bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract IA20: Aberrant leukemic developmental hierarchies and MRD-specific targeting informed by single-cell biophysical and molecular profiling
Authors: Winter Peter S. , Navia Andrew , Strouf Haley , Mirza Mahnoor , Galvez-Reyes Jennyfer , Mulugeta Nolawit , Bilal Laura , Senhaji Nezha , Dennis Peter , Leahy Catharine S. , Shigemori Kay , Powers Foster , Gupta Alejandro , Calistri Nicholas , Van Scoyk Alex , Jones Kristen , Liu Huiyun , Stevenson Kristen E. , Kimmerling Robert , Stevens Mark , Weinstock David M. , Manalis Scott R. , Murakami Mark A. , Shalek Alex K. 
Published: December 2020

Abstract
Targeted inhibitors of essential oncogenic kinases induce high rates of clinical response but cure few patients due to the persistence of minimal residual disease (MRD). BCR-ABL mutant leukemias are a classic example of this paradigm where patients usually achieve deep remissions followed by near inevitable relapses. Multiple factors have been shown to influence how an individual patient’s leukemic cells will navigate treatment including differentiation state, mutational background, and communication with the microenvironment. Here, we use BCR-ABL-rearranged acute lymphoblastic leukemia (BCR-ABL ALL) to interrogate cell-autonomous features leading to therapeutic resistance using low-input single-cell assays. Specifically, we use a combination of primary samples and PDX models to dissect aberrant developmental hierarchies and monitor leukemic cell transcriptional and biophysical phenotype at pretreatment, MRD, and relapse. Using machine learning, we relate malignant B cells to normal development, allowing us to define leukemic developmental programs and demonstrate that these have consequences for the time to progression as well as the genetic alterations seen at relapse. Further, we determine that there are unique biophysical features tied to leukemic developmental states and that these integrative properties co-evolve with transcriptional state over the course of treatment. Finally, we demonstrate in PDX studies that it may be possible to intercept relapse by targeting specific features of MRD cells. Together, these data suggest that significant developmental hierarchies exist in ALL, tumor subpopulations can be identified directly within MRD, and their phenotypic and molecular characterization can be exploited to therapeutic effect.
Citation Format: Peter S. Winter, Andrew Navia, Haley Strouf, Mahnoor Mirza, Jennyfer Galvez-Reyes, Nolawit Mulugeta, Laura Bilal, Nezha Senhaji, Peter Dennis, Catharine S. Leahy, Kay Shigemori, Foster Powers, Alejandro Gupta, Nicholas Calistri, Alex Van Scoyk, Kristen Jones, Huiyun Liu, Kristen E. Stevenson, Robert Kimmerling, Mark Stevens, David M. Weinstock, Scott R. Manalis, Mark A. Murakami, Alex K. Shalek. Aberrant leukemic developmental hierarchies and MRD-specific targeting informed by single-cell biophysical and molecular profiling [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 IA20.
Abstract IA21: Stem cells play a role in human leukemia from origin to relapse
Authors: Dick John E. 
Published: December 2020

Abstract
Individual cancer cells exhibit functional heterogeneity of many cancer hallmarks including the capacity for sustaining long-term clonal maintenance, a stemness property involving self-renewal. Our studies established that only rare AML cells possessed such leukemia stem cell (LSC) properties and that AML is a cellular hierarchy. LSC were found to be highly relevant to human disease as gene signatures specific to LSC were much more predictive of patient response to therapy and overall survival compared to the bulk non-LSC AML cells. We have now provided insights into how LSC develop during leukemogenesis. Through sequencing of purified populations of normal blood cells, AML cells, and xenografts from paired diagnosis/relapse AML samples, we tracked the full arc of leukemia development in humans: from the cell of origin (an HSC) that acquires the first genetic mutation; to pre-leukemic clonal expansion of HSC; the generation of genetically diverse LSC; and finally to the cellular origin of relapse (rare LSC subclones) within the diagnosis sample. Similar studies have been undertaken in B-ALL where relapse-fated subclones were found within the diagnosis sample before exposure to chemotherapy. These clones possess distinct epigenetic and metabolic properties that underlie their partially resistance to chemotherapy and they possess stemness signatures that drive their ability to regenerate relapse disease. These studies resulted in identification of novel therapeutic targets of relapse-fated subclones to begin envisioning approaches to eradicate relapse before it develops. Finally, the identification of clonally expanded pre-leukemic HSPC in the diagnosis blood sample of many AML samples predicted that it should be possible to identify individuals who are at risk for progressing to AML long before AML develops. We genotyped individuals from the general population who were enrolled in the large cohort (EPIC) who eventually developed AML and compared them to the enrollment sample of others who never progressed to AML. We have found a clear signature that is able to predict with high accuracy those individuals who have age related clonal hematopoiesis who progress to AML, almost 10 years prior to AML development. This is distinct from individuals who have benign clonal hematopoiesis who never progress. These new findings offer the potential for future intervention to permit AML prevention trials.
Citation Format: John E. Dick. Stem cells play a role in human leukemia from origin to relapse [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 IA21.
Abstract IA24: Dissecting glioblastoma by single cell RNA-seq
Authors: Hara Toshi , Chanoch Rony , Suva Mario , Tirosh Itay 
Published: December 2020

Abstract
Glioblastoma is an incurable malignancy that remains poorly understood. By large-scale single cell RNA-seq and follow up experiments we found that malignant cells in glioblastoma exist in four main cellular states that recapitulate distinct steps of neural development, are influenced by the tumor microenvironment, and exhibit plasticity. Importantly, we show that while each glioblastoma contains similar cellular states, their relative frequency varies between tumors and is influenced by chromosomal aberrations as well as by the tumor microenvironment. In particular, we demonstrate that macrophages induce a transition of glioblastoma cells into mesenchymal-like (MES-like) states. This effect is mediated, both in vitro and in vivo, by macrophage-derived ligands that interact with receptors on glioblastoma cells. Finally, we show that MES-like glioblastoma states is associated with altered T cells cytotoxicity and response to immunotherapies. Overall, this work dissects the cellular diversity and interactions within the glioblastoma microenvironment, with potential implications for therapies.
Citation Format: Toshi Hara, Rony Chanoch, Mario Suva, Itay Tirosh. Dissecting glioblastoma by single cell RNA-seq [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 IA24.
Abstract IA26: Tumor evolution: From Darwin’s finches to breast cancer
Authors: Polyak Kornelia 
Published: December 2020

Abstract
Tumor evolution is driven by heterogeneity for heritable traits in combination with environmental selection forces including cancer therapies. We have been investigating intratumor cellular genetic and phenotypic heterogeneity in breast tumors and described that higher heterogeneity is associated with poor clinical outcomes. We have also developed experimental models of intratumor subclonal heterogeneity and demonstrated that more heterogeneous tumors grow faster and develop heterogeneous distant metastases. By analyzing the underlying mechanisms we defined that intratumor heterogeneity is maintained by non-cell-autonomous factors and clonal cooperation drives metastases by modulating the local and systemic microenvironments. Lastly, we have identified epigenetic enzymes as regulators of cellular transcriptomic heterogeneity and showed that by modulating the activity of these enzymes, we can decrease cellular heterogeneity and therapeutic resistance. Overall, our studies demonstrate the need to study cancer patients as a whole and to apply a combination of molecular profiling, including single cell assays, and mathematical modeling to understand how tumors evolved and to develop more effective cancer therapeutic strategies based on this knowledge.
Citation Format: Kornelia Polyak. Tumor evolution: From Darwin’s finches to breast 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 IA26.
Abstract PO-003: Bivalent histone modifications: Clinical targets against pancreatic cancer stem cell heterogeneity
Authors: Das Madhumita , Doke Mayur , Gonzalez Edwin , Diaz Daima , Pineda Bryan , Celli Jonathan , Ruiz Marco , Das Jayanta K. 
Published: December 2020

Abstract
Bivalent histone modifications, the pre-transcriptional regulators were known as the chief orchestra underlining the mechanism of development for pancreatic cancer stem cells (PANCSCs) recently. The histone bivalency methylations are related to the transcriptional activation as well as repression of the prominent histone methylations (H3K4me3 and H3K27me3) at the transcript start sequence (TSS). These epigenetic changes are recognized to initiate heterogenic cancer stem cells (CSCs) reprogramming. Recent studies showed that the heterogenic CSCs are more resistant to anti-tumor drug therapy. Our previous study showed the relationship between bivalent histone modifications with the expression of pancreatic CSCs(CD44, CD24, CD133, Ep-CAM, ALDH1A3). Our current study is focused on the importance of designing anti-cancer drugs or epigenetic small molecules against bivalent histone modifications (to inhibit the upregulation of H3K4me3 or down-regulation of H3K27me3) related the expression of heterogenic pancreatic CSCs (CD44, CD24, CD133, Ep-CAM, ALDH1A3). The Cancer Stem Cells Therapeutic Target Database Version 2.0 (CSCTTv2.0) reported the high CD133 as PAN CSCs and high CD133, CD44 showed resistance to anticancer drugs (such as docetaxel, 5-FU, irinotecan, oxaliplatin) in many cancers. The Gemcitabine, a nucleoside analog, and Metformin are only drugs used for pancreatic cancer treatment and showed resistance against heterogenic PANCSCs. The biological informatics analyses (Cytoscape database, HPIDb, Spike, BioGrid, Reactome, MBInfo) were deployed in our study to find the effect of bivalent histone modifications on the TSS of the target genes in heterogenic PANCSCs and we found the effect at TSS of target genes CD44, and EZH2/ENX1. We also found a novel small molecule KY-02111 has an effect to reduce the expression of heterogenic PANCSCs at tumorigenic in vitro 3D spheroids model of PANC-1ORGR (Gemcitabine resistant) cells. Therefore, our preliminary study may give an important clue to find further the role of KY-02111 against the heterogenic pancreatic CSCs by inhibiting the upregulation of H3K4me3 or down-regulation of H3K27me3 as a clinical target for pancreatic cancer therapy.
Citation Format: Madhumita Das, Mayur Doke, Edwin Gonzalez, Daima Diaz, Bryan Pineda, Jonathan Celli, Marco Ruiz, Jayanta K. Das. Bivalent histone modifications: Clinical targets against pancreatic cancer stem cell 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-003.
Abstract PO-006: Single cell transcriptomic analysis of primary head and neck cancer stem cells
Authors: Neal Molly E. Heft , The Stephanie , Owen John Henry J. , Chang Clifford , Prince Mark E.P. , Rao Arvind , Chinn Steven B. 
Published: December 2020

Abstract
Despite advances in treatment modalities for head and neck squamous cell carcinoma (HNSCC) survival rates remain unchanged. Tumor heterogeneity within HNSCC as well as within the tumor microenvironment (TME) has been shown to be a major driver of treatment failure and poor outcomes. A key component of the TME and a potential key to deciphering tumor heterogeneity are cancer stem cells. While numerous studies have demonstrated the tumorigenicity and malignant potential of these cells, few studies have investigated their expression profiles. The aim of this study is to leverage single cell technology to investigate the expression profile of primary HNSCC cancer stem cells. We performed single cell sequencing of five primary HPV-negative head and neck cancers and two HNSCC cell lines that were presorted into the CSC (CD44high/ALDH+) and non-CSC (CD44low/ALDH-) phenotype. We are able to characterize an expression profile of the CSC TME niche and a novel CSC expression profile (DCN, C110rf96, KLF4, MEG3 and NR4A1) relative to non-CSC. We confirm this CSC profile is conserved across all five primary tumors. Together these data provide some of the first insights into CSC transcriptome, further define the CSC-TME niche, and identify conserved targets within HNSCC CSC as a means to decipher the challenges inherent to tumor heterogeneity.
Citation Format: Molly E. Heft Neal, Stephanie The, John Henry J. Owen, Clifford Chang, Mark E.P. Prince, Arvind Rao, Steven B. Chinn. Single cell transcriptomic analysis of primary head and neck 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-006.
Abstract PO-014: Harnessing the heterogeneity of circulating hybrid cells in pancreatic adenocarcinoma
Authors: Walker Brett Scott , Sengupta Sidharth , Parappilly Michael , Ors Aysegul , Fischer Jared , Sutton Thomas , Sheppard Brett , Mayo Skye , Wong Melissa 
Published: December 2020

Abstract
Pancreatic adenocarcinoma (PDAC) remains one of the most lethal malignancies in the United States and tumor heterogeneity has major implications on the effectiveness of systemic therapies. Comprehensive tumor analysis at the single cell level offers an in-depth examination of neoplastic cells with metastatic potential and supports development of individualized treatment strategies to ultimately improve survival. Hybrid cells are a novel cell population derived from immune-cancer cell fusion within solid tumors and disseminate into peripheral blood, where they can be detected as circulating hybrid cells (CHCs) based on their dual expression of tumor and immune cell epitopes. Compared to conventionally-defined circulating tumor cells (CTCs), CHCs are found in patients at higher levels which allows for more robust phenotypic analyses of tumor cell features and collection for downstream multi-omic profiling. To investigate heterogeneity among disseminated CHCs in patients with PDAC, we assessed for tumor cell features using immunohistochemical analyses of single cells from peripheral blood mononuclear cell smears and by single cell RNA sequencing (scRNA-seq) from FACS-isolated cells. Downstream image analyses was performed Zeiss Zen blue software and scRNA-seq was analyzed using the Seurat analysis package. We determined that PDAC patients harbored heterogeneous populations of CHCs with differential protein expression that mirrored expression in corresponding primary tumors. Further, scRNA-seq analyses identified CHC populations with varying degrees of retained tumor identity, as well as subsets derived from different immune cell lineages. Unsupervised clustering of CHCs with tumor-dominate phenotypes demonstrated high differential expression of cancer related genes with known implications in PDAC tumors and treatment resistant pathways. Inference copy number variation analysis revealed chromosomal amplifications of 1q and 19q along with deletions of 6p, 12q, and 22q, characteristic of PDAC tumors. Additionally, a myriad of KRAS mutations were identified in patient CHCs but absent in normal leukocytes. As the product of tumor and immune cell fusion, CHCs provide a rich source for assessing PDAC heterogeneity through genetic and protein expression analyses. Ultimately, CHCs have great potential as a liquid biopsy in pancreatic cancer which could be harnessed to guide therapy.
Citation Format: Brett Scott Walker, Sidharth Sengupta, Michael Parappilly, Aysegul Ors, Jared Fischer, Thomas Sutton, Brett Sheppard, Skye Mayo, Melissa Wong. Harnessing the heterogeneity of circulating hybrid cells in pancreatic adenocarcinoma [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-014.
Abstract PO-020: Inferring copy number substructure from single-cell transcriptomics in human tumors with CopyKat
Authors: Gao Ruli , Bai Shanshan , Ying Henderson , Lin Yiyun , Seth Tapsi , Hu Min , Sei Emi , Davis Alexander , Wang Fang , Wang Jennifer Rui , Chen Ken , Moulder Stacey , Lai Stephen , Navin Nicholas 
Published: December 2020

Abstract
High-throughput single cell transcriptomics analysis is widely used to study human tumors, however a major challenge is distinguishing the stromal cells from the malignant cancer cells, as well as clonal substructure within tumors. To address this challenge, we developed an integrative Bayesian segmentation approach, COPYKAT to estimate genomic copy numbers at 5MB resolution from high-throughput single cell RNA-seq data. We applied COPYKAT to 39,709 single cells from 16 tumors across 4 cancer types, including premalignant and triple-negative breast cancers, pancreatic ductal adenocarcinomas, and anaplastic thyroid cancer. From these data we could accurately (98%) classify tumor cells from stromal cells. In three TNBC tumors COPYKAT resolved multiple clonal subpopulations of genotypes that differed in expression of breast cancer genes and enrichment of cancer hallmarks including EMT and hypoxia. These data show that COPYKAT can accurately resolve clonal copy number substructure in tumors and classify tumor and normal cells in a variety of human cancers.
Citation Format: Ruli Gao, Shanshan Bai, Henderson Ying, Yiyun Lin, Tapsi Seth, Min Hu, Emi Sei, Alexander Davis, Fang Wang, Jennifer Rui Wang, Ken Chen, Stacey Moulder, Stephen Lai, Nicholas Navin. Inferring copy number substructure from single-cell transcriptomics in human tumors with CopyKat [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-020.
Abstract PO-037: Characterization of stemness and immunogenicity of cancer stem cells of intrahepatic cholangiocarcinoma
Authors: Fu Jianyang , Zhu Yunhua , McGrath Nichole A. , Cam Maggie , Xie Changqing 
Published: December 2020

Abstract
Cholangiocarcinoma (CCA) is one of leading causes of cancer related mortality with limited treatment options. Cancer stem cells (CSCs) have been recognized as a critical driving force of CCA initiation and drug-resistance, representing an attractive and innovative therapeutic target. In this study, single-cell transcriptomic landscape of cancer biospecimens from 10 patients with intrahepatic cholangiocarcinoma (iCCA) were investigated. We characterized CSC in CCA subtypes and identified the differential genes between CSCs and malignant cells. We found that there is the heterogeneity of CSCs in iCCA in terms of stemness makers and immunity per se. Our study pointed to low immunity spectrum of CSCs of iCCA that contribute to immune evasion. We found that SPP1 gene is highly expressed compared to malignant cells in CSC, which indicated that Osteopontin, which is coded by SPP1, may acts as an immune checkpoint to suppress T cell activation and confer host tumor immune tolerance. Our analysis from TCGA database also confirmed that, stemness was strongly associated with cell native immunosuppressive pathway and SPP1 gene expression. Our data indicate that CSC evade innate immune suppression through induced SPP1 expression and Osteopontin may serve as a potential therapeutic intervention for CCA patients.
Citation Format: Jianyang Fu, Yunhua Zhu, Nichole A. McGrath, Maggie Cam, Changqing Xie. Characterization of stemness and immunogenicity of cancer stem cells of intrahepatic cholangiocarcinoma [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-037.
Abstract PO-039: Spatially discrete signalling niches regulate fibroblast heterogeneity in human lung cancer
Authors: Hanley Christopher Jon , Waise Sara , Rachel Parker , Lopez Maria-Antoinette , Taylor Julian , Kimbley Lucy , West Jonathon , Ottensmeier Christian , Rose-Zerilli Mat , Thomas Gareth 
Published: December 2020

Abstract
In this study we set out to define the prominent fibroblast subpopulations found in human non-small cell lung cancer. Fibroblasts are functionally heterogeneous cells, capable of promoting and suppressing tumor progression. Across cancer types, the extent and cause of this phenotypic diversity remains unknown. We used single-cell RNA sequencing and multiplexed immunohistochemistry to examine fibroblast heterogeneity in human lung and non-small cell lung cancer (NSCLC) samples. We then performed in silico and in vitro analyses to examine the molecular mechanisms regulating fibroblast phenotypes. Single-cell RNA sequencing identified seven fibroblast subpopulations: including inflammatory fibroblasts and myofibroblasts (representing terminal differentiation states), quiescent fibroblasts, proto-myofibroblasts (x2) and proto-inflammatory fibroblasts (x2). Multiplex immunohistochemistry showed that these fibroblast subpopulations were variably distributed throughout tissues but accumulated at discrete niches associated with differentiation status. Bioinformatics analyses suggested TGF-β1 and IL-1 as key regulators of myofibroblastic and inflammatory differentiation respectively. However, in vitro analyses showed that whilst TGF-β1 stimulation in combination with increased tissue tension could induce myofibroblast marker expression, it failed to fully re-capitulate ex-vivo¬ phenotypes. Similarly, IL-1β treatment only induced upregulation of a subset of inflammatory fibroblast marker genes. In silico modelling of ligand-receptor signaling identified additional pathways and cell interactions likely to be involved in fibroblast activation. This highlighted a potential role for IL-11 and IL-6 (among other ligands) in myofibroblast and inflammatory fibroblast activation respectively. This analysis provides valuable insight into fibroblast subtypes and differentiation mechanisms in NSCLC.
Citation Format: Christopher Jon Hanley, Sara Waise, Parker Rachel, Maria-Antoinette Lopez, Julian Taylor, Lucy Kimbley, Jonathon West, Christian Ottensmeier, Mat Rose-Zerilli, Gareth Thomas. Spatially discrete signalling niches regulate fibroblast heterogeneity in human lung 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-039.