxin Deng, Yanna Jiao, Huifeng Hao, Zhengwang Guo, Dong Xue, Shuyan Han. CUEDC2 involved in the inhibitory effect of dandelion on triple-negative breast cancer stem 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 5435.