bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract PO-043: Plexiform neurofibroma microenvironment at single-cell resolution
Authors: Kershner Leah J. , Wu Jianqiang , Salomonis Nathan , Ratner Nancy 
Published: December 2020

Abstract
Plexiform neurofibromas (PN) are benign nerve sheath Schwann cell tumors, which occur in at least 50% of individuals with loss of function mutations in the NF1 tumor suppressor gene, an off signal for RAS-GTPases. Tumors form, at least in part, through activation of the RAS-MAPK pathway in Schwann cells. Though benign, PN can cause significant morbidity and are often inoperable due to integration with vital peripheral nerves. Recent clinical trials have shown that MEK inhibition can shrink most PN, but continued MEK inhibition is required for sustained response. It is recognized that PN contain many cell types in addition to Schwann cells, and that Schwann cells are present in varying proportions. However, biomarkers for many cell types have not yet been identified, and it is not known whether subpopulations of certain cell types exist within neurofibromas. To address these issues, we performed single cell RNA sequencing on PN using a genetically engineered mouse model which closely recapitulates human PN. We have characterized tumor composition, and identified PN Schwann cells, satellite glial cells, endothelial cells, fibroblasts, macrophages, T cells, dendritic cells, and other previously unreported cell types. We identified multiple subpopulations of Schwann cells, macrophages and fibroblasts within benign PN. Cluster by cluster comparison of PN to age-matched healthy nerve and to pretumor nerve tissue from the same mouse model revealed gene regulatory networks that are significantly altered in PN, after loss of NF1 function. Further, inference of cell-cell communication networks shows robust changes in PN that are absent before tumors form, and that are potentially targetable. Comparison to MEK inhibitor treated PN and to human PN sc-RNASeq is ongoing. Taken together, these approaches characterize PN, provide potential biomarkers for cell populations and identify targets for drug treatment. Supported by NIH (NINDS-28840) and the DOD Program on Neurofibromatosis. LK is supported by NIH Ruth L. Kirschstein T32.
Citation Format: Leah J. Kershner, Jianqiang Wu, Nathan Salomonis, Nancy Ratner. Plexiform neurofibroma microenvironment at single-cell resolution [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 PO-043.
Abstract PO-047: Anti-proliferative effect of cannabidiol (CBD) against B and T-cell lymphoma
Authors: Omer Saba , Boothe Dawn , Mansour Mohammed , Dhanasekaran Muralikrishnan , Pondugula Satyanarayana 
Published: December 2020

Abstract
In the last two decades, Cannabinoids have been studied extensively for its potential use in various fields of medicine including oncology. Today some of the cannabinoids are FDA approved for the treatment of chemotherapy-induced side effects in cancer treatment however, studies are showing their effect against tumor growth as well. Aggressive B cell lymphoma or Non-Hodgkin lymphoma (NHL) is the fifth leading cause of human cancer death and is the second fastest-growing cancer with regard to mortality in people as 30% of patients develop resistance against chemotherapy. For this reason, it is essential to develop novel strategies to improve the outcome of patients suffering from aggressive or therapy-resistant lymphoma. The purpose of this study was to demonstrate the antitumor effects of cannabinoids in B cell lymphoma using canine as a model due to striking similarities b/w canine and human B cell lymphoma in histology, biology and gene expression. For this study, Canine B cell lymphoma cell lines 1771 and CLBL1 were cultured in RPMI. Expression of cannabinoid receptors studied using qPCR. Based on receptor expression cells were treated with receptor agonists (AEA, 2AG, CBD, THC, WIN and HU-210,) and antagonists (S16 and S28). Cell viability assessed using MTT assay. Biochemical analysis performed using spectrofluorometry to evaluate apoptotic makers involved in inducing cell death. Data was analyzed using ordinary one way ANOVA on Prism software. All B cell lymphoma cell lines showed positive expression of CB1 and CB2 receptors. Cell viability assay demonstrated a dose-dependent decrease in cell proliferation with all cannabinoid receptor agonists used except for 2AG. Biochemical analysis showed a decrease in nitrite and caspase activity in treated cells as compared to control untreated cells. Our results suggest that cannabinoids have an anti-proliferative and apoptotic effect on canine lymphoma cells and it can be developed as a potential anti-cancer agent for the treatment of canine and human B cell lymphoma.
Citation Format: Saba Omer, Dawn Boothe, Mohammed Mansour, Muralikrishnan Dhanasekaran, Satyanarayana Pondugula. Anti-proliferative effect of cannabidiol (CBD) against B and T-cell lymphoma [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 PO-047.
Abstract PO-051: Tumor stem cells arising from a non-stem origin maintain a differentiated phenotype and modulate T cell activity
Authors: Scurrah Cherie’ R. , Chen Bob , Markham Nick , Simmons Alan , Southard-Smith Austin , Macedonia Mary , Choi Eunyoung , Liu Qi , Washington Kay , Coffey Bob , Goettel Jeremy , Lau Ken 
Published: December 2020

Abstract
Tumor stem cells (TSCs) contribute to cancer mortality via therapeutic resistance, tumor recurrence, and metastatic mechanisms. However, the origins of the stem capacity to TSCs remains in question, but all TSCs descend from the original tumor cell-of-origin where the first oncogenic event occurred. Tumors arising from different cells-of-origin are histologically identical, but it is unknown whether TSCs that arose from different origins are molecularly and functionally distinct. Using mouse models driving identical Apc mutations from Lrig1-expressing and Mist1-expressing cells, we characterized TSCs of tumors driven from stem and non-stem cells-of-origin using single cell RNA sequencing (scRNA-seq), organoids, and multiplexed imaging. We revealed reduced stem capacity but increased class II antigen presentation ability for non-stem cell (Mist1) driven TSCs compared with stem cell (Lrig1) driven TSCs, which resulted in a favorable immune microenvironment skewed towards active cytotoxic response in Mist1-driven tumors. These results suggest that the cell-of-origin of tumorigenesis provides a specific context by which TSCs are generated, dictating their interactions with the tumor microenvironment.
Citation Format: Cherie’ R. Scurrah, Bob Chen, Nick Markham, Alan Simmons, Austin Southard-Smith, Mary Macedonia, Eunyoung Choi, Qi Liu, Kay Washington, Bob Coffey, Jeremy Goettel, Ken Lau. Tumor stem cells arising from a non-stem origin maintain a differentiated phenotype and modulate T cell activity [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 PO-051.
Abstract PO-055: Global immune characterization of hepatocellular carcinoma identifies macrophage and T cell subsets related to disease progression
Authors: Song Guohe , Shi Yang , Lin Youpei , Zhang Juan , Yang Shuaixi , Gao Qiang 
Published: December 2020

Abstract
Diverse immune cells in the tumor microenvironment form a complex ecosystem, but our knowledge of their heterogeneity and dynamics within hepatocellular carcinoma (HCC) remains poorly understood. We assess the plasticity and phenotypes of immune cells within HCC microenvironment at single-cell level. We performed single-cell RNA sequencing on 41,698 immune cells from 7 pairs of HCC tumors and nontumor liver tissues. We combined bioinformatic analyses, flow cytometry and multiplex immunohistochemistry to assess the heterogeneity of different immune subsets in functional characteristics, transcriptional regulation, phenotypic switching, and interactions. We identified 29 immune subsets of myeloid cells, NK cells, and lymphocytes with unique transcriptomic profiles in HCC. A highly complex immunological network was shaped by immune subsets with diverse characteristics that can transit among different states and mutually engage through intercellular communication. Notably, we identified a subset of M2 macrophage with high expression of CCL18 and transcription factor CREM that was enriched in advanced HCC patients, and potentially participated in tumor progression. We also detected a new subset of activated CD8+ T cells highly expressing XCL1 that correlated with better patient survival, and possibly enhanced anti-tumor response. Meanwhile, distinct transcriptomic signatures, cytotoxic phenotypes and evolution trajectory of effector CD8+ T cells from early-stage to advanced HCC were also identified. Our study presents a comprehensive insight for dissecting the immune microenvironment in HCC and highlights novel macrophage and T cell subsets that could be further exploited in future immunotherapy.
Citation Format: Guohe Song, Yang Shi, Youpei Lin, Juan Zhang, Shuaixi Yang, Qiang Gao. Global immune characterization of hepatocellular carcinoma identifies macrophage and T cell subsets related to disease progression [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 PO-055.
Abstract PO-059: The genomic landscape of the in situ to invasive ductal breast carcinoma transition shaped by the immune system
Authors: Trinh Anne , Gil Del Alcazar Carlos R. , Shukla Sachet A. , Chin Koei , Chen Young Hwan , Thibault Guillaume , Eng Jennifer , Jovanovic Bojana , Aldaz C. Marcelo , Park So Yeon , Jong Joon , Wu Catherine , Gray Joe , Polyak Kornelia 
Published: December 2020

Abstract
Background: The transition from ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) is an evolutionary bottleneck where progression occurs only in 30% of patients. Whilst the genetic drivers of this transition remain poorly understood, we have previously shown that immune escape is a key event. In this study, we profile the evolutionary trajectory of matched pure DCIS and IDC in the context of the immune microenvironment. Methods: We have evaluated changes in copy number profiles, mutational profiles, expression and neoantigen load in 6 cases of matched pure DCIS and IDC using exome and RNA sequencing. We have integrated this information with topologic assessment of H&E images and cyclic immunofluorescence. Results: We provide evidence for an evolutionary bottleneck during DCIS to IDC in matched patient samples, showing that copy number aberrations are early events, but low overlap in mutational profiles. Variation in immune composition and spatial orientation can arise as early as in DCIS and are subtype specific. Tumor-specific copy number changes including loss of MHC-I presentation machinery or changes at cytokine rich loci specifically in ER− tumors could contribute to a more immunosuppressive environment in IDC. Oncogenic hotspot mutations can present as neoantigens yet are paradoxically conserved during the DCIS-to-IDC transition. We suggest these mutations have a secondary immune-modulatory function or may be present in normal tissue, escaping immune surveillance as early as in DCIS. Conclusions: We show both genomic and microenvironmental differences in matched pure DCIS and recurrent IDC, highlighting that progression is shaped by both tumor and immune system at this evolutionary bottleneck.
Citation Format: Anne Trinh, Carlos R. Gil Del Alcazar, Sachet A. Shukla, Koei Chin, Young Hwan Chen, Guillaume Thibault, Jennifer Eng, Bojana Jovanovic, C. Marcelo Aldaz, So Yeon Park, Joon Jong, Catherine Wu, Joe Gray, Kornelia Polyak. The genomic landscape of the in situ to invasive ductal breast carcinoma transition shaped by the immune system [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 PO-059.
Abstract PO-066: Computational identification of key pathway and differentially-expressed gene signatures in ovarian cancer stem cells
Authors: Fu Renata H. , Bai Yongsheng , Wang Qi-En 
Published: December 2020

Abstract
Many studies have demonstrated the causativeness of cancer stem cells (CSCs), which are able to self-renew, metastasize, differentiate, and resist chemotherapy. Although multiple cell surface markers have been used to identify and isolate cancer stem cells, their uncertainty makes these surface markers unreliable in identifying heterogeneous cancer stem cells. Some transcription factors have been shown to be overexpressed in CSCs residing in multiple types of cancers, and some pathways have been found to regulate CSC populations. However, since some CSCs do not express all of the identified genes, it is important to establish a panel of genes and pathways that can consistently distinguish CSCs. To determine a panel of consensus genes or pathways that can be used to recognize CSCs, we attempted to identify differentially expressed genes and enriched pathways in CSCs, which we call cancer stem cell signature. In this study, we employed two ovarian cancer RNA-seq data (GSE33874 and GSE82304) from the Gene Expression Omnibus (GEO) and considered genes with significant fold changes (|logFC|≥1). We used ComPath to identify pathways that are enriched in each of our selected RNA-seq datasets, then we developed a customized python script to reveal pathways commonly enriched in both datasets. We subsequently applied ComPath’s mapping catalog to elucidate equivalent or hierarchical relationships across common pathways from three different databases (KEGG, Reactome, and WikiPathways). In total, we identified 241 commonly upregulated genes and 96 commonly downregulated genes. We also present 30 equivalent relationships and 98 hierarchical relationships between pathways. Our results confirm several pathways that are reported to be involved in CSC regulation, such as the Wnt signaling pathway and the Hedgehog pathway. Furthermore, we also identified multiple pathways that have been previously associated with poor prognosis or high risk of ovarian cancer, such as the Prolactin signaling pathway and the coagulation cascade, indicating that these pathways may also be involved in the maintenance of ovarian cancer stem cells. We will continue to investigate ovarian CSC gene and pathway signatures by involving more RNA-seq data and pathway analysis databases.
Citation Format: Renata H. Fu, Yongsheng Bai, Qi-En Wang. Computational identification of key pathway and differentially-expressed gene signatures in ovarian cancer stem cells [abstract]. In: Proceedings of the AACR Virtual Special Conference on Tumor Heterogeneity: From Single Cells to Clinical Impact; 2020 Sep 17-18. Philadelphia (PA): AACR; Cancer Res 2020;80(21 Suppl):Abstract nr PO-066.
Abstract PO-071: MYC influences metastatic heterogeneity in pancreatic cancer
Authors: Maddipati Ravikanth , Norgard Robert J. , Baslan Timour , Rathi Komal S. , Zhang Amy , Raman Pichai , Wengyn Max D. , Yamazoe Taiji , Li Jinyang , Balli David , LaRiviere Michael , Folkert Ian W. , Millstein Ian D. , Bermeo Jonathan , Carpenter Erica L. , Lowe Scott , Iacobuzio-Donahue Christine , Notta Faiyaz , Stanger Ben Z. 
Published: December 2020

Abstract
Tumor heterogeneity - resulting from genetic and epigenetic alterations acquired during tumor progression - is a critical driver of phenotypic diversity in most cancers. A lethal consequence of tumor heterogeneity is the acquisition of metastatic traits by tumor cells, leading to poor clinical outcomes. This remains a major problem in pancreatic ductal adenocarcinoma (PDAC), which continues to have the worst prognosis of any major cancer type. While most cases of PDAC present with metastatic disease at the time of diagnosis, the patterns and burden of metastasis can vary widely, with some patients exhibiting a limited metastatic burden while others have more extensive spread, which impacts clinical outcomes. However, the biological and functional differences that drive metastatic heterogeneity are poorly understood.
Citation Format: Ravikanth Maddipati, Robert J. Norgard, Timour Baslan, Komal S. Rathi, Amy Zhang, Pichai Raman, Max D. Wengyn, Taiji Yamazoe, Jinyang Li, David Balli, Michael LaRiviere, Ian W. Folkert, Ian D. Millstein, Jonathan Bermeo, Erica L. Carpenter, Scott Lowe, Christine Iacobuzio-Donahue, Faiyaz Notta, Ben Z. Stanger. MYC influences metastatic heterogeneity in pancreatic cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Tumor Heterogeneity: From Single Cells to Clinical Impact; 2020 Sep 17-18. Philadelphia (PA): AACR; Cancer Res 2020;80(21 Suppl):Abstract nr PO-071.
Abstract PO-072: Control of inter- and intra-patient cancer heterogeneity is a predictively accurate explanation for the success of many combination therapies for solid and hematological cancers
Authors: Palmer Adam C. , Izar Ben , Hwangbo Haeun , Sorger Peter K. 
Published: December 2020

Abstract
Developing optimal drug combinations is one of the central challenges of cancer treatment research: drug combinations are used to treat most types of cancer, and are almost exclusively responsible for cures of advanced cancers. However, historically successful combination therapies were developed empirically, and the mechanistic basis for their efficacy has been largely speculative. I will present experiments, models, and computational analyses of clinical trial data, to investigate the mechanistic basis of clinically successful combination therapies across 12 types of cancer and 30 different therapies. These studies consistently identify the control of cancer heterogeneity between-patients (inter-tumor) and within-patients (intra-tumor) by independently active drugs as critical contributors to the efficacy of combination therapies in human patients. The key approaches for data analysis and modeling in these studies consist of adapting classical pharmacological concepts to the complex situation of populations of cancers with heterogeneous drug sensitivity. Synergistic drug interactions in humans appears uncommon among approved combination therapies, and even curative regimens exhibit drug additivity in experimental measurements and in clinical outcomes. Mathematical descriptions of heterogeneity in cellular or patient populations, and quantitative experimental measurements of how drug combinations address heterogeneity, lead to accurate predictions of clinical trial results for a diverse range of combination therapies, including those with immune checkpoint inhibitors (correlation between observed and expected Progression Free Survival in 14 trials, Pearson r = 0.98, P &lt; 10^-8) and curative chemotherapy regimens for hematological cancers (correlation between observed and expected response rates and cure rates in 40 years of trials in childhood ALL, Pearson r = 0.99, P &lt; 10^-10). These results have broad significance for the treatment of cancers, for the interpretation of clinical trials, and point to new opportunities to use combination therapies with greater precision.
Citation Format: Adam C. Palmer, Ben Izar, Haeun Hwangbo, Peter K. Sorger. Control of inter- and intra-patient cancer heterogeneity is a predictively accurate explanation for the success of many combination therapies for solid and hematological cancers [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 PO-072.
Abstract PO-075: Dysfunction of centrosome regulation by BRCA1-containing complex increases tumor heterogeneity
Authors: Chiba Natsuko 
Published: December 2020

Abstract
Centrosomes are the major microtubule-organizing centers in animal cells and are critical for the formation of a bipolar mitotic spindle. Alterations in centrosome number and structure often occur together and are associated with many cancers. Centrosome aberrations results in chromosome segregation errors and abnormal cell division, leading to chromosomal instability (CIN). CIN is a major source of aneuploidy, resulting in tumor heterogeneity. Centrosome aberrations are observed in the early stages of tumorigenesis and are correlated with CIN. Breast cancer gene 1 (BRCA1) is a tumor suppressor that is associated with hereditary breast and ovarian cancer. Functions of BRCA1 in DNA repair, especially homologous recombination, has been focused, whereas BRCA1 regulates centrosome together with BRCA1-associated RING domain protein (BARD1). We identified BRCA1-interacting proteins, Obg-like ATPase 1 (OLA1) and receptor for activated C kinase (RACK1). OLA1 and RACK1 directly bound to BRCA1, BARD1, and γ-tubulin and localized the centrosomes throughout the cell cycle. Overexpression of OLA1 or RACK1 caused centrosome amplification due to centriole overduplication in mammary tissue-derived cells. The number of centrioles in cells was higher in cell lines derived from mammary tissue compared to those derived from other tissues. Knockdown of RACK1 caused abnormal centrosomal localization of BRCA1 and abrogated centriole duplication. Overexpression of RACK1 increased the centrosomal localization of BRCA1. Cancer-derived variants of BRCA1, BARD1, OLA1, and RACK1 abolished or weakened their interaction and function in centrosome duplication. These data suggest that the formation of BRCA1/BARD1/OLA1/RACK1 complex is important for centrosome regulation to maintain genome stability and that dysfunction of this complex will increase tumor heterogeneity that associated with carcinogenesis and cancer progression.
Citation Format: Natsuko Chiba. Dysfunction of centrosome regulation by BRCA1-containing complex increases tumor heterogeneity [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 PO-075.