tbuckley/cabot-search huggingface dataset:
Abstract 1470: Advancing cancer research: A novel PanCancer digital PCR tool for simultaneous detection of multiple hallmark mutations in BRAF and EGFR
Authors: Claudia Kappmeier, Sherina Edward, Corinna Hochstein, Ellen Inga Bruske, Francesca Di Pasquale, Ronny Kellner
Journal: Cancer Research (2024)

Abstract The paradigm shift towards precision medicine in oncology emphasizes the importance of identifying specific genetic mutations driving cancer. Some hallmark mutations in cancer-associated genes, such as BRAF and EGFR, are important in analyzing many cancer types. With the emergence of digital PCR (dPCR) technology, high-sensitivity and quantitative mutation analysis can be performed, lending valuable support to cancer research. In this work, we introduce a new and innovative dPCR method, the dPCR PanCancer assays (RUO), designed for concurrently detecting multiple hallmark mutations in BRAF and EGFR. This work includes two novel PanCancer assays for BRAF and EGFR, each tailored to target a spectrum of mutations associated with these genes, facilitating a comprehensive mutation analysis. The dPCR assay for BRAF targets multiple V600 hallmark mutations, and the dPCR assay for EGFR targets various important deletions on exon 19. This also includes a reference gene as a control for PCR efficiency in the duplex reaction. Here, we present our initial data from various sample types, including blood, plasma and FFPE samples. Through a meticulously optimized dPCR setup, we achieved exceptional sensitivity and specificity, enabling the detection of multiple mutations in a single channel at allelic frequencies below 1%. Both dPCR PanCancer Kits (RUO) have potential use in research for pre-screening samples (e.g., prior to next-generation sequencing) or monitoring cancer cells. They simultaneously assess the mutations, reducing time and costs and saving sample material. Additionally, our technology is adaptable to other cancer-associated genes, where similar assays can potentially be developed. Overall, we have demonstrated that our dPCR PanCancer Kits (RUO) provide a robust, fast and efficient technology to identify critical mutations, ultimately enhancing our understanding of BRAF and EGFR-driven cancers. The dPCR PanCancer Kit is for research use only. Not for the diagnosis, prevention, or treatment of a disease. Citation Format: Claudia Kappmeier, Sherina Edward, Corinna Hochstein, Ellen Inga Bruske, Francesca Di Pasquale, Ronny Kellner. Advancing cancer research: A novel PanCancer digital PCR tool for simultaneous detection of multiple hallmark mutations in BRAF and EGFR [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 1470.
Abstract 1514: A novel workflow to assess the T-cell and patient-derived organoid interaction
Authors: Zhisong Tong, Angeline Lim, Oksana Sirenko
Journal: Cancer Research (2024)

Abstract Immunotherapy is increasingly popular as a type of cancer treatment. These therapies include the use of Chimeric Antigen Receptor-engineered T-cells (CAR T-cells), tumor-infiltrating lymphocytes (TIL), and other genetically modified T-cells to specifically target the cancer cells. Although much success has been achieved with immunotherapy for treatment of blood cancers, its efficacy remains limited in solid tumors. One of the reasons for the low success rate is attributed to the solid tumor microenvironment (TME) where suppressive cytokines limit the tumor killing ability of T-cells. Thus, understanding the role the TME plays in T-cell responses is essential for the development of effective cancer therapies. The benefits of using 3-dimensional (3D) PDOs lie in the physical and chemical cues present within the TME that cannot be mimicked in traditional 2D monolayer cultures. Studies show that PDOs show similar responses to drugs as original tumors, suggesting the value of using PDOs to improve therapeutic outcomes. Thus, PDOs can provide more relevant physiological and pathological cancer models that recapitulate the basic features of primary tumors and is more suited for assessing the effectiveness of T-cell killing than 2D cell models. Despite the benefits associated with the use of PDOs, there are significant barriers to widespread adoption of PDOs in drug discovery. Organoid production is a costly and highly labor-intensive process. Moreover, organoid culture is a skilled manual process, and thus there can be significant variability between operators. To address the challenges associated with the use of PDOs in large scale applications, a semi-automated bioprocess has been developed for the large-scale expansion of assay ready organoids. Here, we developed a method to assess the effectiveness of T-cell invasion in solid tumors using patient derive organoids (PDOs). Using bioreactor expanded patient-derived colorectal cancer organoids (CRCs), activated PBMCs (human peripheral blood mononuclear cells) stained with CellTracker were added to CRCs (stained with MitoTracker) in a 96well microtiter plate and monitored on every 4 hours for 3 days using high content imager. To quantify T-cell invasion, we developed an image analysis method to measure the distance of each T-cell to the nearest organoid (interaction distance). We find that stimulated T-cell resulted in smaller interaction distance than non-stimulated T-cells. The results demonstrate the utility of the bioreactor-expanded organoids in large scale T-cell based screens. Citation Format: Zhisong Tong, Angeline Lim, Oksana Sirenko. A novel workflow to assess the T-cell and patient-derived organoid interaction [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 1514.
Abstract 2092: Genomic and proteomic analysis of glioblastoma recurrences during TTFields exposure
Authors: Francesca Cianci, Guido Rey, Dietmar Krex, Davide Ceresa, Paolo Malatesta, Michele Mazzanti
Journal: Cancer Research (2024)

Abstract Glioblastoma (GB) is the most aggressive type of brain tumor, and current treatments are generally ineffective in preventing recurrence. Tumor Treating Fields (TTFields) are an innovative treatment that has been shown to improve patients' life expectancy in the last two decades. TTFields therapy has an antitumoral effect that involves different mechanisms and is an optional add-on to standard maintenance temozolomide. Although TTFields therapy initially slows tumor progression, it does not prevent tumor relapse in most patients. In the present investigation, we run a genomic and proteomic analysis of surgical material from 10 patients treated with TTFields. GB tissues were obtained from the primary tumor mass and from a second surgery after tumor relapse. All the patients, in addition to brain tumor standard therapies, were treated with TTFields for eighteen hours a day, the time span of treatment application was dependent on GB recurrence. Control samples were obtained from primary and secondary surgeries of 5 patients treated with standard therapy alone. The GB tissue extracts were analyzed with an RNAseq routine, and the results from the secondary surgery were compared with the data obtained from tumor specimens of the primary surgery. A common feature of transcripts among all the patients was the alterations of several pathways promoting the increase of intracellular oxidation and cell cycle regulation. In parallel with the analysis of patient specimens, we developed an in vitro GB cell relapse model. This was instrumental in investigating the beneficial contribution of TTFields action during tumor relapse, but also in uncovering the limitation of this therapeutic procedure. GB primary cultures obtained from patients' surgery were exposed for up to 12 days with 200 kHz TTFields stimulation using the inovitro™ system. After 12 days of continuous TTFields application, GB cells showed an average depolarization of the resting membrane potential, increasing oxidation, and acidification of the cytoplasm. Genomic analysis of treated cells compared with wild-type primary culture, denoted an increase of tumor stem cell markers, activation of several metabolic pathways, and upregulation of different ion channel protein transcripts. Our final goal is to identify specific molecular features enhanced by TTFields treatment to be used as a parallel therapy to fight GB recurrence. Citation Format: Francesca Cianci, Guido Rey, Dietmar Krex, Davide Ceresa, Paolo Malatesta, Michele Mazzanti. Genomic and proteomic analysis of glioblastoma recurrences during TTFields exposure [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 2092.
Abstract 5660: Gene expression signatures from FFPE to predict recurrent metastatic nasopharyngeal cancer
Authors: Joshua K. Tay, Wei Keat Teo, Joseph W. Foley, Luvita Suryani, Bing Cheng Wu, Chor Hiang Siow, Kwok Seng Loh
Journal: Cancer Research (2024)

Abstract Nasopharyngeal cancer (NPC) is an EBV-driven epithelial cancer endemic to Southeast Asia, Southern China and the Middle East. Accurate profiling of the gene expression of NPC has been challenging because of its intense inflammatory infiltrate, as well as the 3 - 4mm size of biopsies limiting the amount of available material. Here we present a large cohort of 339 micro-dissected gene expression libraries from formalin-fixed paraffin-embedded (FFPE) biopsies from NPC patients treated at the National University Health System, Singapore, as well as healthy controls. NPC tumors from patients who subsequently developed recurrent or metastatic disease (Group A), and patients who did not develop recurrent or metastatic disease (Group B) were profiled. Tumor epithelial and microenvironment compartments were separately obtained using laser-capture microdissection, followed by library preparation performed for RNA-Seq using an in-house specialised technique. Gene signatures for NPC tumor epithelial and microenvironment content were used to validate the purity of gene expression libraries. Our preliminary analysis revealed that primary, pre-treatment tumors from patients who subsequently developed recurrence (Group A) showed downregulation of processes related to interferon gamma and interferon alpha response (p-adj &amp;lt;0.001 for both), while processes related to epithelial-mesenchymal transition (p-adj &amp;lt; 0.05) were enriched compared to patients who remained healthy (Group B). In contrast to primary tumors, recurrent tumors in Group A were enriched for cellular respiration including oxidative phosphorylation (p-adj &amp;lt; 0.0001). Our approach highlights the utility of whole transcriptome profiling from small quantities of archival FFPE material. The gene signatures identified from the primary tumors of high-risk patients are biologically relevant and have the potential to be used in precision medicine to guide additional targeted intervention. Citation Format: Joshua K. Tay, Wei Keat Teo, Joseph W. Foley, Luvita Suryani, Bing Cheng Wu, Chor Hiang Siow, Kwok Seng Loh. Gene expression signatures from FFPE to predict recurrent metastatic nasopharyngeal 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 5660.
Abstract 1700: Interplay of pioneer and chromatin remodeling factors: New insights into breast cancer mechanisms
Authors: Motoki Takaku, Mikhal Cooper, Mika Saotome
Journal: Cancer Research (2024)

Abstract Eukaryotic cells utilize chromatin to package their genomic DNA, which can hinder transcription factor binding and gene activation. Pioneer factors, which can activate silent chromatin by binding to nucleosomes in closed (inactive) chromatin regions, thereby increasing chromatin accessibility, are essential in multiple developmental pathways. Their misregulation has been linked to various human diseases, including cancer. Yet, the involvement of pioneer factor mutations in tumorigenesis and tumor progression remains largely unexplored. GATA3 is one of the most frequently mutated genes in breast cancer. We and other groups found that a subset of GATA3 mutations promote tumor growth by redirecting luminal transcriptional network governed by Estrogen Receptor alpha (ER-alpha), FOXA1, and GATA3. Our genomics data also suggested that GATA3 requires multiple co-factors to maintain and establish active enhancers. Through IP-mass spectrometry, we identified several chromatin remodeling factors as potential GATA3 binding partners, with CHD4 being particularly notable. Our genomic data, including ChIP-seq, ATAC-seq, and RNA-seq, suggest that during GATA3-induced mesenchymal-to-epithelial transition (MET), CHD4 plays a critical role in maintaining closed chromatin structure, particularly at enhancer regions. Depletion of CHD4 results in the activation of chromatin and genes that are not essential for successful MET. Furthermore, we observed functional interactions between GATA3 and PARP1 in both luminal and basal breast cancer cells, with notable changes in GATA3 mutant cells. Through these studies, we aim to uncover epigenetic vulnerabilities in GATA3-altered breast cancer cells, ultimately contributing to the development of new breast cancer treatments. Citation Format: Motoki Takaku, Mikhal Cooper, Mika Saotome. Interplay of pioneer and chromatin remodeling factors: New insights into breast cancer mechanisms [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 1700.
Abstract 1699: Defining the impact of aberrant transcription on the chromatin structure
Authors: Naiju Thomas, Timothy E. Reznicek, Erez Lieberman Aiden, M. Jordan Rowley, Eric Wagner, Guy Nir
Journal: Cancer Research (2024)

Abstract Genome organization in humans is governed by two major mechanisms: loop extrusion by cohesin and CTCF and the spatial compartmentalization of the chromosomes. These folding mechanisms have been shown to regulate several genomic functions, including gene expression. However, how transcription might regulate the chromatin structure remains a subject of many ongoing investigations. In this study, we use the Integrator protein complex as a tool to understand the impact of aberrant transcription on the 3D structure of the genome. During transcription initiation, RNA Polymerase-II (Pol-II) often pauses proximally to the promoter before further elongating transcripts. The Integrator protein complex regulates this checkpoint by its endonuclease and phosphatase activity. This protein complex is essential in premature transcription termination in hundreds of protein-coding genes. It also facilitates the synthesis of non-coding (ncRNA), such as enhancer RNAs (eRNAs) and long non-coding RNAs (lncRNAs), which have been shown to support loop extrusion domains, and their absence may disrupt these domains. Using HiC sequencing, we found that depleting Integrator proteins can interfere with forming and maintaining loop domains. This study aims to be the first to decipher the relationship between chromosome structure and Integrator protein activity and address our very little knowledge of how misregulation of transcription termination may influence the folding of chromosomes. Citation Format: Naiju Thomas, Timothy E. Reznicek, Erez Lieberman Aiden, M. Jordan Rowley, Eric Wagner, Guy Nir. Defining the impact of aberrant transcription on the chromatin structure [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 1699.
Abstract 1314: SCHEQ Foundation (STEMM &amp; Cancer Health Equity): Increasing STEMM diversity and outcomes for patients navigating cancer
Authors: Eugene Manley
Journal: Cancer Research (2024)

Abstract Health inequities are estimated to cost $320B annually, while racial and ethnic disparities are estimated to cost $42B in productivity. There are systemic issues at play that contribute to these disparities. These include lack of diversity in Science, Technology, Engineering, Mathematics, and Medicine (STEMM) fields; bias in healthcare delivery and access; underinsurance in patients from low-income backgrounds; and lack of training that advances those from historically underrepresented groups. The SCHEQ Foundation (STEMM &amp; Cancer Health Equity) is a black-founded nonprofit organization that seeks to increase STEMM workforce diversity and improve outcomes for underrepresented, underserved, marginalized, and invisible populations across the cancer care continuum. Herein we describe the formation of SCHEQ Foundation and our core domains that we seek to make change. We seek to increase STEMM access and exposure, increase STEMM workforce diversity, and improve outcomes for underserved populations navigating the cancer care continuum. This will be accomplished in part by 1) engaging professional in STEMM from their lived background and experiences, 2) developing training, mentoring, and professional developing programs across the academic continuum to increase success of minoritized scholars; and 3) providing information and resources in culturally responsive manners to help underserved patient navigate cancer and advocate for the standard of care they deserve. We will change how we convey content, information, and resources to underserved populations by utilizing a combination of multimedia, infographics, webinars, info sheets, and community engagement. The goal is to increase survival for groups that historically have the greatest cancer disparities. Citation Format: Eugene Manley. SCHEQ Foundation (STEMM &amp; Cancer Health Equity): Increasing STEMM diversity and outcomes for patients navigating 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 1314.
Abstract 1615: Balanced molecular feature selection unveils universally tumor-lineage informative methylation sites in colorectal cancer
Authors: Xuan Cindy Li, Yuelin Liu, Alejandro A. Schäffer, Stephen M. Mount, Süleyman C. Sahinalp
Journal: Cancer Research (2024)

Abstract In the era of precision medicine, performing comparative analysis over diverse patient populations is a fundamental step toward tailoring healthcare interventions. However, the critical aspect of equitably selecting molecular features across multiple patients is often overlooked. To address this challenge, we introduce FALAFL (FAir muLti-sAmple Feature seLection), a novel algorithmic approach based on integer linear programming. FALAFL is designed to bridge the gap between molecular feature selection and algorithmic fairness, ensuring a balanced selection of molecular features across different patient samples. We have applied FALAFL to the problem of selecting lineage-informative CpG sites within a cohort of 9 colorectal cancer patients subjected to low-coverage single-cell methylation sequencing. Our results demonstrate that FALAFL excels at rapidly determining the optimal set of CpG sites, which are well covered by cells across the vast majority of the patients, while ensuring that each patient contributes a similar number of sites to the final selection. An analysis of the FALAFL-selected CpG sites reveals that their lineage informativeness exhibits a strong association across diverse patient profiles, suggesting the non-stochasticity and universality of methylation changes in tumor evolution. Furthermore, these universally lineage-informative sites exhibit subclonal level alterations in the colorectal cancer primary tumors and are strongly associated with lineage-specific gene expression patterns. By integrating equity considerations into the molecular feature selection process, FALAFL is poised to propel equitable healthcare data science practices and advance our understanding of cancer and other complex diseases. Citation Format: Xuan Cindy Li, Yuelin Liu, Alejandro A. Schäffer, Stephen M. Mount, Süleyman C. Sahinalp. Balanced molecular feature selection unveils universally tumor-lineage informative methylation sites 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 1615.
Abstract 1494: Clonal dominance defines metastatic dissemination in pancreatic cancer
Authors: I-Lin Ho, Chieh-Yuan Li, Fuchenchu Wang, Li Zhao, Jingjing Liu, Er-Yen Yen, Charles A. Dyke, Rutvi Shah, Zhaoliang Liu, Ali Osman Çetin, Francesca Citron, Sergio Attanasio, Virgina Giuliani, Tim Heffernan, Kim-Anh Do, Gaetano Gargiulo, Giulio Draetta, Alessandro Carugo, Ruitao Lin, Andrea Viale
Journal: Cancer Research (2024)

Abstract Tumors represent ecosystems where subclones compete during tumor growth. While extensively investigated, a comprehensive picture of the interplay of clonal lineages during dissemination is still lacking. Using patient-derived pancreatic cancer cells, we created orthotopically-implanted clonal replica tumors to trace clonal dynamics of unperturbed tumor expansion and dissemination. This model revealed the multifaceted nature of tumor growth, with rapid changes in clonal fitness leading to continuous reshuffling of tumor architecture and alternating clonal dominance as a distinct feature of cancer growth. Regarding dissemination, a large fraction of tumor lineages could be found at secondary sites each having distinctive organ growth patterns as well as numerous undescribed behaviors such as abortive colonization. Paired analysis of primary and secondary sites revealed fitness as major contributor to dissemination. From the analysis of pro- and non-metastatic isogenic subclones, we identified a transcriptomic signature able to identify metastatic cells in human tumors and predict patients’ survival. Citation Format: I-Lin Ho, Chieh-Yuan Li, Fuchenchu Wang, Li Zhao, Jingjing Liu, Er-Yen Yen, Charles A. Dyke, Rutvi Shah, Zhaoliang Liu, Ali Osman Çetin, Francesca Citron, Sergio Attanasio, Virgina Giuliani, Tim Heffernan, Kim-Anh Do, Gaetano Gargiulo, Giulio Draetta, Alessandro Carugo, Ruitao Lin, Andrea Viale. Clonal dominance defines metastatic dissemination 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 1494.