tbuckley/cabot-search huggingface dataset:
Abstract 4998: Integrative analyses in pediatric osteosarcomas to understand the role of GD2 associated to activated mTor for macrophage targeting
Authors: Marina Pierrevelcin, Isabelle Lelong-Rebel, Quentin Fuchs, Monique Dontenwill, Natacha Entz-Werle
Journal: Cancer Research (2020)

Abstract Osteosarcoma is the most common primary malignant bone tumor in children and young adults. Its immune environment was described as predominantly involving M2 macrophages or osteoclasts. Previous studies were observing ganglioside GD2 expression on the osteosarcoma cell surface. Even more and more publications are deciphering the role of hypoxic biomarkers and its metabolic cell impact. Nevertheless, no links were, for instance, described clearly between mTor-HIF1 pathway and the macrophages in osteosarcomas through GD2 targeting. The aim of the study was to understand the role of all those molecular partners in osteosarcoma models. Material and methods: A cohort of 35 patients was explored to determine the expression by immunohistochemistry, as well as semi-quantitative PCR of several hypoxic and macrophages' biomarkers. Additionally, in 2D and 3D in vitro osteosarcoma models, analyses using metabolomics, western blotting, immunofluorescent imaging and RNA sequencing were performed to understand functional interactions between patient-derived osteosarcoma cells and the M2 macrophages. Endly, drug screening studies were testing 3D models (integrating matrix and hypoxic microenvironment) to assess efficacy of combinations using dinutuximab, mTor and HIF inhibitors. Results: Osteosarcoma samples are highly expressing CD163 and CD68 macrophage markers, as well as activated mTORC1 and GD2. Hypoxic biomarkers, when overexpressed, were statistically linked to a worst patient outcome. For macrophages and GD2 markers, a low expression was mostly linked to metastatic disease or poor response to chemotherapy. Specific metabolomic changes through glutaminolysis were frequently present and associated to a transcriptomic signature combining metabolism changes and specific immune macrophage environment. The targeting by dinutuximab associated to hypoxia inhibition was having a clear effect on osteosarcoma cell proliferation decrease, when associated to macrophages in 3D models mimicking osteosarcoma tumors. Conclusion: Macrophage immune environment is a key component of pediatric osteosarcomas and can be targeted in association with hypoxia inhibitors in 3D models recreating the osteosarcoma immune environment and bone matrix. Citation Format: Marina Pierrevelcin, Isabelle Lelong-Rebel, Quentin Fuchs, Monique Dontenwill, Natacha Entz-Werle. Integrative analyses in pediatric osteosarcomas to understand the role of GD2 associated to activated mTor for macrophage targeting [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4998.
Transgenic zebrafish for modeling hepatocellular carcinoma
Authors: Joji Nakayama, Zhiyuan Gong
Journal: MedComm (2020)

Abstract Liver cancer is the third leading cause of cancer‐related deaths throughout the world, and more than 0.6 million people die from liver cancer annually. Therefore, novel therapeutic strategies to eliminate malignant cells from liver cancer patients are urgently needed. Recent advances in high‐throughput genomic technologies have identified de novo candidates for oncogenes and pharmacological targets. However, testing and understanding the mechanism of oncogenic transformation as well as probing the kinetics and therapeutic responses of spontaneous tumors in an intact microenvironment require in vivo examination using genetically modified animal models. The zebrafish ( Danio rerio ) has attracted increasing attention as a new model for studying cancer biology since the organs in the model are strikingly similar to human organs and the model can be genetically modified in a short time and at a low cost. This review summarizes the current knowledge of epidemiological data and genetic alterations in hepatocellular carcinoma (HCC), zebrafish models of HCC, and potential therapeutic strategies for targeting HCC based on knowledge from the models.
Abstract 181: Pan-cancer clinical genomic profiling in circulating tumor DNA from 7345 Chinese advanced cancer patients
Authors: Wenhua Li, Hui Chen, Yifan Zhou, Danpeng Sun, Bei Zhang, Yuezong Bai, Qingqing Ding
Journal: Cancer Research (2020)

Abstract Purpose: Circulating tumor DNA (ctDNA) sequencing was implemented widely in advanced cancer patients for guiding matched therapy, which could avoid invasive specimen collection and tumor heterogeneous. However, clinical ctDNA genomic profiling of Chinese advanced pan-cancer patients is still unknown. Methods: 7624 blood samples were obtained from 7345 Chinese patients with advanced solid tumor, including 3506 lung cancer, 860 liver cancer, 674 colorectum cancer, 343 stomach cancer, 329 biliary tract cancer, 324 breast cancer, and 1588 other 17 tumor types. Genomic alterations (GAs), including SNV/Indels, CNVs, and rearrangements were identified via ctDNA sequencing with a 150 cancer-related gene panel. Potentially actionable GAs was annotated according to OncoKB database. Results: There are 85.2% (6497/7624) samples harbors maximum somatic allele frequency (MSAF) &amp;gt;0.3% and average 5.5 GAs per samples. 21253 known or likely deleterious alterations were identified in 137 genes, and average 3.3 known or likely deleterious GAs per samples. Additionally, 38.4% (2930/7624) samples had at least one potentially actionable GA (PAGA). The most frequently and potentially actionable altered genes were EGFR (13.2%), KRAS (8.6%), PIK3CA (5.1%), ERBB2 (4.0%), FGFR1 (3.6%) and BRAF (3.3%). Importantly, PAGAs in RTK-RAS-MAPK pathway was the most common with 33.7% samples (19.2% SNV/Indels only, 9.8% CNVs only, 1.4% rearrangements only, 3.4% either two or more types of alterations), followed by 5.9% PI3K/AKT/mTOR pathway, 2.1% TP53/cell cycle pathway, 0.8% Epigenetic pathway, 0.1% Hedgehog pathway, and 0.1% DDR pathway. The samples of at least one PAGA in aforementioned pathways were 53.1% in breast cancer, 49.6% in colorectum cancer, 44.0% in bladder/urinary tract cancer, 43.5% in lung cancer, 39.4% in stomach cancer, respectively. In all, 287 cases with PAGAs in RTK-RAS-MAPK pathway (ROS1, ALK, MET) could benefit from crizotinib; 49 cases with PAGAs in RTK-RAS-MAPK pathway (BRAF) could benefit from vemurafenib; 447 cases with PAGAs in PI3K/AKT/mTOR pathway (PIK3CA, PTEN, AKT1, mTOR) could benefit from everolimus; and 6 cases with PAGAs in DDR pathway (ATM) could benefit from olaparib. Conclusions: The study revealed a comprehensive ctDNA genomic profiling of Chinese patients with advanced solid tumors. And further larger cohorts validation for ctDNA sequencing as a diagnostic tool in target-therapy is needed. Citation Format: Wenhua Li, Hui Chen, Yifan Zhou, Danpeng Sun, Bei Zhang, Yuezong Bai, Qingqing Ding. Pan-cancer clinical genomic profiling in circulating tumor DNA from 7345 Chinese advanced cancer patients [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 181.
Abstract 2000: Systemic and tumor associated IL-8 correlates with resistance to PD-L1 blockade
Authors: Kobe Yuen, Lifen Liu, Congfen Li, Deepali Rishipathak, Patrick Williams, Edward Kadel, Hartmut Koeppen, Shravan Madireddi, Shilpa Keerthivasan, Ying-Jun Chen, Zora Modrusen, Romain Banchereau, Ning Leng, Priti Hegde, Mahrukh Huseni, Sanjeev Mariathasan
Journal: Cancer Research (2020)

Abstract Elevated plasma interleukin-8 (IL-8) is a poor prognostic factor for many cancers. However, the association of IL-8 with clinical outcomes to checkpoint inhibition has not been comprehensively evaluated in randomized studies. Moreover, the source of IL-8 and the underlying biology that influences resistance to immune checkpoint inhibitors remain unknown. Here we analyzed circulating IL-8 protein in plasma, and IL8 gene expression in peripheral blood mononuclear cells (PBMC) and tumors of patients treated with atezolizumab (anti-PD-L1 mAb), from multiple randomized trials in metastatic urothelial carcinoma (mUC) and metastatic renal cell carcinoma (mRCC). High levels of IL-8 in plasma, PBMCs and tumors, were associated with decreased efficacy in mUC and mRCC patients treated with atezolizumab, even in tumors that were classically CD8+ T cell inflamed. mUC patients treated with atezolizumab, but not with chemotherapy, who experienced an on-treatment decrease in plasma IL-8, exhibited improved overall survival. IL-8 is primarily expressed in circulating and intratumoral myeloid cells, and high IL8 expression was associated with the downregulation of the antigen presentation machinery in myeloid cells. A better understanding of IL-8-mediated myeloid inflammation in curtailing responses to checkpoint inhibitors is essential for developing new therapies for patients. Citation Format: Kobe Yuen, Lifen Liu, Congfen Li, Deepali Rishipathak, Patrick Williams, Edward Kadel, Hartmut Koeppen, Shravan Madireddi, Shilpa Keerthivasan, Ying-Jun Chen, Zora Modrusen, Romain Banchereau, Ning Leng, Priti Hegde, Mahrukh Huseni, Sanjeev Mariathasan. Systemic and tumor associated IL-8 correlates with resistance to PD-L1 blockade [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2000.
Abstract 744: Volatile organic compounds (VOCs) from exhaled Breath for lung cancer Staging using TD-GC-MS
Authors: Kanhar Ghulam Muhammad, Channa Madeeha, Fu Wei, Xu Lin Xin, Yanjie Hu, Kejing Ying, Jun Liu, Xing Chen
Journal: Cancer Research (2020)

Abstract Background: Breath analysis is a promising noninvasive screening technique that offers a wide range of probable possibilities to facilitate early diagnosis of lung cancer (LC). Method: Exhaled breath samples of 352 subjects were analyzed to detect C6∼C30 VOCs through thermal desorption coupled with gas chromatography-mass spectrometry (TD-GC-MS). Data were divided into three categories Lung Cancer (LC), Benign Pulmonary Disease (BPD) and Healthy control (HC). Statistical classification models were used to analyze VOCs to distinguish between HC, BPD and LC patient's early and advanced stages. Receiver operator characteristics (ROC) curves were used to select different VOCs to evaluate the accuracy, specificity, and sensitivity of the diagnostic model. Results: The analysis resulted that 10,9,11 and 10 VOCs have a significant correlation to discriminate Histology, stage, BPD from LC and HC from LC. The diagnostic model predicted accuracy, sensitivity, and specificity of NSCLC vs. SCLC is 92%, 96% and 90% with area under curve AUC&amp;gt;0.913. As of ROC curve with AUC&amp;gt;0.819 has distinguished Stage I-II vs. stage III-IV with accuracy, sensitivity, and specificity 72%, 84%, and 80%. Whereas the ROC curve with AUC&amp;gt;0.795 has distinguished BPD from LC with accuracy, sensitivity, and specificity 83%, 89%, and 84%. While ROC curve with AUC&amp;gt;0.945, accuracy, sensitivity and specificity 92%, 96%, and 90% have distinguished HC from LC. Conclusion: This study confirms that TD GC-MS is a sensitive and dependable method to distinguish the VOCs in exhaled breath. We have witnessed significant differences in breath of BPD, HC and LC subjects. Where 10,8,11 and 10 VOCs have distinguished between early from the advance stage, NSCLC from SCLC, BPD from LC and HC from LC. These VOCs has the potential to help improve LC diagnosis and prognosis. However, with the expansion of multi centers to other regions could result in more vital findings and will help improve breath analysis and the diagnosis standard. Keywords: Breath Analysis, VOC markers, lung cancer, TD-GC-MS. Citation Format: Kanhar Ghulam Muhammad, Channa Madeeha, Fu Wei, Xu Lin Xin, Yanjie Hu, Kejing Ying, Jun Liu, Xing Chen. Volatile organic compounds (VOCs) from exhaled Breath for lung cancer Staging using TD-GC-MS [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 744.
Abstract 5861: BOP1 expression contributes to the proliferative/invasive phenotype in melanoma
Authors: Mitchell S. Stark, Sabrina Hammerlindl, Lisa Tom, Kasturee Jagirdar, Jean-Marie Tan, Helmut Schaider, Richard A. Sturm, Blake O'Brien, Michael Walsh, Angus Collins, H.Peter Soyer
Journal: Cancer Research (2020)

Abstract We recently performed whole exome sequencing of 30 melanocytic nevi which surprisingly revealed numerous regions of copy number loss. It was found that common reticular nevi (mostly with a junctional component) have a high incidence of copy number aberrations (CNA). Importantly, concurrent with the loss of tumor suppressor genes (e.g. CDKN2A, TP53, and NF1) was the loss of potent oncogenes (e.g. NRAS, MITF, and MDM2). We postulated that the balanced nature of these CNAs confers protection from transformation, thus keeping the lesion in the benign state. Along with copy-number loss of these well-known genes, further interrogation of these data revealed a loss on chr8q24.3 which was frequently observed in 7/30 (23%) nevi. In the smallest region of overlap, the block of proliferation 1 (BOP1) gene was identified as a candidate for functional validation. BOP1 is part of the trimeric “PeBoW” complex, essential for ribosome biogenesis and cell cycle progression. In melanoma cell lines (MM96L, HT144, and MM253), we used siRNA mediated gene targeting to achieve differing BOP1 expression levels (high, low, absent), which resulted in altered cell states. For example, high BOP1 expression caused an increase in proliferation and colony formation, whereas low BOP1 expression conferred reduced proliferation, colony formation, and a senescent like phenotype. Interestingly, low BOP1 expression also resulted in increased migration and invasive capacity. BOP1 immunofluorescence assessment of benign nevi revealed limited expression whereas in early invasive melanomas, BOP1 expression was clearly evident in proliferative melanoma nests. These data support the role of BOP1 playing a role in melanoma progression by contributing to phenotype switching. Citation Format: Mitchell S. Stark, Sabrina Hammerlindl, Lisa Tom, Kasturee Jagirdar, Jean-Marie Tan, Helmut Schaider, Richard A. Sturm, Blake O'Brien, Michael Walsh, Angus Collins, H.Peter Soyer. BOP1 expression contributes to the proliferative/invasive phenotype in melanoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5861.
Abstract NG01: MADR: Rapid generation of somatic mosaics to model cancer in mice and human organoids
Authors: Gi Bum Kim, David Rincon Fernandez Pacheco, David Saxon, Amy Yang, Sara Sabat, Marina Dutra-Clarke, Rachelle Levy, Ashley Watkins, Hannah Park, Aslam Abbasi Akhtar, Paul W. Linesch, Naomi Kobritz, Swasty S. Shandra, Katie Grausam, Alberto Ayala-Sarmiento, Jessica Molina, Kristyna Sedivakova, Daniel S. Gareau, Mariella G. Filbin, Serguei Bannykh, Jie Tang, Mario L. Suva, Bin Chen, Moise Danielpour, Joshua J. Breunig
Journal: Cancer Research (2020)

Abstract In situ transgenesis methods such as virus and electroporation can create somatic transgenic mice quickly, but they lack the exquisite control over copy number, zygosity, and locus specificity. We have recently established mosaic analysis by dual recombinase-mediated cassette exchange (MADR), which permits stable labeling of mutant cells expressing transgenic elements from precisely-defined chromosomal loci. MADR provides a toolkit of elements for combinatorial labeling, inducible/reversible transgene manipulation, VCre recombinase expression, and genetic manipulation of human cells. Further, we have demonstrated the versatility of MADR by creating glioma models with mixed, reporter-identified zygosity or with “personalized” driver mutations from pediatric glioma. For example, introducing H3f3a mutation variants with MADR regulates the spatiotemporal profile of glioma, and single-cell RNA and ATAC sequencing analysis demonstrates a recapitulation of developmental hierarchy seen in K27M-mutant human glioma. Moreover, we have generated novel models of supratentorial ependymoma using patient-derived oncofusion transgenes. These models display a high degree of fidelity and we now compare these models on a single-cell level with our previous models and human tumor cell transcriptomes. In addition, we now demonstrate the ability to generalize the MADR technology to other non-CNS tissues using local plasmid delivery. Finally, we have engineered human cells to allow for MADR transgenesis and somatic transgenic organoids. These combined approaches will enable researchers to discovery disease mechanisms and test therapeutics in more physiologically relevant cancer models.MADR is extensible to thousands of existing mouse lines and can be adapted to human cells, providing a flexible platform to democratize the generation of somatic transgenic disease models. Citation Format: Gi Bum Kim, David Rincon Fernandez Pacheco, David Saxon, Amy Yang, Sara Sabat, Marina Dutra-Clarke, Rachelle Levy, Ashley Watkins, Hannah Park, Aslam Abbasi Akhtar, Paul W. Linesch, Naomi Kobritz, Swasty S. Shandra, Katie Grausam, Alberto Ayala-Sarmiento, Jessica Molina, Kristyna Sedivakova, Daniel S. Gareau, Mariella G. Filbin, Serguei Bannykh, Jie Tang, Mario L. Suva, Bin Chen, Moise Danielpour, Joshua J. Breunig. MADR: Rapid generation of somatic mosaics to model cancer in mice and human organoids [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr NG01.
Inflammatory bowel diseases among first-generation and second-generation immigrants in Denmark: a population-based cohort study
Authors: Manasi Agrawal, Giulia Corn, Sarita Shrestha, Nete Munk Nielsen, Morten Frisch, Jean-Frederic Colombel, Tine Jess
Journal: Gut (2020)

Our objective was to estimate the relative risk of IBD among first-generation and second-generation immigrants in Denmark compared with native Danes.Using national registries, we established a cohort of Danish residents between 1977 and 2018. Cohort members with known country of birth were followed for Crohn's disease (CD) and ulcerative colitis (UC) diagnoses. Incidence rate ratios (IRRs) served as measures of relative risk and were calculated by log-linear Poisson regression, using rates among native Danes as reference, stratified by IBD risk in parental country of birth, and among first-generation immigrants by age at immigration and duration of stay in Denmark.Among 8.7 million Danes, 4156 first-generation and 898 second-generation immigrants were diagnosed with CD or UC. Overall, comparing first-generation immigrants with native Danes, the IRR was 0.80 (95% CI 0.76 to 0.84) for CD and 0.74 (95% CI 0.71 to 0.77) for UC. The IRR of IBD increased with ≥20 years stay in Denmark. The IRR of CD increased with immigration at ≥40 years of age. Comparing second-generation immigrants with native Danes, the IRR of IBD was 0.97 (95% CI 0.91 to 1.04). There was significant interaction with sex, with higher IRR of IBD in male than in female immigrants.Relative to native Danish men and women, IBD risk among first-generation immigrants was lower, reflected the risk in their parental country of birth and increased with ≥20 years stay in Denmark. For second-generation immigrants, relative risk of IBD was lower only among women. These complex patterns suggest the role of environmental IBD risk factors.
Abstract 5112: Interaction between <i>RHOA</i> mutated gastric cancer cells and cancer associated fibroblasts promotes tumorigenesis
Authors: Daye Jeon, Yuri Choi, Seon Jin Lee, Kyung Un Choi, Do Youn Park, Chae Hwa Kwon
Journal: Cancer Research (2020)

Abstract Background: We previously observed that RHOA-mutated gastric cancer has desmoplastic morphological feature. Although desmoplastic reaction is known to consist mainly of cancer associated fibroblasts (CAF), the relationship cancer cells with RHOA mutation and CAF have not been reported. Thus, in this study, we investigated the interaction between RHOA-mutated gastric cancer cells and CAF and its underlying mechanism. Methods: We established stable gastric cell lines (AGS, MKN-45) expressing RHOA wild type (WT) of mutation (G17E, T37I, E40K, Y42C) using lentiviral vector and cocultured these cells with CAF using transwell. And proliferation and migration of RHOA-mutated gastric cancer cells were examined. To understand molecular mechanism of RHOA-mutated gastric cancer cells proliferation and migration, RNA-sequencing was conducted and the results were analyzed and validated. Results: Cocultivation of gastric cancer cells expressing RHOA WT or mutation (G17E, T37I, E40K, Y42C) with CAF increased proliferation relative to cells expressing an empty vector (EV). In addition, migration of RHOA mutant cells, except for cells with RHOA WT and Y42C, was increased by CAF relative to EV cells. Genes related to IL-17, IL-15, and IGF-1 signaling pathways were differentially expressed between RHOA WT or mutant cells and EV cells, suggesting that proliferation and migration of RHOA mutant cells promoted by CAF through these pathways. Furthermore, we identified CXCL1 and IGFBP2 as mediator of interaction between RHOA mutated gastric cancer cells and CAF. Conclusion: In summary, we found that gastric cancer cells with RHOA mutation have tumor-promoting activity by interaction with CAF. Thus, molecules for impairing their interactions could be potential therapeutic targets in gastric cancer patients with RHOA mutation. Citation Format: Daye Jeon, Yuri Choi, Seon Jin Lee, Kyung Un Choi, Do Youn Park, Chae Hwa Kwon. Interaction between RHOA mutated gastric cancer cells and cancer associated fibroblasts promotes tumorigenesis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5112.