tbuckley/cabot-search huggingface dataset:
Abstract 6612: Therapy-resistant endocycling cancer cells alter mitochondrial structure and metabolism to survive therapeutic stress
Authors: Melvin Li, Sarah R. Amend, Kenneth J. Pienta
Journal: Cancer Research (2024)

Abstract Therapy resistance is responsible for 90% of cancer-related deaths. We identified a novel mechanism of therapy resistance in which cancer cells enter an endocycling cell state, undergoing repeated S and G phases without dividing. As a result, resistant endocycling cells are 40 times larger than mitotic cancer cell controls. Interestingly, we observed that these non-proliferative endocycling cells can eventually give rise to proliferative progeny weeks after chemotherapy is removed, modeling cancer recurrence. We hypothesize that this endocycling cancer cell state is a critical driver of therapy resistance and cancer lethality. We evaluated oxidative stress in endocycling cells that survived the days and weeks following chemotherapy treatment using DCF-DA staining. We found increased levels of reactive oxygen species (ROS) in endocycling prostate cancer cells compared to untreated mitotic cells when normalized to cell size. Given that mitochondria are major producers and regulators of ROS, we hypothesize that cells surviving in this resistant state alter mitochondrial structure and function in response to increased oxidative stress. We performed immunofluorescence and confocal microscopy on mitochondria in untreated cells and cells following chemotherapy treatment to observe their morphology. Surviving endocycling cells had increased mitochondrial fragmentation when compared to the untreated group, a result that was further supported by reduced expression of phospho-DRP1 Ser637 via western blot. To assess changes in glucose metabolism, we then utilized isotope tracing-based metabolomics with [U-13C]glucose on untreated and surviving endocycling cells following chemotherapy. Endocycling cells had decreased labeling of 13C in TCA cycle metabolites, suggesting a decrease in mitochondrial function when compared to untreated cells. Ongoing work involves further studying metabolic reprogramming as cells enter this resistant state with parallel labeling experiments using [1,2-13C]glucose and [U-13C]glutamine to perform mathematical modeling-based 13C-metabolic flux analysis. In addition, we engineered a cell line to track mitochondria in real-time to quantify mitochondrial dynamics underlying the morphology observed in untreated and surviving cells. Our goal is to characterize how this therapy-resistant cell state alters its mitochondrial structure and function to survive therapeutic stress. Identifying vulnerabilities of this phenotype will enable new approaches for eliminating drug resistance in cancer. Citation Format: Melvin Li, Sarah R. Amend, Kenneth J. Pienta. Therapy-resistant endocycling cancer cells alter mitochondrial structure and metabolism to survive therapeutic stress [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 6612.
Abstract 4133: Hyaluronidase inhibitor delphinidin inhibits cancer metastasis
Authors: Jeremy Jonathan McGuire, Taketo Taguchi, Greg Tombline, Victoria Paige, Michelle Janelsins, Nikesha Gilmore, Andrei Seluanov, Vera Gorbunova
Journal: Cancer Research (2024)

Abstract Cancer remains a formidable global health challenge, with metastasis being a key contributor to its lethality. Abundant high molecular weight hyaluronic acid, a major non-protein component of extracellular matrix, protects naked mole rats from cancer and reduces cancer incidence in mice. Hyaluronidase plays a critical role in degrading hyaluronic acid and is frequently overexpressed in metastatic cancer. We investigated the potential of targeting hyaluronidases to reduce metastasis. High throughput screening identified delphinidin, a natural plant compound found in fruits and vegetables, as a potent hyaluronidase inhibitor. Delphinidin-mediated inhibition of hyaluronidase activity led to an increase in high molecular weight hyaluronic acid in cell culture and in mouse tissues, and significantly reduced proliferation, migration and invasion of breast (EO771), prostate (RM1), and melanoma (B16-F10) metastatic cell lines. Addition of exogenous hyaluronidase partially reversed all of these effects. Moreover, delphinidin treatment suppressed melanoma (B16-F10) metastasis in a spontaneous mouse model of metastasis. These results provide a proof of principle that inhibition of hyaluronidase activity suppresses cancer cell migration, invasion and metastasis. These results combined with the lack of adverse effect make delphinidin an attractive potential therapeutic option for inhibition of metastasis. We believe further investigation is warranted to fully elucidate the mechanisms and optimize the use of delphinidin in cancer therapy. Citation Format: Jeremy Jonathan McGuire, Taketo Taguchi, Greg Tombline, Victoria Paige, Michelle Janelsins, Nikesha Gilmore, Andrei Seluanov, Vera Gorbunova. Hyaluronidase inhibitor delphinidin inhibits cancer 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 4133.
Abstract 5466: <i>In vivo</i> characterization of neuroblastoma intratumoral heterogeneity
Authors: Willow R. Squires, Alex Weiss, Sarah Cohen-Gogo, Adam Shlien, David Kaplan, Meredith S. Irwin, Madeline N. Hayes
Journal: Cancer Research (2024)

Abstract Background: Neuroblastoma is a pediatric solid tumor that arises from neural crest-derived progenitor cells of the peripheral sympathetic nervous system (PSNS). Neuroblastoma patients display a significant level of genetic and phenotypic heterogeneity, with amplification of the MYCN oncogene associated with poor clinical outcomes. To better understand underlying genetic mechanisms associated with aggressive neuroblastoma, our group incorporated patient-relevant loss-of-function mutations into the established MYCN-driven zebrafish model of neuroblastoma (Tg(dbh:EGFP-MYCN)), which resulted in increased tumor penetrance and a highly metastatic phenotype. Aims &amp; Methods: We aimed to investigate metastases-associated intratumoral heterogeneity in vivo using our patient-relevant metastatic zebrafish models, with functional validations performed using human neuroblastoma cell lines. Results: Single-cell RNA sequencing of metastatic zebrafish neuroblastoma tumors revealed intra-tumor cell heterogeneity, with a subset of cells highly expressing markers of more differentiated adrenergic-like cell fates (th, dbh, phox2a) while others enriched for markers of less differentiated mesenchymal-like progenitor cells (prrx1a, vim, fn1a). Differential cell labeling in zebrafish neuroblastoma suggests distinct tumor cell populations for follow-up validation and characterization throughout metastatic progression. Conclusion: Single-cell RNA sequencing of zebrafish metastatic neuroblastoma showed evidence of intratumoral heterogeneity that warrants further investigation. We are characterizing neuroblastoma intratumoral heterogeneity in our in vivo metastatic zebrafish models to examine the association between neuroblastoma tumor composition and metastatic potential. Altogether, this work aims to improve our understanding of the evolution of tumor cell heterogeneity associated with neuroblastoma metastasis and uncover novel therapeutic opportunities to improve patient outcomes. Citation Format: Willow R. Squires, Alex Weiss, Sarah Cohen-Gogo, Adam Shlien, David Kaplan, Meredith S. Irwin, Madeline N. Hayes. In vivo characterization of neuroblastoma intratumoral heterogeneity [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 5466.
Abstract 921: The value of cancer genomic data sharing
Authors: Stefanie Nelson, Charlisse Caga Anan, Elizabeth Gillanders
Journal: Cancer Research (2024)

Abstract Our understanding of and ability to combat cancer relies on the generation, analysis, and sharing of data. The Epidemiology and Genomics Research Program in the National Cancer Institute’s Division of Cancer Control and Population Sciences (DCCPS) has supported generation of large genomic data sets and advocated for and/or required broad sharing of this data. One of DCCPS’s scientific priorities is focused on data strategies namely, “the use, enhancement, expansion, and accessibility of new and existing DCCPS-supported data resources to accelerate cancer control research” (https://cancercontrol.cancer.gov/overview-highlights/2022/future_directions.html).EGRP funded the Genetic Associations and Mechanisms in Oncology (GAME-ON) Initiative, a multidisciplinary collaboration of researchers focused on understanding the genetic architecture, biology, and clinical and epidemiologic utility of common cancer risk variants. This program focused on 5 common cancer types - breast, colorectal, lung, ovarian, and prostate - and required research that incorporated multiple research domains and sharing of any data generated. A major accomplishment of this program was development of the OncoArray genotyping chip, which used information from genetic epidemiology studies, biological/functional analyses, and clinical and epidemiologic insights to create a comprehensive, high-density genotyping array for pan-cancer studies that has led to the discovery of hundreds of new cancer predisposition variants. This chip was used in a massive, coordinated genotyping effort that culminated in the generation of 7 datasets comprising genotyping data for nearly 500,000 individuals. All the data were deposited in dbGaP between 2014 and 2021 and are available (via controlled access) to any investigators. To understand the secondary use of these data, we determined the number of times the data had been downloaded, who downloaded the data, and types of research for which it was used. We also identified publications using OncoArray data and characterized the publications by research type, cancer type, and other details. Through this analysis, we explore how well the GAME-ON initiative and the OncoArray projects promote the DCCPS scientific priority of optimizing secondary research by making the data findable, accessible, interoperable, and reusable (FAIR). Citation Format: Stefanie Nelson, Charlisse Caga Anan, Elizabeth Gillanders. The value of cancer genomic data sharing [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 921.
Abstract 1419: Locoregional delivery with engineered stem cells modulates immunosuppressive tumor microenvironment in brain leptomeningeal metastasis
Authors: Nobuhiko Kanaya, Waleed Seddiq, Kok-Siong Chen, Yoshinori Kajiwara, Lucia Moreno Lama, Shinji Kuroda, Toshiyoshi Fujiwara, Hiroaki Wakimoto, Khalid Shah
Journal: Cancer Research (2024)

Abstract Leptomeningeal metastasis (LM) is one of the severe disease conditions in brain metastasis (BM) and results in poor prognosis and reduction of quality of life. Immunotherapies such as anti-Programmed cell Death (PD)-1 antibodies have shown improved overall survival against non-small cell lung cancer (NSCLC).. However, the clinical benefit of patients with NSCLC derived LM is still limited due to poor penetration of therapeutic agents into the brain and cerebrospinal fluid (CSF) and lack of understanding of the tumor microenvironment in LM. In this study, we first developed immune-competent mouse models of LM which show significantly decreased immune cells and increased PD-1+ T cells in the tumor microenvironment as compared to primary NSCLC tumors, thus mimicking primary and LM NSCL in patients. Next, we explored the use of oncolytic herpes simplex virus (oHSV) that selectively replicate in tumor cells and illicit an antitumor effect via oncolysis and production of neoantigens for targeting LM NSCLC. Given that virus neutralization, and inefficient extravasation are the major barriers to the effective systemic delivery of oHSV to target metastatic tumor lesions in the brain, we utilized mesenchymal stem cells (SC) and created two population of mesenchymal SC types: one for loading oncolytic herpes simplex virus (oHSV) and another one, engineered with knockout of Nectin-1 receptor by CRISPR/Cas9 technique to be resistant to oHSV, for secreting single-chain variable fragment (scFv) anti-PD-1. We show that locoregional treatment improved therapeutic outcomes by inducing oHSV-mediated immunogenic cell death, and activation of anti-tumor T cell signaling in mouse NSCLC LM tumors. Our novel SCs based immunotherapeutic strategy provides a roadmap towards treatment of lung to brain leptomeningeal metastatic patients. Citation Format: Nobuhiko Kanaya, Waleed Seddiq, Kok-Siong Chen, Yoshinori Kajiwara, Lucia Moreno Lama, Shinji Kuroda, Toshiyoshi Fujiwara, Hiroaki Wakimoto, Khalid Shah. Locoregional delivery with engineered stem cells modulates immunosuppressive tumor microenvironment in brain leptomeningeal 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 1419.
Abstract 5160: Evaluation of circulating microRNAs as predictive and prognostic biomarkers for advanced melanoma patients
Authors: Giorgio Durante, Francesca Comito, Maria Naddeo, Serena De Matteis, Massimiliano Bonafè, Emi Dika, Andrea Ardizzoni, Manuela Ferracin
Journal: Cancer Research (2024)

Abstract Introduction Metastatic melanoma is the deadliest form of skin cancer whose incidence has been rising dramatically over the last few decades. The advent of Immune checkpoint inhibitors (ICIs) has strongly improved the survival of melanoma patients. However, a high fraction of patients shows primary resistance or will develop secondary resistance during therapy. For these reasons, it is of utmost importance to develop biomarkers that could predict response or resistance to therapies. Among the most promising biomarkers analyzed in peripheral blood there are circulating microRNAs (miRNAs). The aim of this study is to identify a miRNA signature able to predict prognosis and clinical relapse in advanced melanoma patients treated with ICIs. Methodology We collected longitudinal blood draws from metastatic melanoma patients treated with ICIs at Bologna University-Hospital (Italy). We separated plasma from whole blood, extracted RNA and determined the absolute levels of miR-155-5p, miR-424-5p and miR-320a using EvaGreen-based droplet digital PCR. Moreover, in the subset of first-line anti-PD-1 treated patients, we performed cytofluorimetric leukocyte analysis. Results and discussion We found that patients with pre-therapy (baseline) high expression of circulating miR-155-5p, miR-320a and mir-424-5p had longer progression-free survival (PFS), and overall-survival (OS). In patients treated with anti PD-1 as first-line treatment, we found that baseline miR-155-5p levels were significantly higher in patients who responded to therapy, and therefore miR-155-5p could have a predictive value. Moreover, using a flow cytometric approach, we noted that baseline miR-155-5p levels correlated with CD4+Naïve (r:-0.91, p:0.027) and CD4+PD1+ T-cells (r:0.94, p:0.015) in patients treated with first-line anti-PD-1 treatment. Conclusion These preliminary findings propose baseline circulating miRNAs as potential predictive and prognostic biomarkers in the setting of advanced melanoma patients treated with immunotherapy. Citation Format: Giorgio Durante, Francesca Comito, Maria Naddeo, Serena De Matteis, Massimiliano Bonafè, Emi Dika, Andrea Ardizzoni, Manuela Ferracin. Evaluation of circulating microRNAs as predictive and prognostic biomarkers for advanced melanoma patients [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 5160.
Abstract 303: Revealing molecular mechanism of G protein-coupled receptor kinase 2 (GRK2)-mediated extracellular matrix remodeling in ovarian cancer
Authors: Weng I Lei, Shan Yu, Chi Teng Lei, Zhiming Zhang, Tzu Ming Liu, Wakam Chang, Leo Tsz On Lee
Journal: Cancer Research (2024)

Abstract G protein-independent pathway (β-arrestin dependent signaling cascade) is initiated by activated GPCRs phosphorylated by G protein-coupled receptor kinases (GRKs), triggering multiple signaling pathways. The purpose of this research is to reveal the role of GRK2 on the tumor microenvironment (TME). Through in vitro assays, we showed that GRK2 overexpression led to loss of cell-matrix and cell-cell adhesion. The cell spreading assay further indicated that the loss of focal adhesion (FA) assembly and cell size decreased in GRK2-overexpressing cells. In vivo experiments demonstrated that tumor formation and metastasis were suppressed in xenograft mouse models implanted with GRK2-overexpressing ovarian cancer cells. In addition, label-free imaging detection of the collagen pattern suggested that GRK2 overexpression caused bundle loss but the formation of thicker, twisted collagen fibers in xenograft tumor samples. Together with the transcriptome and proteomic data, we hypothesize that GRK2 suppresses cell motility and metastasis by reducing FA and extracellular matrix (ECM) remodeling in ovarian cancer. This research revised the mechanisms underlying GRK2-mediated ovarian cancer metastasis and suggested the potential to target the GRK2-meditated pathway for cancer suppression. Citation Format: Weng I Lei, Shan Yu, Chi Teng Lei, Zhiming Zhang, Tzu Ming Liu, Wakam Chang, Leo Tsz On Lee. Revealing molecular mechanism of G protein-coupled receptor kinase 2 (GRK2)-mediated extracellular matrix remodeling in ovarian 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 303.
Abstract 6546: Spatial immunology landscapes that correlate with survival in triple negative breast cancer
Authors: Ali Foroughi pour, Jan Martinek, Te-Chia Wu, Santhosh Sivajothi, Zichao Liu, Jie Zhou, David Rimm, Paul Robson, Katherine Bates, Karolina Palucka, Jeffrey H. Chuang
Journal: Cancer Research (2024)

Abstract Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer characterized by negative immunohistochemistry staining for estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Treatment options for TNBCs are limited due to lack of tumor-specific targeted therapies, resulting in poor prognosis and patient survival. This is exacerbated by lack of prognostic markers of response. While current studies suggest tumor immune interactions are important, current immune activity quantifications, such as scores quantifying abundance of tumor-infiltrating lymphocytes (TILs), are not sufficient to define tumor immune status. We used imaging mass cytometry (IMC) to measure 33 markers on primary tumors of 100 patients undergone chemotherapy with long-term follow-up to explore the tumor immune microenvironment of TNBCs. Concordant with previous studies, a higher ratio of T-cells was associated with response to chemotherapy and longer overall survival (adjusted p-value&amp;lt;0.05). Moreover, using Kmeans clustering we identified 13 distinct cellular neighborhoods, reflective of the heterogenous nature of TNBCs. Among others, we identified a neighborhood, characterized by low CD14+ expression, low cytokeratin, high vimentin expression and high CD45RO, that contributes highest impact on correlation with overall survival (adjusted p-value&amp;lt;0.01). These results suggest an important role for memory T cells in the stroma. Thus, resolving spatial organization of the tissue is important to understanding patient response to therapy in TNBCs. Citation Format: Ali Foroughi pour, Jan Martinek, Te-Chia Wu, Santhosh Sivajothi, Zichao Liu, Jie Zhou, David Rimm, Paul Robson, Katherine Bates, Karolina Palucka, Jeffrey H. Chuang. Spatial immunology landscapes that correlate with survival in triple negative 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 6546.
Abstract 655: Fungal extract screening reveals malformin C to preferentially kill glioblastoma stem-like cells via concerted induction of proteotoxic stress and autophagic flux blockade
Authors: Emma L. Phillips, Sizèd van Enk, Sara Kildgaard, Silja Schlue, Mona Göttmann, Victoria Jennings, Frederic Bethke, Gabriele Müller, Christel Herold-Mende, Daniel Pastor-Flores, Martin Schneider, Dominic Helm, Thomas Ostenfeld Larsen, Violaine Goidts
Journal: Cancer Research (2024)

Abstract Glioblastoma is a highly aggressive brain tumor for which there is no cure. The dire prognosis of this disease is largely attributable to a high level of heterogeneity, including the presence of a sub-population of tumor initiating glioblastoma stem-like cells (GSCs), which are refractory to chemo- and radiotherapy. Here, in an unbiased marine-derived fungal extract screen, together with bioguided dereplication based on high resolution mass spectrometry, we identified malformin C to preferentially induce cell death in patient-derived GSCs, and explore the potential of this cyclic peptide as a therapeutic agent for glioblastoma. Malformin C significantly reduced tumor growth in an in vivo xenograft model of glioblastoma. Using transcriptomics and chemoproteomics, we found that malformin C binds to many proteins leading to aggregation, and rapidly induces unfolded protein response, including autophagy, in GSCs. Malformin C also appears to accumulate in lysosomes, disrupting autophagic flux and driving cells to death. Supporting this, malformin C synergizes with chloroquine, an inhibitor of autophagy. Strikingly, we observed that autophagic flux is differentially regulated in GSCs compared with normal astrocytes. The sensitivity of GSCs to malformin C highlights the relevance of proteostasis and autophagy as a therapeutic vulnerability in glioblastoma. Citation Format: Emma L. Phillips, Sizèd van Enk, Sara Kildgaard, Silja Schlue, Mona Göttmann, Victoria Jennings, Frederic Bethke, Gabriele Müller, Christel Herold-Mende, Daniel Pastor-Flores, Martin Schneider, Dominic Helm, Thomas Ostenfeld Larsen, Violaine Goidts. Fungal extract screening reveals malformin C to preferentially kill glioblastoma stem-like cells via concerted induction of proteotoxic stress and autophagic flux blockade [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 655.