bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract IA022: Aberrant transcriptional condensates in cancer: Mechanisms and implications
Authors: Wan Liling 
Published: December 2022

Abstract
While growing evidence suggests the prevalence of nanoscale protein condensates on chromatin, their mechanisms of formation and functional significance in normal and disease states remain largely unclear. I will present our ongoing work linking aberrant condensates and cancer. In Wilms tumor and leukemia, a series of mutations in the histone acetylation reader ENL create gain-of-function mutants with increased transcriptional activation activity. We discover that these mutations, clustered in ENL’s structured acetyl-binding YEATS domain, trigger aberrant condensates at endogenous genomic targets through a network of multivalent homotypic and heterotypic interactions. Crystal structures of four different ENL mutant YEATS domains reveal structural changes critical for condensate formation. In addition, two oppositely charged disordered regions in ENL mutants play distinct yet complementary roles in regulating the initiation and growth of condensates. ENL mutant condensates enrich for an aberrantly high amount of transcription elongation factors which, in turn, also contribute to condensate formation. Importantly, perturbing these condensates in situ via extensive mutagenesis establish their causal role in oncogenic gene activation. Interestingly, expression of ENL mutants beyond endogenous levels results in larger droplet-like condensates that suppress oncogenic gene activation, indicating a dosage-sensitive function of oncogenic proteins prone to condensation. Together, by elucidating how cancer-associated transcriptional condensates occur and function, our work reveals a poorly recognized role of structured domains in the formation of biomolecular condensates and lends crucial experimental support to establish condensate dysregulation as an under-appreciated oncogenic mechanism. These insights would open new areas of investigation and nominate novel therapeutic approaches.
Citation Format: Liling Wan. Aberrant transcriptional condensates in cancer: Mechanisms and implications. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr IA022.
Abstract PR005: Targeting EP300 and CBP for therapeutic benefit in pediatric solid tumors
Authors: Durbin Adam D. , Shendy Noha , Mercier Audrey , Zhang Yang , Bikowitz Melissa J. , Sigua Logan H. , Robinson Sarah , Wang Tingjian , Jonchere Barbara , Look A. Thomas , Zimmerman Mark W. , Roussel Martine , Abraham Brian J. , Schonbrunn Ernst , Stegmaier Kimberly , Qi Jun 
Published: December 2022

Abstract
Gene expression is regulated by promoters and enhancers marked by histone H3 lysine 27 acetylation (H3K27ac), which is established by the paralogous, multidomain-containing histone acetyltransferases (HAT) EP300 and CBP. These enzymes display overlapping regulatory roles in untransformed cells, but less characterized roles in cancer cells. We demonstrate that the majority of high-risk pediatric neuroblastoma (NB) depends on EP300, whereas CBP has a limited role. To disrupt EP300, we developed a proteolysis-targeting chimera (PROTAC) compound termed “JQAD1” that selectively targets EP300 for degradation. JQAD1 treatment causes loss of H3K27ac at the enhancers that regulate NB master transcription factors, and drives rapid NB apoptosis, with limited toxicity to untransformed cells where CBP may compensate. In parallel, we demonstrate that EP300 and CBP have subdomain-specific functions, with enriched activity for individual domains in distinct tumor lineages. These data provide a foundation for interrogation of these histone acetyltransferases in distinct tumor types and new strategies for therapeutic disruption of subdomain and scaffolding activities of these multidomain proteins in cancer.
Citation Format: Adam D. Durbin, Noha Shendy, Audrey Mercier, Yang Zhang, Melissa J. Bikowitz, Logan H. Sigua, Sarah Robinson, Tingjian Wang, Barbara Jonchere, A. Thomas Look, Mark W. Zimmerman, Martine Roussel, Brian J. Abraham, Ernst Schonbrunn, Kimberly Stegmaier, Jun Qi. Targeting EP300 and CBP for therapeutic benefit in pediatric solid tumors. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr PR005.
Abstract A014: Identifying and overcoming resistance to RAS targeted therapy in colorectal cancer
Authors: Parsons Marie J. , Zafra Maria , Goswami Sukanya , Fernandez Maria Teresa Calvo , Wilkinson John E. , Dow Lukas E. 
Published: December 2022

Abstract
KRAS is the most frequently mutated oncogene in human cancer and a potent oncogenic driver. In colorectal cancer (CRC), pathogenic KRAS mutations are observed in up to 50% of cases, yet there is little understanding of how distinct mutations dictate tumor biology including initiation, progression and therapy response. The recent approval of targeted KRASG12C inhibitors brings promise to transform the therapeutic landscape for many patients who lack effective, personalized treatment. Clinically acquired resistance is already observed, highlighting the need to identify mechanisms of resistance and approaches to overcome them. The aim of this study is to understand how distinct Kras alterations drive tumorigenesis and identify reasons underlying the failure of KRAS inhibitors in CRC. To explore the clinical significance of distinct KRAS mutations in tumor development and therapy response, we used Cre- conditional (Lox- stop- Lox) Kras mutant mouse strains crossed to the colon specific promoter Fabp1-Cre and Apc(flox/flox) mice. In the absence of Apc, we demonstrated that distinct Kras mutations G12C and G13D drive unique phenotypes in the colon which demonstrates that subtle mutational changes can dramatically alter the physiological response in vivo, and make distinct KRAS alleles an attractive target for targeted therapeutics. In tumor bearing models of CRC, we observed that KrasG12D drives large numbers of smaller tumors, while KrasG13D drives smaller numbers of larger tumors. To investigate the differences observed in tumorigenesis, we are studying the potential role of Kras to prime the colon for APC loss and the consequences of Kras alterations on the stem cell dynamics in driving tumorigenesis. Further, we employed our unique LSL-Kras mutant mouse strains and colon derived organoids to assess the therapeutic response of G12C and pan Kras inhibitors alone or in combination with upstream target drugs including inhibitors targeting EGFR signaling (EGFR, SHP2, SOS1 and MEK) and the Wnt signaling pathway. Together, this work has identified that distinct mutations in KRAS creates colon cancer specific vulnerabilities which dictates tumor biology. The unique in vivo and ex vivo organoid models provide an ideal platform to identify the underlying cause of failure of G12C inhibitors and developing effective approaches to target RAS in CRC.
Citation Format: Marie J. Parsons, Maria Zafra, Sukanya Goswami, Maria Teresa Calvo Fernandez, John E. Wilkinson, Lukas E. Dow. Identifying and overcoming resistance to RAS targeted therapy in colorectal cancer [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr A014.
Abstract A034: Cancer and immunology: The homeostasis dance
Authors: Ekine-Afolabi Bene Akromaa 
Published: December 2022

Abstract
The human body is made up of not only tissues and blood, but also present are microbiota on surfaces of the skin, mucosal membrane of the intestine, urogenital, lungs, and mouth, to form ecological niches. Some of these niches have been well studied, while some are yet to be elucidated due to the unknown presence of these microbiota in such system. T cell response by immune system is one step of the cancer-immunity cycle, that maintains the prevention of autoimmunity. Cancer cells have T cell inhibitory signals including PD-L1 which have been identified for the development of new immunotherapy that are specifically responsible for hindering immune effector inhibition, thereby reinvigorating, and enhancing pre-existing anticancer immune response. Previous activity in immune therapies have always considered suppressive factors in the tumor microenvironment without consideration to other factors such as the genetic basis of the immune system. Attention to the immune system has always been on the response to the pathogens, or the threatening foreign target, but not on the genes responsible for regulating the immune system. The immune system is a concert of interactions between existing microbes and host. One of the major tools of cellular interaction is epigenetics. Epigenetic information regulates differentiation and development, thus can impact on pathological condition. Therefore, epigenetics interaction between microbes and host is vital in cancer development and treatment. Diagnostic and prognosis will be impacted by the understanding of the interactions between microbes and host, thereby informing on precision medicine.
Citation Format: Bene Akromaa Ekine-Afolabi. Cancer and immunology: The homeostasis dance [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr A034.
Abstract B003: Cross-reacting antigens between the intestinal microbiome and tumor neoantigen are associated with immune checkpoint inhibitor response in a gastrointestinal tumor cohort
Authors: Poudel Ravin , Dai Die , Li Fang , Yin Xiaochen , Kou Yan , Gomes Antonio L. C. 
Published: December 2022

Abstract
Background: Immune checkpoint inhibitor (ICI) is a revolutionary therapy that promotes the activation of effector T cells against tumors. Despite the potential for long-term benefit, a large proportion of patients does not respond to ICI therapy. One reason for this heterogenic response is due to the high variability in the intestinal microbiota among different patients. The abundance of certain bacteria has been associated with different responses and fecal meta transplant from responding donors was shown to rescue a beneficial phenotype in refractory patients. The presence of cross-reactive antigens (CRAgs) between the gut microbiome and tumor neoantigens has been proposed as a potential mechanism that could link the intestinal microbiota with ICI response. However, empirical evidence of CRAg’s role in ICI therapy is limited to a few studies. Methods: We investigated ICI response in a cohort of 22 stage IV gastrointestinal (GI) tumor patients in which whole-exome and gut metagenomic sequencing data were available. This cohort included patients with gastric cancer (n=11), esophageal carcinoma (n=6), and colon cancer (n=5). For each patient, we characterized the tumor neoantigen load based on epitopes that show high affinity and presentability in HLA molecules. Neoantigens were matched to the intestinal microbiome to identify corresponding CRAgs. CRAg quality, which ranks CRAgs according to their immunogenic potential, was defined based on matches in immunogenic protein or epitope databases. Results: We found the total number of CRAgs varied per tumor type, with a higher abundance in colon cancer (median µ=619) followed by esophageal (µ =287.5) and gastric (µ = 243). Interestingly, colon cancer patients showed a better progression-free survival (PFS) curve followed by esophageal and gastric cancer patients, respectively. We also observed that CRAg load was better associated with longer PFS (p=.03) than neoantigen load (p=0.07). Moreover, CRAg’s quality showed to be an important predictor of PFS. Patients with a high proportion of CRAgs matching at least one of the quality databases showed better PFS (p=0.02). Further, a taxa-specific analysis indicated that commensal CRAgs load was a better predictor of PFS (p&lt;0.008) than relative abundance. Altogether, our work supports a mechanistic link between the microbiome, neoantigens, and immuno-therapy.
Citation Format: Ravin Poudel, Die Dai, Fang Li, Xiaochen Yin, Yan Kou, Antonio L. C. Gomes. Cross-reacting antigens between the intestinal microbiome and tumor neoantigen are associated with immune checkpoint inhibitor response in a gastrointestinal tumor cohort [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr B003.
Abstract B032: Native sgRNA capture and sequencing (NSC-seq) reveals tumor formation in ApcMin/+ mice and in human colorectal cancer is an oligoclonal process
Authors: Islam Mirazul , Yang Yilin , Shah Vishal M. , Simmons Alan J. , Xu Yanwen , Coffey Robert J. , Lau Ken S. 
Published: December 2022

Abstract
CRISPR-Cas9-based technologies have been developed to address a wide range of biological questions, including molecular recording of embryonic development, genetic screening, and tracking tumor evolution at the single-cell resolution. We developed a single-cell lineage tracking platform called native sgRNA Capture and sequencing (NSC-seq) to leverage CRISPR technology for clonal analysis of intestinal tumors in the ApcMin/+ mouse model. We combined CRISPR-induced mutations with spontaneously accumulating mitochondrial variants to enable highly efficient lineage-tracking of single cells. We generated lineage-tracked ApcMin/+ tumors and found that there are more than two independently arising clones within a tumor. We also found oligoclonal tumors within human colorectal specimens using this technology, supporting the oligoclonality of intestinal tumor development across species. Finally, we demonstrated the application of this technology in understanding the rate of loss-of-heterozygosity events in Apc as related to the cellular turnover rates of different intestinal regions. Overall, NSC-seq enables in vivo molecular recording of spontaneous intestinal tumor development at single-cell resolution.
Citation Format: Mirazul Islam, Yilin Yang, Vishal M. Shah, Alan J. Simmons, Yanwen Xu, Robert J. Coffey, Ken S. Lau. Native sgRNA capture and sequencing (NSC-seq) reveals tumor formation in ApcMin/+ mice and in human colorectal cancer is an oligoclonal process [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr B032.
Abstract IA018: Microbiome and intestinal barriers in colon cancer
Authors: Sun Jun , Zhang Jilei , Xia Yinglin , Zhang Yong-Guo 
Published: December 2022

Abstract
Multiple factors (e.g., risk genes, environmental triggers, immunity, and microbiome) contribute to the pathogenesis of colorectal cancer (CRC). The intestinal dysbiosis and disruption of barrier function are common manifestations of CRC. Vitamin D/Vitamin D receptor (VDR) is known to protects against dysbiosis and tumorigenesis. Considering the multiple functional roles of VDR in the development of cancer, it is important to dissect the mechanisms by which host factors contribute to the intestinal barrier function in protecting cells from tumorigenesis. Here, we reported that in human tissue, reduced VDR in the colon of CRC patients is associated with the reduced intestinal barrier and enhanced bacterial translocation to tumors. VDR deficiency in the intestinal epithelial cells led to the reduced thickness of mucus layer and enhanced penetration of microbiota into the epithelial cells. VDR was a transcriptional factor regulating the genes of some tight junction (TJ) Claudins. The positively correlated status of VDR and Claudins (e.g., Claudin- 5 and10) contribute to the altered intestinal permeability in tumorigenesis. In the intestinal epithelial VDR conditionally knockout VDR∆IEC mice and myeloid VDR deletion mice, dysbiosis and inflammatory cytokines in the VDR deficient context further altered TJ proteins and manipulated the barrier functions in the development of colon cancer. Furthermore, we found that mice with colonic adenomatous polyposis coli (APC) mutation reduced thickness of mucus layer and enhanced penetration of microbiota into the epithelial cells, thus enhancing tumorigenesis in the colon. Studies on host factor regulation of microbiome and barriers could be potentially applied to risk assessment, early detection, and prevention of colon cancer. These studies will provide an additional avenue to restore microbiome and barrier functions for risk assessment and prevention of CRC and other cancers.
Citation Format: Jun Sun, Jilei Zhang, Yinglin Xia, Yong-Guo Zhang. Microbiome and intestinal barriers in colon cancer [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr IA018.
Abstract IA025: Stem and metaplastic cell states and their influences on the tumor immune microenvironment in colonic pre-cancerous lesions
Authors: Lau Ken S. 
Published: December 2022

Abstract
The immune microenvironment is critical to colorectal cancer (CRC) pathogenesis, regarding both prognosis and therapeutic responses. While much work has been done to characterize tumor microenvironments, less is known about those environments are established following transformation of epithelial cells. We hypothesize that mapping routes towards CRCs, from normal human colonic tissues and precursor polyps, will uncover additional mechanisms that define the CRC cellular landscape and identify targets with diagnostic or therapeutic utility. Here, we present a comparative atlas of the two most common colorectal precursor lesions, conventional adenomas and serrated polyps, and their resulting CRC counterparts using single-cell transcriptomics and multiplex imaging across two cohorts of human participants. Integrative analysis reveals adenomas arise from dysregulated WNT-driven expansion of stem cells, while serrated polyps are depleted of stem cell populations and are derived from differentiated cells transitioning through a pyloric metaplasia program. Mucosal damage associated with metaplasia is coupled to a cytotoxic immune microenvironment that precedes hypermutation. Mouse and organoid experiments validate the importance of the differentiation states of colonic tumor cells in driving cytotoxic immunity partly through increased expression of antigen-presentation machinery. These data provide constitute a rich resource into malignant progression of colorectal polyps and their microenvironments, serving as a framework for precision surveillance and prevention of CRC.
Citation Format: Ken S. Lau. Stem and metaplastic cell states and their influences on the tumor immune microenvironment in colonic pre-cancerous lesions [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr IA025.
Abstract IA027: Recent advances in the study of extracellular vesicles and nanoparticles in colorectal cancer
Authors: Coffey Robert J. 
Published: December 2022

Abstract
Extracellular vesicles (EVs) and nanoparticles (NPs) are increasingly recognized as important mediators of intercellular communication with implications for the diagnosis, monitoring and possibly treatment of colorectal cancer. We recently reviewed this topic in Gastroenterology. EVs are lipid bilayer-enclosed vesicles that can be classified as small (s) some of which are tetraspanin-containing, endosomally-derived exosomes (5-120 nm) and large that include plasma membrane-budding microvescles (150-800 nm). Nanoparticles are more recently discovered smaller amembranous nanoparticles that include exomeres (30-50 nm) and supermeres (25-35 nm). We have performed a comprehensive proteomic and RNA analysis of sEVs, exomeres and supermeres. Highlights from this analysis will be presented with a focus on their clinical relevance and the merits of parsing versus pooling biofluid fractions.
Citation Format: Robert J. Coffey. Recent advances in the study of extracellular vesicles and nanoparticles in colorectal cancer [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr IA027.
Abstract PR001: The use of risk prediction for patients with abnormal fecal testing (FIT) to prioritize patient navigation
Authors: Petrik Amanda F. 
Published: December 2022

Abstract
Context: “Precision delivery involves using an individual’s electronic health data to predict risk and personalize care to substantially improve value” (Parikh). Rates of completion of the follow-up colonoscopy following an abnormal FIT are low in community clinics. Tools like predictive analytics can be used for population management and more precise delivery of care to those who need it the most. Objective: We describe 3 studies use of predictive analytics after abnormal FIT testing to prioritize patient navigation to complete subsequent colonoscopies. Study design and analysis: The Strategies and Opportunities to Prevent Colorectal Cancer (STOP CRC) trial developed an initial risk prediction model identifying patients unlikely to complete a follow-up colonoscopy on their own. Kaiser Permanente Northwest (KPNW) then redeveloped the model for use with Navigation. The Predicting and Addressing Colonoscopy Non-adherence in Community Settings (PRECISE) study then redeveloped the model for use with Navigation in a large Federally Qualified Health Center (FQHC). Results: The STOP CRC model included 8 variables, 1596 patients had an abnormal FIT result, 34.8% had a recorded colonoscopy within 6 months. The model shows an adequate separation of patients across risk levels for non-adherence to follow-up colonoscopy (bootstrap-corrected C-statistic &gt; 0.63). The KPNW model included 14 variables, and the performance of the model was adequate with a bootstrap corrected C-statistic of 0.65. The PRECISE model included 12 variables and a bootstrap corrected C-statistic of 0.58. Here we will describe each of the models and the differences in the application of the models. Conclusions: Risk prediction can be used to identify patients unlikely to complete colonoscopies, and as a population management tool to tailor interventions to specific populations. Tailoring interventions can save money, and increase patient satisfaction.
Citation Format: Amanda F. Petrik. The use of risk prediction for patients with abnormal fecal testing (FIT) to prioritize patient navigation [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr PR001.