bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3022: Tryptophan metabolism is associated with obesity and triple negative breast cancer risk in black and white women
Authors: Smith Alana , Gu Qingqing , Amos-Abanyie Ernestine Kubi , Tolley Elizabeth , Lu Lu , Lyn-Cook Beverly , Starlard-Davenport Athena 
Published: June 2022

Abstract
Non-Hispanic black (NHB) women are more likely to be diagnosed and die from triple negative breast cancer (TNBC) than non-Hispanic white (NHW) women. We previously showed that TNBC tissues display a distinct microbial signature. Obesity which contributes to chronic low-grade inflammation and gut microbial dysbiosis further exacerbates TNBC outcomes for NHB women. However, it is unclear the extent to which microbial differences in breast tumor tissues may be driven by alterations in microbial metabolites as a result of obesity status. Therefore, the aim of this global metabolomic profiling study was to investigate alterations in microbial metabolism pathways in breast tissues of NHB and NHW obese women (avg. BMI = 35.7) relative to non-obese women (avg. BMI = 23.4) with and without TNBC. In this study, we analyzed 984 metabolites derived from a total of 51 NHB and NHW women, including 15 patients with TNBC, 12 patients with less aggressive Luminal A-type breast cancer, and 24 healthy controls for comparison using ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) to identify microbial metabolites and metabolomic signatures that differ by breast tumor subtype and obesity status. We detected 501 significantly increased metabolites and 33 significantly decreased metabolites in TNBC patients compared to controls. Principal component analysis and hierarchical clustering of the global metabolite profiling data revealed separation between the metabolic signatures of normal and breast tumor tissue. Random forest analysis revealed a unique biochemical signature associated with elevated L-Tryptophan (Trp) and Kynurenine (Kyn) metabolites and lower levels of microbial-derived metabolites critical for controlling inflammation and immune response in obese individuals and those with TNBC. TCGA analysis further revealed that expression of key Trp enzymes was significantly associated with worse survival outcomes in TNBC patients compared to other breast tumor subtypes. Our findings highlight a potential role for Trp metabolism through the Kyn pathway in obesity and TNBC risk. Further investigations into the Kyn metabolomic pathway may prove to be a novel therapeutic target for TNBC.
Citation Format: Alana Smith, Qingqing Gu, Ernestine Kubi Amos-Abanyie, Elizabeth Tolley, Lu Lu, Beverly Lyn-Cook, Athena Starlard-Davenport. Tryptophan metabolism is associated with obesity and triple negative breast cancer risk in black and white women [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 3022.
Abstract 3027: Elucidating the role of glutamine metabolism in head & neck squamous cell carcinoma
Authors: Allevato Michael , Yokoyama Yumi , Wild Robert , Gutkind J. Silvio 
Published: June 2022

Abstract
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, resulting in over 14,600 deaths each year in the United States alone. HNSCC is associated with human papillomavirus (HPV) infection, tobacco use, and abusive alcohol intake. Without truly effective targeted therapies, surgery and radiotherapy represent the primary treatment options for most patients. Unfortunately, these treatments are associated with significant morbidity and a reduction in quality of life. Immunotherapies have recently revolutionized HNSCC treatment, but &lt;20% of patients exhibit clinical responses, albeit often not durable (Saddawi-Konefka et al. Frontiers in Oncology 2021). This highlights the unmet need to identify novel therapeutic options and biomarkers predicting a more favorable response to maximize the efficacy of targeted cancer strategies for HNSCC treatment. Glutamine is a conditionally essential amino acid for rapidly proliferating cancer cells making glutamine pathway inhibition an attractive approach for anti-cancer therapy. We found that treatment with the broad glutamine antagonist sirpiglenastat (DRP-104), which irreversibly inhibits all known enzymes involved in glutamine metabolism, results in metabolically halted cell growth in a large panel (n=8) of HPV- and HPV+ HNSCC cell lines (IC50 of 0.2-25uM). Interestingly, HNSCC cells bearing genetic alterations in PIK3CA and PTEN were significantly more sensitive to glutamine antagonism than unaltered HNSCC cells. The dependence of glutamine in HNSCC growth and the increased sensitivity of PIK3CA/PTEN aberrant cells was also observed in orosphere assays and HNSCC tumor xenografts in mice in vivo. We next explored the mechanism of glutamine suppression in HNSCC by integrating the results from genome-wide CRISPR-Cas9 knockout library screens and broad-spectrum metabolomics analysis. Both approaches converged on the identification of a dysregulated metabolic pathway that represents a synthetic lethal vulnerability that can be exploited via targeted therapies. Our data suggest that broad glutamine antagonism using sirpiglenastat (DRP-104) has therapeutic potential in HNSCC by dismantling cancer metabolism and sensitizing cells to additional perturbations leading to specific cell death. A clinical trial of sirpiglenastat (DRP-104) is currently ongoing (NCT04471415).
Citation Format: Michael Allevato, Yumi Yokoyama, Robert Wild, J. Silvio Gutkind. Elucidating the role of glutamine metabolism in head & neck squamous cell carcinoma [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 3027.
Abstract 3033: Glucose deprivation promotes lung adenocarcinoma de-differentiation due to unbalanced EZH2 activity
Authors: Saggese Pasquale , Pandey Aparamita , Fung Eileen , Giurato Giorgio , Weisz Alessandro , Dubinett Steven M. , Scafoglio Claudio 
Published: June 2022

Abstract
Lung cancer is the most frequent cancer-related cause of death, and adenocarcinoma (LUAD) is the most frequent type. Despite the recent success of immunotherapies, survival of lung cancer patients has not significantly improved in the last decades. New therapies are necessary. We have previously identified sodium-glucose transporter 2 (SGLT2) as the major responsible for glucose uptake in LUAD, and we have showed that treatment with SGLT2 inhibitors significantly delays LUAD development and prolongs survival in murine models. However, our data shows that SGLT2 inhibitors also induce de-differentiation of LUAD cells, leading to a more aggressive phenotype and increased resistance to cisplatin. Glucose deprivation causes reduced αKG levels, leading to reduced activity of αKG-dependent histone demethylases and consequent histone hypermethylation. Supplementation of αKG or inhibition of the histone methyltransferase EZH2 reverse this phenotype, suggesting that this de-differentiated phenotype depends on insufficiency of αKG-dependent histone demethylases and unbalanced EZH2 activity. Consistently, double treatment with an SGLT2 inhibitor and an EZH2 inhibitor significantly reduces the tumor burden in a genetically engineered murine model of LUAD. We further characterized the effect of low glucose-induced tumor de-differentiation, identifying stabilization of hypoxia inducible factor 1α (HIF1α) as a major pathway responsible for the acquisition of a more aggressive phenotype following glucose deprivation. Finally, we identified an HIF1α-dependent transcriptional signature with prognostic significance in human LUAD. Our studies further our knowledge of the relationship between glucose metabolism and cell differentiation in cancer, characterizing the epigenetic adaptation of cancer cells to nutrient deprivation and identifying novel targets to prevent the development of resistance to metabolic therapies.
Citation Format: Pasquale Saggese, Aparamita Pandey, Eileen Fung, Giorgio Giurato, Alessandro Weisz, Steven M. Dubinett, Claudio Scafoglio. Glucose deprivation promotes lung adenocarcinoma de-differentiation due to unbalanced EZH2 activity [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 3033.
Abstract 3048: CSI-Microbes: Identifying cell-type specific intracellular microbes from single-cell RNA-seq data
Authors: Robinson Welles , Schischlik Fiorella , Gertz E. Michael , Lee Joo S. , Zhu Kaiyuan , Sahinalp S. Cenk , Patro Rob , Leiserson Mark D. , Schaffer Alejandro A. , Ruppin Eytan 
Published: June 2022

Abstract
Despite recent reports of microbes living within tumor cells, the identification of intracellular microbes remains an open and important challenge. Here we introduce CSI-Microbes (computational identification of Cell type Specific Intracellular Microbes), a computational approach for the discovery of cell-type specific intracellular microbial taxa from single-cell RNA sequencing of host cells. It is first validated on two gold-standard datasets of human immune cells exposed to Salmonella. Next, CSI-Microbes is tested on Merkel cell and colorectal carcinoma where it identifies both reported and previously unknown tumor-specific intracellular microbes. Finally, CSI-Microbes is applied to analyze the intracellular microbiome of thirteen lung tumors where it identifies four tumors with bacterial taxa enriched in tumor cells and two tumors with bacterial taxa enriched in stroma or immune cells. Notably, the infected tumor cells down-regulate pathways associated with anti-microbial response and antigen processing and presentation, testifying to the functional significance of bacterial presence.
Citation Format: Welles Robinson, Fiorella Schischlik, E. Michael Gertz, Joo S. Lee, Kaiyuan Zhu, S. Cenk Sahinalp, Rob Patro, Mark D. Leiserson, Alejandro A. Schaffer, Eytan Ruppin. CSI-Microbes: Identifying cell-type specific intracellular microbes from single-cell RNA-seq data [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 3048.
Abstract 3071: A reconstruction of evolutionary trajectories in primary tissue and PDTOs in a patient with metastatic osteosarcoma
Authors: Davarifar Ardy , Yanagawa Jane , Al Shihabi Ahmad , Nguyen Huyen T. , Liu Lydia Y. , Salcedo Adriana , Gonzalez Alfredo , Yamaguchi Takafumi N. , Bernthal Nicholas , Nelson Scott D. , Federman Noah , Boutros Paul C. , Soragni Alice 
Published: June 2022

Abstract
Metastatic osteosarcoma is a rare and highly lethal cancer that affects children and young adults. The rarity of osteosarcoma and its highly heterogeneous genetic composition have resulted in a lack of curative treatments for recurrent and metastatic disease.
In this study, we present the functional and molecular characterization of a case of a pediatric patient with left distal femur osteosarcoma and pulmonary metastases at presentation. Through longitudinal sampling over the course of the patient’s illness, we have procured tissue from the initial treatment-naïve diagnostic biopsy, primary tumor resection and multiple subsequent lung metastasectomies, and have developed patient-derived tumor organoids (PDTOs) from the viable samples. PDTOs are useful pre-clinical models that are representative of the source tissue and allow further interrogations of the biology of tumors. These models can also help with the identification of effective personalized therapies (Al Shihabi et al, 2021). We applied our mini-ring organoid screening technology (Phan et al, 2019; Nguyen et al, 2020) to perform high-throughput drug screening with different pharmacologic agents. We also performed deep whole-genome sequencing on all collected samples and corresponding organoids to reconstruct their evolutionary history, identify driver mutations and quantify heterogeneity in mutational processes across time and space.
Our preliminary data show that the subclonal content of the tumor and derivative organoids as well as the PDTO drug responses vary with the patient’s treatment history. We identify the genomic makeup of the subclones and posit changes that may be responsible for chemoresistance. Furthermore, our data shows correlations between the subclonal genomic composition of the PDTOs and source tissue, thereby reinforcing that PDTOs are capable of accurately recapitulating the subclonal heterogeneity of the parental tumor.
Citation Format: Ardy Davarifar, Jane Yanagawa, Ahmad Al Shihabi, Huyen T. Nguyen, Lydia Y. Liu, Adriana Salcedo, Alfredo Gonzalez, Takafumi N. Yamaguchi, Nicholas Bernthal, Scott D. Nelson, Noah Federman, Paul C. Boutros, Alice Soragni. A reconstruction of evolutionary trajectories in primary tissue and PDTOs in a patient with metastatic osteosarcoma [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 3071.
Abstract 3077: Leveraging a 3D organoid library to identify novel therapeutic targets during ESCC initiation and progression
Authors: Flashner Samuel , Shimonosono Masataka , Takada Satoshi , Matsuura Norihiro , Tomita Yasuto , Chen Xiao , Taylor Alison , Klein-Szanto Andres , Momen-Heravi Fatameh , Diehl J. Alan , Lu Chao , Nakagawa Hiroshi 
Published: June 2022

Abstract
Esophageal squamous cell carcinoma (ESCC) is a devastating and common disease worldwide. Despite recent advances annotating the genetic and epigenetic changes underlying the initiation and development of ESCC and its precursor lesion, esophageal squamous dysplasia, more work is needed to translate these findings into novel therapeutic strategies. This gap is due in part to the lack of tractable models of ESCC initiation and development that can then be manipulated ex vivo for preclinical testing. Currently, the large-scale studies characterizing the aforementioned molecular changes have used primary tissue for their analyses and have subsequently been unable to test the specific hypotheses that arise from their data using the original tissue that they profiled. To address this gap, we have generated a large (n = 54) three-dimensional organoid library from the esophagi of mice treated with the carcinogen 4-Nitroquinoline N-oxide (4-NQO) representing each stage of esophageal squamous cell initiation and progression from early intraepithelial dysplasia through lung metastasis. We have determined that these organoids faithfully recapitulate the molecular biology, histology, and oncogenic phenotype of their tissue of origin. Through integrative analysis of both RNA sequencing and whole exome sequencing data, we have identified several novel therapeutic targets that contribute to ESCC initiation and development including the DNA damage response and NOTCH1 signaling. Together, our work capitalizes on the intersection of large-scale multiomics and sophisticated 3D organoid models to identify novel therapeutic targets for the treatment of a devastating disease.
Citation Format: Samuel Flashner, Masataka Shimonosono, Satoshi Takada, Norihiro Matsuura, Yasuto Tomita, Xiao Chen, Alison Taylor, Andres Klein-Szanto, Fatameh Momen-Heravi, J. Alan Diehl, Chao Lu, Hiroshi Nakagawa. Leveraging a 3D organoid library to identify novel therapeutic targets during ESCC initiation and progression [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 3077.
Abstract 3081: High-speed live cell interferometry captures heterogeneity in bioprinted tumor organoids
Authors: Tebon Peyton J. , Wang Bowen , Markowitz Alexander L. , Murray Graeme , Davarifar Ardalan , Nguyen Huyen T. , Tavanaie Nasrin , Nguyen Thang L. , Boutros Paul C. , Teitell Michael A. , Soragni Alice 
Published: June 2022

Abstract
As interest grows in using tumor organoids as models for drug discovery and precision medicine, platforms for the reliable functional testing and analysis of these organoids are needed. Existing functional approaches in precision medicine face difficulties in the creation, scaling, and analysis of physiological tumor organoid models. We present a method for the automated bioprinting of tumor organoids coupled with real-time biomass quantification using high-speed live cell interferometry (HSLCI). This workflow enhances consistency, preserves sample viability, and assesses response to treatment with single-organoid resolution. First, we describe the bioprinting protocol used to achieve the deposition of organoids in uniformly thin three-dimensional layers of Matrigel. Then we show that bioprinting preserves the histological and molecular characteristics of manually seeded organoids. In drug screening experiments, we demonstrate the simultaneous monitoring of thousands of individual organoids and show that HSLCI can rapidly identify drug sensitivity and resistance to treatment. We observe significant heterogeneity in the drug responses of single organoids and discuss the potential implications for use of this pipeline in the clinical setting.
Citation Format: Peyton J. Tebon, Bowen Wang, Alexander L. Markowitz, Graeme Murray, Ardalan Davarifar, Huyen T. Nguyen, Nasrin Tavanaie, Thang L. Nguyen, Paul C. Boutros, Michael A. Teitell, Alice Soragni. High-speed live cell interferometry captures heterogeneity in bioprinted tumor organoids [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 3081.
Abstract 3086: Organoids standardized to a clinically validated drug response assay for truly predictive in vitro drug response profiling
Authors: Millard Melissa , Williams Natalie A. , Elrod Ashley K. , DesRochers Teresa M. 
Published: June 2022

Abstract
Unlike cell lines, organoids maintain most of the biological properties of the parental tissue from which the starting cells were isolated including the histology and gene expression. When organoids include clinical annotation, they become a useful, renewable tool for clinical correlation studies, but to be truly predictive the drug profiling assays utilized to screen organoid response must have measurable correlation with patient response. 3D Predict™ is a highly accurate assay that is 89% and 85% predictive of response in first-line ovarian cancer and high-grade gliomas (HGG) respectively. We have developed a panel of organoids that are clinically annotated, include correlative primary tissue 3D Predict™ drug response data, and have been assessed for the recapitulation of primary tissue histology and genomics. Additionally, our organoid models incorporate matched immune cells, a key component of the tumor microenvironment, making them an ideal model for immune-oncology studies. Here we present data on 15 available organoid models across HGG, breast, colorectal and bladder cancer. We have applied these models to drug response studies, including checkpoint inhibitors and shown correlation to primary patient response. The assurance of predictive capacity is unique to KIYATEC’s organoids and is significant because it avoids the pitfalls of comparing drug responses across non-concordant assay platforms while providing assurance that the models are reflective of individual patient response and outcomes.
Citation Format: Melissa Millard, Natalie A. Williams, Ashley K. Elrod, Teresa M. DesRochers. Organoids standardized to a clinically validated drug response assay for truly predictive in vitro drug response profiling [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 3086.
Abstract 3087: The identification and characterization of FOLFOX chemotherapy resistant cell lineages in colorectal cancer organoids
Authors: Morris Julia M. , Thorne Curtis A. 
Published: June 2022

Abstract
Resistance to chemotherapy drugs is a well-documented issue inhibiting the treatment of a wide variety of cancers. Colorectal cancer (CRC) is the third most common neoplasm worldwide and has the third highest mortality rate. However, the longtime gold-standard FOLFOX chemotherapy regimen, consisting of 5-FU and Oxaliplatin, results in only 70% survival rates in Stage 3 CRC patients, worse in Stage 4. More recent targeted therapies have marginally improved on this number, but the fact remains that CRC represents a highly heterogeneous neoplasm and resistance to standard chemotherapeutic regimens poses a significant barrier in treating this devastating disease.
There is an immediate need to better understand how this resistance arises. We hypothesize that a small number of cells with high phenotypic plasticity (HPP) are able to remain dormant during the initial chemotherapy treatment then reenter the cell cycle to cause recurrence and metastasis months or even years after treatment has concluded. Patient-derived organoids (PDOs) are a recently developed ex vivo model that allows for the study and extensive characterization of such HPP cell populations that may be found in patient tumors. We are developing and expanding various PDO populations to examine them genotypically and phenotypically on the single-cell level through RNA sequencing and high throughput imaging, respectively. By identifying these HPP cell populations, we then discover drugs that prevent the development of drug-resistant subpopulations. In the long term, we use our tumor heterogeneity profile to develop models that predict the responsiveness of tumors, including their drug-resistant HPP subpopulations, to well-documented and clinically used oncology drugs, streamlining treatment and improving survival outcomes.
Citation Format: Julia M. Morris, Curtis A. Thorne. The identification and characterization of FOLFOX chemotherapy resistant cell lineages in colorectal cancer organoids [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 3087.