bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B21: The gastrointestinal microbiota controls cancer cell intrinsic mechanisms to promote the progression of acute lymphoblastic leukemia
Authors: Mahauad-Fernandez Wadie , Zlitni Soumaya , Bhatt Ami , Felsher Dean 
Published: December 2020

Abstract
Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer and the second most common acute leukemia in adults. Despite best existing therapy, older children and elderly ALL patients have poor prognoses. Thus, there is a need to identify alternative therapeutics for these patients. There has been controversy about the function of the gut microbiota in cancer, with some reports showing that it supports tumor growth and others showing tumor growth inhibition. Recently, Dr. Melvyn Greaves proposed that ALL development may have a microbial trigger; however, gut microbiota studies in ALL are scarce. Little is known about the role of the gut microbiota in ALL progression and in reshaping cancer cell-intrinsic pathways that are as important as immune responses in the outcome of ALL. Recently, we found that gut microbiota depletion in immunocompromised mice reduces ALL growth by inducing apoptosis and inhibiting proliferation. We show that in immunocompromised microbiome-depleted mice, the rate of ALL tumor growth is reduced compared to microbiome-competent mice. Molecularly, we found that microbiome ablation results in changes in cancer cell-intrinsic pathways of apoptosis and proliferation in these tumors. To further understand how the gut microbiota affects these cancer cell-intrinsic pathways, we have performed RNA sequencing on tumors from microbiome-competent and microbiome-depleted mice accompanied by 16s rRNA sequencing from stool samples and mass spectrometry of blood serum to identify metabolites secreted by the gut microbiota that reach the tumor site, affecting cancer cell growth. Our goal is to define bacterial species and metabolites involved in ALL progression and to mechanistically determine how these bacterial species and metabolites regulate ALL growth via regulation of cancer cell-intrinsic pathways. These data suggest that the gut microbiota may regulate ALL progression in an immune-independent manner via transcriptional changes of cancer cell-autonomous pathways. We envision that the gut microbiota can be reshaped in ALL patients who are elderly, chemo-refractive, and/or immunocompromised to alter cancer cell-intrinsic pathways to treat ALL. The clinical impact of these findings is significant given that ALL patients who are immunocompromised could still benefit from therapeutics aiming at modulating the gut microbiota.
Citation Format: Wadie Mahauad-Fernandez, Soumaya Zlitni, Ami Bhatt, Dean Felsher. The gastrointestinal microbiota controls cancer cell intrinsic mechanisms to promote the progression of acute lymphoblastic leukemia [abstract]. In: Proceedings of the AACR Special Conference on the Microbiome, Viruses, and Cancer; 2020 Feb 21-24; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2020;80(8 Suppl):Abstract nr B21.
Abstract B22: The human skin bacteria Staphylococcus epidermidis ameliorates UVB-induced free radicals through reduction of labile iron
Authors: Balasubramaniam Arun , Keshari Sunita , Adi Prakaso , Huang Chun-Ming 
Published: December 2020

Abstract
UVB-induced skin damage results in various inflammatory disorders through the induced generation of reactive oxygen species (ROS) that quickly inundate tissue antioxidants and chronic disorders; in severe cases it can lead to skin cancer. We investigated efficacies of human skin commensal bacteria S. epidermidis (ATCC12228) with glycerol, which on fermentation produces electrons. In vivo affirmation on ICR mice has confirmed the antioxidative role of topically applied S. epidermidis with glycerol against UVB irradiation and maintained sufficient expression of 4-hydroxynonenal (4-HNE) and cyclobutane pyrimidine dimer (CPD), a major biomarker for lipid peroxidation and DNA damage. Upon UVB irradiation in keratinocyte cell lines treated with glycerol mediated S. epidermidis fermentation product show the reduced intracellular oxidative stress. S. epidermidis or glycerol alone in In vivo topical application in mice skin and in vitro fermentation product treatment in keratinocytes does not influence the level of oxidative stress. Further electrochemical behavior of glycerol mediated S. epidermidis fermented medium found to produce electron transfer; this result suggests the electrogenic and antioxidant property of S. epidermidis. The electrons produced by S. epidermidis fermentation product initiate reduction of free radicals by converting toxic Fe3+ (ferric ion) back to nontoxic Fe2+ (ferrous ion); thereby it terminates Fenton’s reaction and maintains iron hemostasis. The novel pathway linking electrons produced by probiotic skin bacteria and iron metabolism has been further analyzed.
Note: This abstract was not presented at the conference.
Citation Format: Arun Balasubramaniam, Sunita Keshari, Prakaso Adi, Chun-Ming Huang. The human skin bacteria Staphylococcus epidermidis ameliorates UVB-induced free radicals through reduction of labile iron [abstract]. In: Proceedings of the AACR Special Conference on the Microbiome, Viruses, and Cancer; 2020 Feb 21-24; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2020;80(8 Suppl):Abstract nr B22.
Abstract B30: Intratumoral microbes correlate with tumor-infiltrating lymphocytes in lung cancer RNAseq
Authors: Spakowicz Daniel , Hoyd Rebecca , Liu YunZhou , Sahasrabudhe Janhavi , Singh Malvenderjit J. , Arefi Isaac , Denney Andrew , Carbone David , Mo Xiaokui 
Published: December 2020

Abstract
Nonhuman sequences have been found in many tumors, but their effect on outcomes remains poorly understood. We hypothesize that intratumoral microbes affect the recruitment of immune cells through local immunostimulatory effects including activation nucleic acid sensing pathways. We obtained RNA-seq data from 480 tumor biopsies including melanoma (16), bladder (104), colorectal (20), renal cell carcinoma (20), sarcoma (118), and lung (202) from patients treated at The Ohio State University Comprehensive Cancer Center as part of the Oncology Research Information Exchange Network (ORIEN). Reads were aligned to human and exogenous genomes using TopHat2 and Kraken2/Bracken, respectively. Human gene expression was deconvolved to absolute abundances of immune cells using CIBERSORT. An average of 99.87% of reads aligned to the human reference genome across all samples. Inferred counts of tumor-infiltrating lymphocytes (TILs), and particularly the immune cell types CD8+ T-cells and M1 macrophages, were significantly enriched in lung cancer relative to the other tested cancers (p-values &lt;0.0001). TILs significantly correlated with both RIG-I and cGAS expression (p-values &lt;0.0001). Exogenous reads aligned to 1328 genomes of bacteria, archaea, viruses, and fungi after filtering. The most abundant phyla within exogenous counts were the Proteobacteria (39.5%), Firmicutes (20.1%), and Actinobacteria (5.16%). Lung cancer samples showed positive correlations between Acinetobacter junii and CD8+ T-cells (p-value=0.035) and between Acidipropionibacterium virtanenii and activated NK cells (p-value=0.035). This suggests a mechanism by which intratumoral microbes may affect immune cell infiltration and cancer outcomes.
Citation Format: Daniel Spakowicz, Rebecca Hoyd, YunZhou Liu, Janhavi Sahasrabudhe, Malvenderjit J. Singh, Isaac Arefi, Andrew Denney, David Carbone, Xiaokui Mo. Intratumoral microbes correlate with tumor-infiltrating lymphocytes in lung cancer RNAseq [abstract]. In: Proceedings of the AACR Special Conference on the Microbiome, Viruses, and Cancer; 2020 Feb 21-24; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2020;80(8 Suppl):Abstract nr B30.
Abstract B31: Microbiota composition in bilateral healthy breast tissue and breast tumors
Authors: Klann Emily M. , Williamson Jessica M. , Tagliamonte Massimiliano S. , Ukhanova Maria , Asirvatham Jaya Ruth , Chim Harvey , Yaghjyan Lusine , Mai Volker 
Published: December 2020

Abstract
Purpose: The purpose of this pilot study was to assess the differences in breast tissue microbiota composition by breast side (left versus right) within an individual woman and compare the microbiota of healthy and breast tumor tissue between women. We further aimed to determine whether certain bacterial taxa may be associated with breast tumors.
Methods: Bilateral healthy breast tissue samples (n=36) were collected from ten women who received routine mammoplasty procedures at the University of Florida Department of Surgery. Archived breast tumor samples (n=10) were obtained from an established biorepository. Bacterial DNA was extracted from tissues, amplified via polymerase chain reaction (PCR), and sequenced on the Illumina MiSeq platform. Microbiota data were analyzed using QIIME and RStudio.
Results: The most abundant phyla in both tumor and healthy tissues were Bacteroidetes, Firmicutes, Proteobacteria, and Actinobacteria. A total of 38 operational taxonomic units (OTUs) were found to be significantly different in terms of differential abundance between tumor and healthy tissues (absolute effect size range: 0.761-3.98). The OTUs with the largest absolute effect size associated with higher relative abundance in breast tumors were of Flavobacterium species (R2=3.98), Acinetobacter species (R2=3.64), [Mogibacteriaceae] family (R2=3.34), and Clostridiales order (R2=3.21). Alpha diversity (Shannon Diversity Index) was similar in healthy and tumor tissue (4.98 vs. 4.84; p=0.350). Based on unweighted UniFrac measures, breast tumor samples clustered distinctly from healthy samples (R2=0.10; p=0.001). Microbiota composition in healthy samples clustered within women (R2=0.20; p=0.012) and by breast side (left or right) within a woman (R2=0.36; p=0.001).
Conclusion: We identified significant differences in microbiota composition between women and between breasts of the same woman. These results warrant further investigation to elucidate the potential relationship between breast tissue microbiota and breast cancer.
Citation Format: Emily M. Klann, Jessica M. Williamson, Massimiliano S. Tagliamonte, Maria Ukhanova, Jaya Ruth Asirvatham, Harvey Chim, Lusine Yaghjyan, Volker Mai. Microbiota composition in bilateral healthy breast tissue and breast tumors [abstract]. In: Proceedings of the AACR Special Conference on the Microbiome, Viruses, and Cancer; 2020 Feb 21-24; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2020;80(8 Suppl):Abstract nr B31.
Abstract IA10: Epigenetic remodeling of host metabolic pathways by Epstein-Barr virus (EBV) immortalization
Authors: Lamontagne Jason , Wiedmer Andreas , Lieberman Paul M. 
Published: December 2020

Abstract
Epstein-Barr virus (EBV) reprograms host metabolism and gene expression during B-cell immortalization through a highly orchestrated process. The regulatory mechanisms coordinating this reprogramming are not fully elucidated but reflect important events in viral oncogenesis. One clue to this coordinate regulation is provided by the viral-encoded tegument protein BNRF1 that functions in viral chromatin assembly during primary infection and shares extensive structural similarity to a purine biosynthetic enzyme FGARAT (also called PFAS). FGARAT shows strong evolutionary conservation from bacteria to human. Orthologues of BRNF1 are found in all gamma herpesviruses, including KSHV ORF75, and share the common function of disarming components of the PML-nuclear body (PML-NB) and its antiviral functions. We have previously shown that the BNRF1 interacts with the histone H3.3 chaperone DAXX and displaces its interaction with ATRX. ATRX is thought to target Daxx-H3.3 to GC-rich repetitive DNA to repress viral and host telomeric transcription. We found that the BNRF1-DAXX complex changes these functions to facilitate viral gene expression during primary infection, enabling the establishment of EBV latency. However, it is not yet known how the viral FGARAT homology is linked to cellular metabolism and purine biosynthesis. Using metabolomics mass spectrometry, we provide new data indicating that the metabolic pathways are among the most significantly perturbed by EBV during B-cell immortalization. Integrating gene expression (RNA-Seq), chromatin accessibility (ATAC-Seq), and EBV transcription factor binding (ChIP-Seq) we identified several cellular metabolic genes, including adenine deaminase (ADA) and arginosuccinate synthase (ASS1), as a direct target of EBV transcriptional regulation during EBV immortalization. We find that EBV nuclear antigen EBNA1 binds directly to the ADA transcriptional regulatory regions and induces epigenetic changes at this locus. Failure to activate ADA compromises B-cell immortalization. The relationship between BNRF1, EBNA1, and nucleotide metabolism during EBV immortalization will be discussed. These findings suggest that EBV captured a highly conserved purine biosynthetic enzyme to coordinate epigenetic reprogramming with nucleotide metabolism during EBV induced B-cell immortalization.
Citation Format: Jason Lamontagne, Andreas Wiedmer, Paul M. Lieberman. Epigenetic remodeling of host metabolic pathways by Epstein-Barr virus (EBV) immortalization [abstract]. In: Proceedings of the AACR Special Conference on the Microbiome, Viruses, and Cancer; 2020 Feb 21-24; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2020;80(8 Suppl):Abstract nr IA10.
Abstract IA24: Engineered Salmonella for drug delivery to solid tumors
Authors: Forbes Neil S. 
Published: December 2020

Abstract
Engineered bacteria have the potential to overcome the limitations that cause cancer therapies to fail. We are engineering bacteria to deliver therapeutic payloads and quantifying the mechanisms that control bacterial therapy. We have shown that bacteria preferentially target tumors and actively penetrate tissue. Bacterial motility has a linear relationship with colonization density. Manipulating chemoreceptors in the membrane can direct bacteria to drug-resistant tumor regions, and inducing inflammation can promote colonization by modifying tumor vasculature. When engineered to express α-hemolysin from Staphylococcus aureus, bacteria kill 99% of culture cells in 5 minutes and reduce tumor volume in mice. Engineering Salmonella with quorum-sensing provides a density-dependent switch that induces protein expression only after bacteria have colonized tumor tissue. This technique prevents system toxicity after delivery of therapeutic molecules. We have also developed bacteria that selectively invade cancer cells and release molecules that modulate epigenetic targets, e.g., EZH2 and PP1. Salmonella were engineered with a genetic cassette that induces lysis specifically after invasion into mammalian cells. Lysis releases the bacterial content into the cytoplasm of cells. In culture, Salmonella lyse inside cancer cells and release GFP, which diffuses throughout the cellular cytoplasm. Releasing a peptide that interferes with the binding of the phosphatase, PP1, with its regulator, NIPP1, induces cell death after bacterial lysis. In three-dimensional tissue culture, administration of these bacteria induces cell death. These techniques establish Salmonella as a tunable platform for cancer therapy. By understanding the mechanisms of bacterial delivery, new strategies will be developed to treat hard-to-treat cancers.
Citation Format: Neil S. Forbes. Engineered Salmonella for drug delivery to solid tumors [abstract]. In: Proceedings of the AACR Special Conference on the Microbiome, Viruses, and Cancer; 2020 Feb 21-24; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2020;80(8 Suppl):Abstract nr IA24.
Abstract IA01: Single cell analysis of CRISPR T cells
Authors: Stadtmauer Edward , Fraietta Joseph , Satpathy Ansuman , June Carl H. 
Published: December 2020

Abstract
CRISPR-Cas9 gene editing provides a powerful tool to enhance the natural ability of human T cells to fight cancer. We report a first-in-human phase 1 clinical trial to test the safety and feasibility of multiplex CRISPR-Cas9 editing to engineer T cells in three patients with refractory cancer. Two genes encoding the endogenous T cell receptor (TCR) chains, TCRα (TRAC) and TCRβ (TRBC), were deleted in T cells to reduce TCR mispairing and to enhance the expression of a synthetic, cancer-specific TCR transgene (NY-ESO-1). Removal of a third gene encoding programmed cell death protein 1 (PD-1; PDCD1), was performed to improve antitumor immunity. Adoptive transfer of engineered T cells into patients resulted in durable engraftment with edits at all three genomic loci. Although chromosomal translocations were detected, the frequency decreased over time. Modified T cells persisted for up to 9 months, suggesting that immunogenicity is minimal under these conditions and demonstrating the feasibility of CRISPR gene editing for cancer immunotherapy.
Citation Format: Edward Stadtmauer, Joseph Fraietta, Ansuman Satpathy, Carl H. June. Single cell analysis of CRISPR T cells [abstract]. In: Proceedings of the AACR Virtual Special Conference on Tumor Heterogeneity: From Single Cells to Clinical Impact; 2020 Sep 17-18. Philadelphia (PA): AACR; Cancer Res 2020;80(21 Suppl):Abstract nr IA01.
Abstract IA02: Slide-seq: A platform for understanding cellular circuits in tissue
Authors: Chen Fei 
Published: December 2020

Abstract
The precise spatial localization of molecular signals within tissues richly informs the mechanisms of tissue formation and function. Here we introduce Slide-seq, a technology which enables transcriptome-wide measurements with near-single cell spatial resolution. We’ll describe recent experimental and computational advances to enable Slide-seq in biological contexts in biological contexts where high detection sensitivity is important. More broadly, we’ll discuss the promise and challenges of spatial transcriptomics for tissue genomics.
Citation Format: Fei Chen. Slide-seq: A platform for understanding cellular circuits in tissue [abstract]. In: Proceedings of the AACR Virtual Special Conference on Tumor Heterogeneity: From Single Cells to Clinical Impact; 2020 Sep 17-18. Philadelphia (PA): AACR; Cancer Res 2020;80(21 Suppl):Abstract nr IA02.
Abstract IA08: Tracking the impact of tumor mutations in the T cell differentiation landscape of lung cancer
Authors: Quezada Sergio A. 
Published: December 2020

Abstract
Tumour mutational burden (TMB) predicts immunotherapy outcome in non-small cell lung cancer (NSCLC), consistent with immune recognition of tumour neoantigens. However, persistent antigen exposure is detrimental for T cell function. How TMB affects CD4 and CD8 T cell differentiation in untreated tumours and whether this affects patient outcomes is unknown. Here, we paired high-dimensional flow cytometry, exome, single-cell and bulk RNA sequencing from patients with resected, untreated NSCLC to examine these relationships. TMB was associated with compartment-wide T cell differentiation skewing, characterized by loss of TCF7-expressing progenitor-like CD4 T cells, and an increased abundance of dysfunctional CD8 and CD4 T cell subsets with strong phenotypic and transcriptional similarity to neoantigen-reactive CD8 T cells. A gene signature of redistribution from progenitor-like to dysfunctional states was associated with poor survival in lung and other cancer cohorts. Single-cell characterization of these populations informs potential strategies for therapeutic manipulation in NSCLC.
Citation Format: Sergio A. Quezada. Tracking the impact of tumor mutations in the T cell differentiation landscape of lung cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Tumor Heterogeneity: From Single Cells to Clinical Impact; 2020 Sep 17-18. Philadelphia (PA): AACR; Cancer Res 2020;80(21 Suppl):Abstract nr IA08.
Abstract IA16: Cancer evolution, immune evasion and metastasis
Authors: Swanton Charles 
Published: December 2020

Abstract
Increasing evidence supports complex subclonal relationships in solid tumours, manifested as intratumour heterogeneity. Parallel evolution of subclones, with distinct somatic events occurring in the same gene, signal transduction pathway or protein complex, suggests constraints to tumour evolution that might be therapeutically exploitable. Data from TRACERx, a longitudinal lung cancer evolution study will be presented. Drivers of tumour heterogeneity change during the disease course and contribute to the temporally distinct origins of lung cancer driver events. APOBEC driven mutagenesis appears to be enriched in subclones in multiple tumour types. Oncogene, tumour suppressor gene and drug induced DNA replication stress are found to drive APOBEC mutagenesis. Phylogenetic tracking detects minimal residual disease and clonal evolution of disease from primary to metastatic sites, presenting opportunities for drug development. On-going chromosomal instability, manifested as Mirrored Subclonal Allelic Imbalance (MSAI) is found to be a major driver of intratumour heterogeneity across cancer types, contributing to parallel evolution and selection. The finding of subclonal driver events, evidence of ongoing selection within subclones, combined with genome instability driving cell-to-cell variation is likely to limit the efficacy of targeted monotherapies, suggesting the need for new approaches to drug development and clinical trial design and integration of cancer immunotherapeutic approaches. Multiple adaptive mechanisms to neo-antigen evolution have been found in TRACERx that emphasise the role of cancer chromosomal instability driving immune evasion and HLA/MHC loss and loss of clonal neo-antigens as well as epigenetic repression of neo-antigens. The clonal neo-antigenic architecture may act as a tumour vulnerability, targeting multiple clonal neo-antigens present in each tumour to mitigate resistance and treatment failure.
Citation Format: Charles Swanton. Cancer evolution, immune evasion and metastasis [abstract]. In: Proceedings of the AACR Virtual Special Conference on Tumor Heterogeneity: From Single Cells to Clinical Impact; 2020 Sep 17-18. Philadelphia (PA): AACR; Cancer Res 2020;80(21 Suppl):Abstract nr IA16.
Abstract IA22: Single cell proteomics to capture human dysplasia and dysfunction
Authors: Bendall Sean 
Published: December 2020

Abstract
Single cell analysis, starting with the earliest low parameter fluorescent cytometry and microscopy experiments, helped define the major cell subsets of human cellular systems as we understand them today. Now, a novel combination of elemental mass spectrometry with single cell analysis (mass cytometry – CyTOF, Science 2011) and imaging (multiplexed ionbeam imaging – MIBI, Nature Med. 2014, Cell 2018) offers routine examination of &gt;50 parameters without fluorescent agents or interference from spectral overlap using heavy metal isotopes as reporters. With these platforms, we have reached new levels of organizational understanding in human pathobiology. Here, we will review the evolution of these technologies and present our latest efforts to create assays with these platforms in order to quantify multiple levels of regulation including metabolism, proteome dynamics, and chromatin content regulating the epigenome. Further to this, we will highlight recent efforts to leverage structural characteristics of leukemia dysplasias to facilitate automated identification and classification from multiplexed single cell datasets (Tsai & Glass et al. Nature Med. 2020). Overall, these new approaches can reveal new layers of human cellular organization and structure that can be exploited to understand dysfunction in general and provide avenues for more automated and robust clinical classification.
Citation Format: Sean Bendall. Single cell proteomics to capture human dysplasia and dysfunction [abstract]. In: Proceedings of the AACR Virtual Special Conference on Tumor Heterogeneity: From Single Cells to Clinical Impact; 2020 Sep 17-18. Philadelphia (PA): AACR; Cancer Res 2020;80(21 Suppl):Abstract nr IA22.