bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 889: NF-κB-mediated mitophagy contributes to the maintenance of cancer stem cells in ovarian cancer
Authors: Li Na , Pal Tejinder , Cai Shurui , Banerjee Ananya , Bai Xuetao , Lavudi Kousalya , Wang Qi-En 
Published: June 2022

Abstract
Tumors contain phenotypically and functionally heterogeneous cancer cells. Among them, a minority of cell subpopulation, termed cancer stem cells (CSCs), which possess the self-renewal capacity and are able to generate the heterogeneous lineage of cancer cells, has been believed to be responsible for the initiation and progression of the tumor. However, it is still unclear how the stemness properties of CSCs are maintained in the tumor. Mitophagy is a process by which damaged mitochondria are cleared via autophagy. The significance of mitophagy in the maintenance of CSC has been investigated in multiple CSC types. Our recent study shows that ovarian CSCs also exhibit enhanced mitophagy, which is mainly attributed to elevated expression of mitophagy receptors BNIP3 and BNIP3L. Downregulation of BNIP3 or BNIP3L significantly diminished mitophagy in ovarian CSCs and compromised their self-renewal capability. Mechanistic investigation further revealed that enhanced NF-κB signaling contributes to the increased expression of BNIP3 and BNIP3L. Inhibition of NF-κB signaling pathway via p65 knockdown or specific inhibitors is able to reduce mitophagy in ovarian CSCs. In summary, our data suggest that selective inhibition of NF-κB is able to deplete CSCs by interfering with mitochondria quality control in these cells and has potential to prevent tumor relapse and metastasis.
Citation Format: Na Li, Tejinder Pal, Shurui Cai, Ananya Banerjee, Xuetao Bai, Kousalya Lavudi, Qi-En Wang. NF-κB-mediated mitophagy contributes to the maintenance of cancer stem cells in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 889.
Abstract 93: Soluble mesothelin acts as a signaling molecule
Authors: Ewa Theressa , Avula Leela , Joseph Sarah , Rudloff Michael , Sevilla Samantha , Koparde Vishal , Zhang Xianyu , Alewine Christine 
Published: June 2022

Abstract
Mesothelin (MSLN) is a cell surface glycoprotein that is expressed by most pancreatic ductal adenocarcinoma (PDAC) and is used as a target for anti-cancer therapy. MSLN expression appears to make pancreatic cancer more aggressive. Previously, we found that MSLN KO PDAC cells grow in culture and as subcutaneous tumors similarly to wild-type (WT) cells but form intraperitoneal metastases poorly. MSLN pre-cursor (pre-MSLN) is a 71-kD glycosylphosphatidylinositol (GPI)-anchored protein that is cleaved intracellularly to make the 31-kD secreted protein Megakaryocyte Potentiating Factor (MPF), and a 40-kD mature MSLN (mMSLN) that retains membrane attachment. The mMSLN can be shed from the cell surface by the action of specific proteases, resulting in release of soluble MSLN (sMSLN) to both the tumor microenvironment and serum. The goal of this study is to see if sMSLN promotes cancer cell aggressiveness. We transduced MSLN KO pancreas cancer cells to express: 1) a mutant, secreted-only pre-MSLN (includes WT MPF) with a C-terminal truncation (MSLNΔ599) that prevents GPI-linkage of MSLN to the membrane, and 2) truncated pre-MSLN consisting of MPF only. Results show that complementation of KO cells with MPF or MSLNΔ599 does not rescue the MSLN KO phenotype, while MSLNΔ599 bearing a Y318A point mutation that disrupts the binding of MSLN to MUC16/CA125 does restore growth of peritoneal metastasis. We performed RNA-deep sequencing on MSLN KO cells exposed to WT or Y318A sMSLN from conditioned medium. We identified 2000 genes that were differentially expressed across the treatment groups. Exposure to sMSLN resulted in changes in expression of cell adhesion and sterol biosynthetic synthesis pathway genes. Individual genes that were top hits were also identified and are under investigation. Exposure to sMSLN changes the transcriptomic program of pancreas cancer cells and may promote peritoneal colonization.
Citation Format: Theressa Ewa, Leela Avula, Sarah Joseph, Michael Rudloff, Samantha Sevilla, Vishal Koparde, Xianyu Zhang, Christine Alewine. Soluble mesothelin acts as a signaling molecule [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 93.
Abstract 933: Macrophage-derived C/EBPb promotes breast tumorigenesis
Authors: Dow Alexa M. , Rojo Michelle D. , Treadwell Scout M. , Machado Heather L. 
Published: June 2022

Abstract
Breast cancer growth and progression relies on complex interactions between tumor cells and surrounding stromal cells, including immune cells. Infiltrating immune cells, including macrophages, have been shown to promote tumor progression and metastasis, and efforts have aimed at the tumor microenvironment as a therapeutic strategy. Although tumor-promoting roles of macrophages are well-established, the specific macrophage factors and transcription factor-mediated regulatory programs that drive breast cancer progression are less understood. Using a p53-/- syngeneic model of premalignant progression to invasive cancer, we identified distinct subpopulations of macrophages that resemble both normal tissue resident macrophages and tumor-associated macrophages. Interestingly, most of these macrophage subsets highly express C/EBPβ, suggesting a global function of C/EBPβ in macrophages. C/EBPβ is a transcription factor that is overexpressed in breast cancer tissues and is important for monocyte differentiation and myeloid-derived suppressor cell function. To address the function of macrophage C/EBPβ during tumorigenesis, Cebpb-floxed mice were bred to iCsf1r-Cre mice to generate mice (CebpbΔM) where Cebpb is selectively deleted in macrophages (CSF1R-expressing myeloid cells). Genetic ablation of macrophage C/EBPβ in premalignant lesions results in a significant decrease in progression to invasive cancer. In established claudin-low tumors, deletion of macrophage C/EBPβ results in decreased tumor latency and the re-expression of cytokeratin 8+E-cadherin+ cells, reminiscent of luminal-like tumors. This phenoytpe was recapitulated in an ex vivo 3D co-culture model, where uniformly round structures that lack mesenchymal projections form in the presence of CebpbΔM BMDMs. These data suggest that macrophage C/EBPβ may help maintain a mesenchymal phenotype in claudin-low tumors. Ongoing studies are aimed at identifying the Cebpb-induced gene networks in macrophages that mediate tumor progression. These studies will have critical implications for whether inhibition of C/EBPβ-regulated genes may revert claudin-low tumors to a luminal-like phenotype, rendering tumors responsive to current therapies. This work is supported by NIH R01CA212518 (H.L.M.).
Citation Format: Alexa M. Dow, Michelle D. Rojo, Scout M. Treadwell, Heather L. Machado. Macrophage-derived C/EBPb promotes breast tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 933.
Abstract 949: Novel stilbene compounds inhibit triple-negative breast cancer invasive potential
Authors: Rhodes Lyndsay V. , Julmeus Kaelyn 
Published: June 2022

Abstract
Triple-negative breast cancer (TNBC) is a highly aggressive breast subtype of breast cancer that lacks targeted therapies. We have previously identified several novel stilbene compounds that effectively decreased viability of TNBC. Stilbenes are natural defense compounds produced by plants and have been popularized in recent years due to general observed health benefits. Resveratrol, the most widely studied stilbene, has been revealed to possess significant antioxidant and anti-cancer effects. Many stilbenes are classified as phytoestrogens, but unlike estrogens, stilbenes do not appear to negatively impact normal breast tissue or reproductive organ health. Thus, these compounds represent new alternatives for cancer therapeutic development. The focus of this research was to identify stilbene compounds with anti-migration and/or anti-invasive properties in TNBC cells and to determine the mechanism of these inhibitory effects. Two TNBC cell lines, MDA-MB-157 and BT-549, were treated with stilbene compounds at sub-lethal doses and assessed for effects on migration and invasion using transwell assays. Cell morphology changes were evaluated with results suggestive of reversal of epithelial-to-mesenchymal transition (EMT), a key contributor in the metastatic process and a common characteristic of many TNBC cells. Gene expression analysis confirmed stilbene-induced changes of EMT-related genes. These data indicate that stilbenes, like resveratrol and related analogues, reduce cell motility and invasion through regulation of EMT gene expression in TNBC cells. Development of synthetic analogs of natural compounds remains a viable drug development opportunity for new therapeutics.
Citation Format: Lyndsay V. Rhodes, Kaelyn Julmeus. Novel stilbene compounds inhibit triple-negative breast cancer invasive potential [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 949.
Abstract CT569: Combination of reovirus (pelareorep) and granulocyte-macrophage colony-stimulating factor (GM-CSF) alongside standard chemoradiotherapy and adjuvant chemotherapy (temozolomide) for patients with glioblastoma multiforme (GBM): Long term follow up results of the ReoGlio phase Ib trial
Authors: Short Susan C. , Kendall Jessica , Chalmers Anthony , McBain Catherine , Melcher Alan , Samson Adel , Phillip Rachel , Brown Sarah 
Published: June 2022

Abstract
Background: Oncolytic viruses are of increasing interest as an immunologic approach to treating glioma. We previously reported safety data from a phase Ib, open-label study of intravenous pelareorep with GM-CSF alongside standard chemoradiotherapy in newly diagnosed glioblastoma and confirmed that the combination is tolerable. Following agreement from the relevant ethics authorities we have now completed long term follow up data on all patients treated in the study to investigate whether there is a signal of impact on survival. METHODS: 15 patients with newly diagnosed GBM were treated with GM-CSF 50μg subcutaneously on days 1-3 and pelareorep on days 4-5 in weeks 1 and 4 of chemoradiotherapy, and subsequently in week 1 of each adjuvant temozolomide course: 7 patients received 1x1010TCID50 (dose level 1); 8 received 3x1010TCID50 (dose level 2). The primary objective was to determine the maximum tolerated dose of pelareorep and GM-CSF with standard chemoradiotherapy. Following end of study patients were followed up as per institutional practice. Ethical approval was granted to collect survival data in all patients who survived beyond study closure up to June 2021.
Results: We showed that using intravenous pelareorep with GM-CSF alongside standard chemoradiotherapy in patients with GBM was tolerable with 87% of patients completing treatment as planned. Survival data analysis showed that median OS was 12.6 months for patients in dose level 1 and 16.1 months in dose level 2, giving median OS for all patients 13.1 months. It was notable however that a small number of patients survived beyond 24 months. The 24-month survival estimate for all patients was 33%, 16.7% for dose level 1 and 50% for dose level 2. One patient in dose level 2 remains alive at 42 months.
Conclusion: We previously reported that intravenous delivery of pelareorep with standard chemoradiotherapy is tolerable in newly diagnosed GBM. Although based on small numbers, these long-term follow up data suggest that this may be an active combination in a subset of GBM patients and further randomized studies are warranted.
Citation Format: Susan C. Short, Jessica Kendall, Anthony Chalmers, Catherine McBain, Alan Melcher, Adel Samson, Rachel Phillip, Sarah Brown. Combination of reovirus (pelareorep) and granulocyte-macrophage colony-stimulating factor (GM-CSF) alongside standard chemoradiotherapy and adjuvant chemotherapy (temozolomide) for patients with glioblastoma multiforme (GBM): Long term follow up results of the ReoGlio phase Ib trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT569.
Abstract LB024: Cancer stem cells are enriched in human recurrent glioblastoma
Authors: Xie Xuanhua Peter , Ganbold Mungunsarnai , Pedraza Alicia , Parada Luis 
Published: June 2022

Abstract
A number of studies have described an essential role of cancer stem cells (CSC) in glioblastoma (GBM) progression and recurrence based on isolation by candidate markers. However, a systematic evaluation of the proposed CSC in paired human primary and recurrent glioblastoma has been lacking and whether they represent a unified cell type with conserved features over tumor evolution is unresolved. In this study, we used human patient derived xenografts (PDX) to investigate the status of these cells in patients following therapeutics and recurrence. Firstly, to ensure the fidelity of tumor heterogeneity in serially passaged orthotopic GBM PDX, we collected samples at different passages and performed whole tumor single cell RNA sequencing analysis. The results illustrate the preservation of all unsupervised transcriptional cell clusters through multiple passages. Furthermore, treatment of tumor bearing mice with temozolomide, the standard of care chemotherapeutic drug for glioblastoma patients, increased apoptosis and decreased tumor cell burden but spared CSC. We then turned to paired human primary and recurrent GBM samples to inquire cancer stem cell marker expression and cell distribution. In all three pairs of PDX studied, cancer stem cell marker F3 serves as a reliable means to isolate sphere formation cells and is augmented in the recurrent samples. Inspection of whole tumors with single cell RNA sequencing nails down the enrichment of CSC in recurrent tumors, thus emphasizing the importance to eradicate these cells in future therapeutics.
Citation Format: Xuanhua Peter Xie, Mungunsarnai Ganbold, Alicia Pedraza, Luis Parada. Cancer stem cells are enriched in human recurrent glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB024.
Abstract LB051: IL-6 and CCL18 mediate reciprocal interactions between VHL-deficient kidney cells and macrophages during development of ccRCC
Authors: Hsu Tien , Nguyen Thi Ngoc , Nguyen-Tran Hieu-Huy , Chen Chen-Yun 
Published: June 2022

Abstract
Loss of the von Hippel-Lindau (VHL) tumor suppressor gene function accounts for 70-80% of all clear-cell renal cell carcinoma (ccRCC) cases, the most prevalent form of RCC. Accumulating evidence has indicated that ccRCC arises at the site of chronic inflammation; however, how the ccRCC tumor cells interact with the immune components of the microenvironment has remained unclear. In this study we employed unbiased proteomic and genomic analyses on components of the tumor microenvironment under different conditions. We have identified the molecular and cellular mechanisms that underlie the crosstalk between VHL-deficient kidney tubule cells and macrophages with relevance to tumor-associated inflammation and ccRCC development. We demonstrate that the VHL-deficient non-cancerous kidney epithelial cells, representing the early stage of ccRCC initiation, secrete IL-6 that recruits macrophages and induces their polarization toward the pro-tumorigenic M2 phenotype in vitro and in the mouse Vhlh gene conditional knockout model. The activated human macrophages reciprocally secrete CCL18 and TGF-beta1 to stimulate epithelial-to-mesenchymal transition (EMT) of the kidney tubule cells. Importantly, treatment with anti-IL-6 neutralizing antibody can rescue inflammatory, proliferative, and EMT phenotypes of Vhlh conditional knockout in vivo. Furthermore, in a human ccRCC xenograft model, exogenous human macrophages can significantly promote primary tumor growth and metastasis; and this oncogenic function is dependent on the expression of CCL18. These findings identify specific factors involved in a reciprocal crosstalk between the tumor cells and the immune components such as macrophages in the microenvironment. These results thus suggest an avenue for early intervention of ccRCC.
Citation Format: Tien Hsu, Thi Ngoc Nguyen, Hieu-Huy Nguyen-Tran, Chen-Yun Chen. IL-6 and CCL18 mediate reciprocal interactions between VHL-deficient kidney cells and macrophages during development of ccRCC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB051.
Abstract LB059: Subtype classification of pediatric high-grade glioma tumors by comparative transcriptomics
Authors: Mawla Gina D. , Lyle A. Geoffrey , Kephart Ellen T. , Learned Katrina , Beale Holly C. , Goldford Joshua E. , Vaske Olena M. 
Published: June 2022

Abstract
Pediatric high-grade glioma (pHGG) is a highly malignant and poorly understood cancer driven by diverse genetic and epigenetic mechanisms. Here, we use comparative RNA sequencing, outlier analysis, and spectral clustering approaches to analyze transcriptomic data of 1,543 pediatric brain tumor specimens from the UCSC Treehouse Childhood Cancer Initiative (Treehouse) and Open Pediatric Brain Tumor Atlas (OpenPBTA) to identify subpopulations of pHGG patients with characteristic gene expression profiles. We find that approximately half (45%) of pHGG tumors from OpenPBTA exist in three subgroups defined by high outlier-level expression either of: mitochondrially-encoded 12S and 16S rRNAs; genes enriched in the HSF1-mediated heat shock response and activation pathways; or six C/D box snoRNA (SNORD) genes originating from the paternally-expressed SNORD116 locus involved in Prader-Willi syndrome, a complex neurodevelopmental disorder. Interestingly, the same set of HSF1-dependent pathway genes is also significantly upregulated in a subset (~11%) of pHGG tumors from Treehouse, validating this finding in two independent compendia with different transcript isolation strategies (Treehouse, polyA selection; OpenPBTA, ribodepletion). Our work identifies distinct classes of tumors with outlier-level expression of genes with previously unknown roles in pHGG and provides a framework for subtyping tumors by comparative transcriptomics that is adaptable to any cancer type. We are currently investigating the molecular roles of HSF1-response genes and the imprinted SNORD116 gene cluster in pHGG. Our ongoing research into the biomolecular signatures and mechanisms of the three major tumor classes of pHGG as defined in our study will contribute to a greater understanding of pHGG disease manifestation and progression, and will inform strategies of tailored therapeutic interventions for children with this devastating disease.
Citation Format: Gina D. Mawla, A. Geoffrey Lyle, Ellen T. Kephart, Katrina Learned, Holly C. Beale, Joshua E. Goldford, Olena M. Vaske. Subtype classification of pediatric high-grade glioma tumors by comparative transcriptomics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB059.
Abstract LB110: Twist pan-cancer synthetic reference materials for cell-free DNA (cfDNA) assay development
Authors: Cherry Patrick D. 
Published: June 2022

Abstract
Liquid biopsies hold great promise in reducing the burden of the disease of cancer on patients. Early detection of cancer via the cell free DNA represents the broadest vision and requires highly specificity. Ongoing disease monitoring is another important application of liquid biopsy and requires high sensitivity. Assay development requires analytical validation, and assays must be monitored for ongoing performance. These assays demand reference materials at specific variant allele frequencies for the assessment of specificity and sensitivity. Previously, obtaining reference materials was a laborious process of finding or engineering mutant cell lines. Here, we describe the design, manufacture, and quality control of a synthetic reference standard: the Twist Pan-Cancer Reference Standards, developed using Twist’s proprietary DNA printing platform to include a wide selection of both common and rare cancer targets for analytical validation. The reference material closely mimics the size distribution and content of cell-free DNA, with a primary peak at 167 bp and a secondary peak at 334 bp. The background cfDNA is derived from a single donor and highly characterized through NGS. The reference standard includes over 400 variant sites across 84 genes, including literature-curated, clinically-relevant variant sites. Additional panel-wide variants were included to aid in troubleshooting capture panels. The variant DNA is synthetically printed at 167 bp ± 5 bp and tiles over the site with extensive overlap, providing diversity of DNA termini relative to the position of the site of variation. Variant sites were printed and quantified independently so they can be pooled uniformly. NGS quality controls are implemented at multiple steps to ensure quality. The final products are available in a variant allele frequency (VAF) dilution series. The dilution series is quality controlled using droplet digital PCR (ddPCR) to ensure precision of variant allele frequencies. The Twist Pan Cancer Reference Standards provide a valuable solution for NGS-based assay developers seeking reference materials for a wide array of cancer variants, advancing adoption of liquid biopsy tests toward routine clinical practice.
Citation Format: Patrick D. Cherry. Twist pan-cancer synthetic reference materials for cell-free DNA (cfDNA) assay development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB110.