bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract IA06: Colon cancer: Microbes and communities in microbiome translation
Authors: Sears Cynthia L. 
Published: December 2020

Abstract
Intensive efforts are under way to understand how the colon microbiome contributes to the pathogenesis of colorectal cancer (CRC) and to determine if and how the microbiome can be utilized in the prevention and/or therapy of CRC. Both single microbes and microbial communities are proposed as contributors to human CRC. Among single microbes, attention to date has focused on enterotoxigenic Bacteroides fragilis (ETBF), (pks+) Escherichia coli, and Fusobacterium spp., although other candidates are emerging. Among communities, one aspect has been the potential contribution of mucus-invasive, dense mucosal microbial communities termed biofilms to CRC disease pathogenesis. This talk will review select concepts within ETBF’s and biofilm contribution to colon carcinogenesis. While ETBF exposure is common, the risk of colon carcinogenesis in an individual is unknown but potentially influenced by colonization state, B. fragilis toxin isotype secreted by ETBF, colon site, and the underlying genomic state of the colonic epithelial cells. With respect to colon biofilms, about 50% of human sporadic colon cancer, particularly in the right colon, display polymicrobial biofilms with marked tumor infiltration with bacteria whereas ~15% of normal colonoscopy biopsies also reveal polymicrobial biofilms. These polymicrobial biofilms are typically composed of Bacteroidetes and Lachnospiraceae with a subset of tumors, but not biopsies, also displaying Fusobacterium. Further, samples from biofilm-positive human colon cancers induce assembly of biofilms in the distal germ-free mouse colon within a week following inoculation and are procarcinogenic (JCI 129:1699, 2019). One of the common hereditary human colon cancers (familial adenomatous polyposis; APC+/−) also displays biofilms but dominated by two bacteria, (pks+) E. coli and ETBF. A mouse model of (pks+) E. coli and ETBF cocolonization exhibited accelerated tumor formation and mortality when cocolonized with the cancer-inducing bacteria, potentially by fostering increased microbial adherence, IL-17, changes in gene expression, and enhanced colonic epithelial cell DNA damage (Science 2018;359:592-97). Current directions of translational research will be presented.
Citation Format: Cynthia L. Sears. Colon cancer: Microbes and communities in microbiome translation [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 IA06.
Abstract IA07: The plasticity of the intestinal microbiota in colorectal cancer
Authors: Yang Ye , Gharaibeh Raad , Jobin Christian 
Published: December 2020

Abstract
Gene-environment interaction plays a key role in disease susceptibility, including colorectal cancer. Microbiota, particularly the intestinal bacteriome, plays a central role in host physiology, and the composition and activity of this consortium of microorganisms is directly influenced by known cancer risk factors such as lifestyle, diet, and inflammation. Accumulating evidence points to a role of microbiota in carcinogenesis. The mechanism by which microbiota impacts on cancer development is still unclear, but alteration in genomic stability (genetics and epigenetics) is considered a converging point. Inflammation represents a powerful condition by which microbial composition and biologic activities are altered. Using gnotobiotic technology, microbial genetic manipulation, genetically engineered mice (Apcmin/+; Il10-/-), and microbial genomics, we investigated the role of specific bacterial or consortium of bacteria in the development of colitis-associated colorectal cancer. In this lecture, I will provide evidence that specific microbial genotoxic activities originating from various strains such as Escherichia coli and Campylobacter jejuni promote development of CRC. For example, the presence of DNA-damaging toxins such as colibactin from adherent invasive Escherichia coli or cytolethal distending toxins (cdt) from Campylobacter jejuni is critical for development of colorectal cancer. I will address the relationship between inflammation and bacteria-induced carcinogenesis by studying the effect of neutralizing TNFa antibody, a biologic used to manage intestinal bowel disease, on microbial community activity. These studies represent the first step toward understanding mechanisms by which microbiota influences development of colorectal cancer, and shed light on how alteration of environmental factors modulates microbial carcinogenic potential.
Citation Format: Ye Yang, Raad Gharaibeh, Christian Jobin. The plasticity of the intestinal microbiota in colorectal cancer [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 IA07.
Abstract IA12: Fusobacterium persistence and antibiotic response in colorectal cancer
Authors: Bullman Susan 
Published: December 2020

Abstract
In colorectal cancer (CRC), malignant cells are surrounded by a complex microenvironment encompassing a range of nontransformed cells, but also a diverse collection of microorganisms. A growing body of evidence demonstrates the role of particular microorganisms in modulating inflammatory environments and promoting tumor growth and metastasis. Genomic analyses have consistently revealed an enrichment of the invasive bacterium Fusobacterium nucleatum in human colorectal tumors relative to noncancerous colorectal tissues. Exogenous F. nucleatum infection in animal and cellular models has also supported its cancer-promoting role. We demonstrate via microbiome analysis and microbial culture that Fusobacterium species and their co-occurring microbiota, including Bacteroides, Prevotella, and Selenomonas species, persist in liver metastasis of Fusobacterium-positive CRC. Many of the liver metastasis share the same dominant microbiome as the paired primary CRC tumors. Additionally, we have cultured Fusobacterium species from paired primary and metastatic tumors, and whole-genome sequencing analysis revealed that the same strains of Fusobacterium are present in the primary tumors and distant site metastasis, despite the tissue being resected months or even years apart. In situ hybridization analyses show that Fusobacterium is invasive in the primary tumors and distal metastasis and is associated with malignant cells. We demonstrate via microbiome analysis and microbial culture that Fusobacterium and its co-occurring microbiota also persist and remain viable in patient-derived xenografts of CRC for multiple generations in vivo. Antibiotic treatment of mice harboring these patient colon cancer xenografts led to a significant reduction in tumor Fusobacterium load, cancer cell proliferation, and overall tumor growth, suggesting that microbiome modulation could change the course of this disease. Ultimately, if a bacterial agent can directly or indirectly contribute to cancer initiation or progression, then these organisms are viable targets for cancer prevention and treatment.
Citation Format: Susan Bullman. Fusobacterium persistence and antibiotic response in colorectal cancer [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 IA12.
Abstract IA14: Characterizing the tumor microbiome and its effects on response to therapy
Authors: Straussman Ravid 
Published: December 2020

Abstract
The presence of bacteria in human solid tumors has been documented for over 100 years. Still, it is only in recent years that a more thorough characterization of this low-biomass microbiome has been pursued. In my lecture, I will describe our efforts to characterize the type of bacteria present across multiple human solid tumors as well as their intratumor location. I will also describe our efforts to study the effect that intratumor bacteria may have on different tumor phenotypes in general and on response to therapy in particular.
Citation Format: Ravid Straussman. Characterizing the tumor microbiome and its effects on response to therapy [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 IA14.
Abstract IA19: Fungal infection and carcinogenesis
Authors: Hu Yinling 
Published: December 2020

Abstract
Increased fungal infection has been reported in oral and esophageal squamous cell carcinomas (SCCs) derived from patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, immunodeficient patients, and non-autoimmune patients, as well as patients with other cancer types after radiation and chemotherapy. Thus, it is important to understand the role of increased fungal infection in tumor development. Our lab used several animal models to demonstrate that increased oral infection or colonization with Cladosporium cladosporioide (one of the most common fungi indoor and outdoor) or Candida albicans, which is one of the human commensal yeasts and opportunistic pathogens, promoted SCCs in the oral-esophageal-forestomach organs as well as distal cutaneous carcinogenesis. We revealed the mechanism underlying the relationship of increased fungal colonization with inflammatory pathways, epithelial cancer cell-oncogenic pathways, and bacteria during carcinogenesis. Those fungus-associated pathogenic phenotypes, inflammatory signaling, and epithelial oncogenic pathways observed in mice were also seen in human cancers. Based on these results in mice and human, we speculate that increased oral fungal colonization promotes human carcinogenesis.
Citation Format: Yinling Hu. Fungal infection and carcinogenesis [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 IA19.
Abstract PR02: A mutational signature in human colorectal cancer induced by genotoxic pks+ E. coli
Authors: Puschhof Jens , Pleguezuelos-Manzano Cayetano , Huber Axel Rosendahl , van Bostel Ruben , Clevers Hans 
Published: December 2020

Abstract
Various species of intestinal microbiota have been associated with the development of colorectal cancer (CRC), yet a direct role of bacteria in the occurrence of oncogenic mutations has not been established. Escherichia coli can carry the pathogenicity island pks within their genomes, which encodes a set of enzymes that synthesize colibactin. This compound can alkylate nascent DNA on adenine residues, and it has been shown to induce double-strand breaks in cultured cells. We hypothesized that pks+ E. coli are carcinogenic through the mutagenic action of colibactin. To test this, we exposed human intestinal organoids for 5 months to genotoxic pks+ Escherichia coli by repeated luminal injection. Whole-genome sequencing (WGS) of clonal organoids before and after exposure revealed a distinct and reproducible mutational signature, which was completely absent in organoids that were injected with isogenic pks-deficient bacteria. This signature encompasses a single base substitution trinucleotide signature (SBS-pks) with a marked transcriptional strand bias in line with damage on adenine residues, which was accompanied by a specific indel signature (ID-pks). Moreover, a distinct preference for the wider sequence context was detected, fitting a structural model of colibactin bound to DNA. This mutational signature was detected in three cohorts containing more than 6,000 human cancer genomes, and contribution of this signature could be detected in a subset of CRC genomes and more rarely in other cancer types. Finally, we identified driver genes harboring the colibactin target motif and could attribute driver mutations from CRC genomes to the signature. Our study describes a highly specific mutational cancer signature that reflects mutagenic activity of pks+ bacteria in the intestinal lumen, which can induce oncogenic mutations and could contribute to cancer initiation.
This abstract is also being presented as Poster A02.
Citation Format: Jens Puschhof, Cayetano Pleguezuelos-Manzano, Axel Rosendahl Huber, Ruben van Bostel, Hans Clevers. A mutational signature in human colorectal cancer induced by genotoxic pks+ E. coli [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 PR02.
Abstract PR05: Elucidating role of bacteria during pancreatic ductal adenocarcinoma (PDAC)
Authors: Chandra Vidhi , Le Roux Olivereen , Riquelme Erick , Zhang Yu , Maitra Anirban , White James. R , McAllister Florencia 
Published: December 2020

Abstract
Long-term survival in pancreatic cancer (PC) is rare as only a minority of all resected patients survive for &gt;5 years. Interestingly, somatic mutations do not predict long-term survivorship, highlighting the potential role of extrinsic factors. Recent studies have reported the role of the gut and tumor microbiome in pancreatic tumorigenesis and PC treatment responses. Since intratumoral bacteria have been detected in human PC tumors, possibly arising from relocation of intestinal bacteria, it is possible that intratumoral T cells get primed with microbial antigens within the tumor microenvironment. To reconstruct bacterial phylogenies, we performed prokaryotic 16S ribosomal RNA sequencing and immunoprofiling of PC tumors from “Long-Term Survivors-LTS” (&gt;5y post-resection) and “Short-Term Survivors-STS” (&lt;5y post-resection). Strikingly, we found that LTS from both discovery and validation cohorts had higher microbial diversity and LTS from both cohorts were enriched for a tumor microbial signature: Pseudoxanthomonas, Streptomyces, Saccharopolyspora, and Bacillus clausii. Moreover, the most overrepresented species in LTS tumors strongly correlated with enhanced immunoactivation of the tumor microenvironment, suggestive of bacterial-mediated immune cell recruitment and activation. Based on these findings, we hypothesized that gut bacteria affect PC by triggering immune responses either locally by migrating to the tumor or systemically through responses originating in the gut. To test this, we performed in vitro studies and found that single bacterial species identified from LTS tumor microbial signature can induce activation of cytotoxic T lymphocytes (CD8+ CD69+ IFNg+) only when in direct contact with antigen-presenting cells, suggesting that bacterial antigens need to be processed and presented to intratumoral T cells to induce their activation. Furthermore, through preliminary in vivo studies, we have found that orally administered single bacterial species can be delivered to the pancreas via the gut. Further work needs to determine whether single/specific LTS bacteria play a causative role in regulating tumor immunity in vivo. If the beneficial modulatory role of specific bacteria is established, then bacteriotherapy as single therapy or in combination with fecal microbial transplants could be used as innovative strategies for treatment of pancreatic cancer.
This abstract is also being presented as Poster B27.
Citation Format: Vidhi Chandra, Olivereen Le Roux, Erick Riquelme, Yu Zhang, Anirban Maitra, James. R White, Florencia McAllister. Elucidating role of bacteria during pancreatic ductal adenocarcinoma (PDAC) [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 PR05.
Abstract IA07: UVB-induced tumor heterogeneity directs immune response in melanoma
Authors: Bartok Osnat , Patkar Sushant , Cohen Sapir , Litchfield Kevin , Karathia Hiren , Lee Joo Sang , Jiménez-Sánchez Alejandro , Day Chi-Ping , Eisenbach Lea , Miller Martin , Merlino Glenn , Pikarsky Eli , Admon Arie , Swanton Charles , Ruppin Eytan , Samuels Yardena , Wolf Yochai 
Published: December 2020

Abstract
Little is known regarding the relationship between intra-tumor heterogeneity (ITH) and immune response in melanoma. Here, we explored the role of ITH in tumor rejection by establishing a melanoma mouse model and inducing UVB-derived mutations that increase both ITH and mutational load. This induction gives rise to highly aggressive tumors and decreased cytotoxic activity of tumor infiltrating lymphocytes (TILs). Conversely, single cell-derived melanoma clones with reduced ITH are swiftly rejected. Tumor rejection is accompanied by increased TIL reactivity and increased infiltration into the tumor core. Using phylogenetic tree analyses and mixing experiments of 20 single cell clones that lie along the phylogenetic tee we show that tumor rejection is strongly affected by number of injected clones and genetic diversity. We have, thus set up a novel, highly controlled system that enables us to study the interphase between the immune system and different layers of intra-tumor heterogeneity. Finally, the analysis of melanoma patient data identifies parallel observations, supporting the importance of ITH in determining patient survival and response to checkpoint blockade.
Citation Format: Osnat Bartok, Sushant Patkar, Sapir Cohen, Kevin Litchfield, Hiren Karathia, Joo Sang Lee, Alejandro Jiménez-Sánchez, Chi-Ping Day, Lea Eisenbach, Martin Miller, Glenn Merlino, Eli Pikarsky, Arie Admon, Charles Swanton, Eytan Ruppin, Yardena Samuels, Yochai Wolf. UVB-induced tumor heterogeneity directs immune response in melanoma [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 IA07.
Abstract IA10: Uncovering the ecology of glioblastoma with spatial digital profiling and single cell genotyping
Authors: Walentynowicz Kacper A. , Yadav Shreya , Vincentelli Cristina , Janiszewska Michalina 
Published: December 2020

Abstract
Glioblastoma (GBM) remains one of the biggest challenges in oncology, with median survival of ~15 months. Extreme heterogeneity of the GBM cells within each tumor results in resistance to most of the available therapies. Understanding the relationships between the heterogenous populations of GBM cells and the diverse niches they rely on is key to developing more effective treatment for this aggressive brain tumor. Analysis of the spatial localization of cells with different properties can shed light on their microenvironmental preferences, interactions and potential vulnerabilities. Therefore, we set out to profile 20 GBM cases using methods allowing for single-cell assessment of select genomic features and protein marker expression in intact tissue samples from each tumor. We constructed a tissue microarray (TMA), containing four distant areas from each tumor block to represent the intratumor heterogeneity within each tumor fragment. Based on multicolor immunofluorescent staining with markers of glial cells, immune cells and vasculature, we selected 96 regions of interest, which were then subject to digital spatial profiling for 90 protein markers associated with glioblastoma biology, neurobiology and immunology. Pearson’s correlation and Shannon index calculation based on our profiling results showed that majority of the regions cluster by their tumor of origin, however several highly diverse tumors were also identified. To link the diversity of the protein expression found with the digital spatial profiling with underlying genomic alterations, using the same TMA slide, we performed multiplexed fluorescence in situ hybridization for genes most frequently amplified in GBM. Automated quantification allowed us to collect information from 38,000 individual cells. Based on the presence or absence of the amplifications each cell was assigned a genotype. Since mutation in hTERT promoter has been reported as one of the drivers of GBM, we used STAR-FISH, an in situ single-cell mutation detection assay, to record the frequency and spatial localization of cells harboring this mutation on our TMA. Our datasets provide a unique opportunity to link single-cell genetic diversity to the phenotypic heterogeneity of the tumor cells and their microenvironment. Spatial localization of cells with distinct genotypes allows us to further dissect the interactions between the distinct subclones of GBM cells and uncover their novel dependencies.
Citation Format: Kacper A. Walentynowicz, Shreya Yadav, Cristina Vincentelli, Michalina Janiszewska. Uncovering the ecology of glioblastoma with spatial digital profiling and single cell genotyping [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 IA10.
Abstract IA14: Breast cancer evolution – Insights from single cell genomics
Authors: Navin Nicholas E. 
Published: December 2020

Abstract
In this talk I will discuss our efforts to develop and apply single cell genome sequencing methods to study premalignant breast cancer invasion, as well as our efforts to build an atlas of normal cell types in human breast tissues. To study invasion in 10 patients with ductal carcinomas in situ (DCIS) premalignancies we developed a Topographic Single Cell Sequencing (TSCS) method that has spatial resolution to measure genomic copy number profiles in patients with synchronous DCIS-IDC tissues. Our data revealed a multi-clonal invasion model, in which genome evolution occurred within the ducts leading to the generation of multiple clones that co-migrated across the basement membrane to establish the invasive carcinomas. Our group is leading a collaborative effort to establish a human breast atlas of normal tissues using single cell RNA sequencing of 30 women. These data have identified major cell types including epithelial cells (luminal HR+, luminal secretory, basal), fibroblasts, adipocytes and endothelial cells (vascular, lymphatic) as well as immune cells (lymphocytes, myeloid). For each cell type, we have identified multiple (2-5) expression states that correspond to different biological functions. Collectively these data provide a ‘human genome’ reference of normal cell types and cell states in the human breast tissues to understand how the stromal and immune microenvironment is reprogrammed in breast cancers.
Citation Format: Nicholas E. Navin. Breast cancer evolution – Insights from single cell genomics [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 IA14.
Abstract IA15: Inflammatory memory and tumorigenesis
Authors: Naik Shruti 
Published: December 2020

Abstract
Our body’s epithelia are barriers that interface with the terrestrial environment and routinely experience inflammation. Although a vast majority of these inflammatory reactions resolve, they imprint the tissue with a memory. Cells of the immune system are traditionally thought to be the bearers of this memory, allowing them to react faster to subsequent inflammatory pressures. Yet, barrier tissues are composites of epithelial, mesenchymal, nervous, vascular, and immunological networks working in unison to sustain optimal function. I discuss the enduring impact of inflammatory exposures on the skin epithelia and in particular on their long-lived stem cells, and the implications for such inflammatory training in tumor predisposition.
Citation Format: Shruti Naik. Inflammatory memory and tumorigenesis [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 IA15.