bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3691: XPC inhibits lung cancer cell dedifferentiation by suppressing Snail expression
Authors: Cai Shurui , Wu Dayong , Banerjee Ananya , Liu Lu , Han Chunhua , Cui Tiantian , Wang Qi-En 
Published: August 2019

Abstract
Lung cancer remains a leading cause of cancer-related deaths in the United States with unfavorable prognosis mainly due to tumor relapse and metastasis, which are recently believed to be caused by a specific population of cancer cells within tumor termed “cancer stem cells (CSCs)”. These cells share the common characteristic of self-renewal and differentiation as normal stem cell, but also show resistance to chemotherapy and radiation therapy. Thus, targeting CSC populations in lung tumors is critical to the prevention of tumor metastasis. Xeroderma pigmentosum group C (XPC) was first recognized as a DNA repair protein. As a DNA repair factor, XPC plays an important role in preventing carcinogenesis. However, it has also been reported that XPC insufficiency is associated with poor treatment outcomes for a variety of cancers, and low expression of XPC is correlated with poor prognosis of lung cancer patients, suggesting that XPC may suppress lung cancer progression. Here, we show that downregulation of XPC expanded lung CSCs characterized by CD133+, while overexpression of XPC limited this cell population, as well as reduced the tumorigenic potential of the lung cancer cell line. Furthermore, we found that XPC knockdown is able to promote the CD133--to-CD133+ cell conversion in A549 cells, indicating that XPC can inhibit lung cancer cell dedifferentiation. Mechanistic investigation demonstrated that XPC can suppress Snail expression by directly binding to the promoter region of the SNAI1 gene, leading to the enrichment of histone H3 trimethylation at serine 27 (H3K27me3) and loss of histone H3 acetylation at serine 27 (H3K27Ac) in this region. Given that Snail plays a critical role in the induction of epithelial-mesenchymal transition (EMT), which is a major mechanism for the acquisition of stem cell-like properties, we believe that XPC can limit the CSC population by inhibiting cancer cell dedifferentiation. In summary, we conclude that low expression of XPC in lung tumors can de-repress the expression of Snail, promote EMT, and increase the de novo production of CSCs, eventually facilitating lung tumor progression.
Citation Format: Shurui Cai, Dayong Wu, Ananya Banerjee, Lu Liu, Chunhua Han, Tiantian Cui, Qi-En Wang. XPC inhibits lung cancer cell dedifferentiation by suppressing Snail expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3691.
Abstract 3723: Fatty acid synthase: A new therapeutic target for pancreatic cancer
Authors: Steen Travis Vander , Ding Li , Zhang Yu , Kemble George , Billadeau Daniel , Lupu Ruth 
Published: August 2019

Abstract
Pancreatic cancer is the fourth leading cause of cancer related deaths in the United States and continues to be hindered with limited treatment options. One of the current therapeutic regimens for pancreatic cancer often include the nucleoside analog gemcitabine (Gem), while it has been used for many years, the overall survival rate lingers around 6%. New therapies are needed to treat this disease. Fatty acid synthase (FASN) has received increased attention as a potential target for cancer therapy in the last decade. FASN is the key enzyme in the de novo synthesis of palmitate from malonyl-CoA. Palmitate is the precursor other long-chain fatty acids (FA). However, the precise mechanism by which pharmacological interference with endogenous FA biogenesis might facilitate apoptosis in tumor cells remains unresolved. We herein explored the molecular relationship between FASN activity, oxidative stress/redox balance, and the intrinsic apoptotic pathway in FASN overexpressing-dependent pancreatic cancer cells. About 68% of Pancreatic Ductal Carcinomas (PDA) expresses high levels of Fatty acid synthase (FASN), and its expression is correlated with disease free survival. A newly developed FASN inhibitor with excellent pharmaceutical properties was used for our studies TVB-3166 (in vitro) and TVB-3664 (in vivo) and ten different PDX derived cells were used for the studies. Pharmacological blockade of FASN activity significantly increased the NADPH/NADP+ ratio, promoted the production of reactive oxygen species (ROS). Accordingly, the inhibition of endogenous FA synthesis promoted mitochondrial membrane permeabilization, cytochrome c release, and apoptotic cell death. Each step of the FASN inhibition/BH3-only protein axis could be reversed with a ROS scavenger or the FASN end-product palmitate, thus confirming that the delineated pro-apoptotic cascade likely reflects on-target effects of FASN inhibition. Most importantly, the in vivo studies using PaCa-PDX reveal a significant decrease in tumor growth and furthermore a synergistic effect of between TVB-3664 and Gem. In conclusion, our findings uncover a novel FASN-dependent mitochondrial priming that links de novo FA biosynthesis with the intrinsic apoptotic threshold in cancer cells. The discovery that FASN-inhibited cancer cells exist in an apoptosis-prone state highly sensitive to BH3 mimetics warrants clinical exploration in FASN-overexpressing pancreatic cancer patients.
Citation Format: Travis Vander Steen, Li Ding, Yu Zhang, George Kemble, Daniel Billadeau, Ruth Lupu. Fatty acid synthase: A new therapeutic target for pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3723.
Abstract 3725: Numerical simulation of tumor treating fields effects on cell structures: Mechanism and signaling pathway candidates
Authors: Carlson Kristen W. , Paudel Nirmal , Tuszynski Jack A. , Bomzon Zeev 
Published: August 2019

Abstract
Tumor Treating Fields (TTFields) have become a fourth modality for cancer treatment. Mild electric fields (~1-4 V/cm) produce few side effects and significantly extend overall survival of glioblastoma patients, and TTFields are in clinical trials for a variety of tumor cell types. Our goal is to uncover TTFields’ mechanism and cell signaling pathways by numerically modeling their effects on sub-cellular structures, such as microtubules (MTs) and their interactions with motor proteins. METHODS: We have built finite element models in COMSOL Multiphysics (tm) of the MT and its micro-environment to test hypotheses on TTFields’ mechanism of action by predicting effects on sub-cellular structures. RESULTS: One model prediction is that current density induced in the MT counter-ion layer by TTFields essentially shunts electric current within them. The strongest current flows through the counter-ion layer surrounding the MT’s C-termini and energy density in this layer likely exceeds the level to disrupt motor protein ‘walk’ along the MT. The energy density is predicted at 10-20 Joules when both the field and the MTs are aligned with the cell axis. A second mechanism examined by our model is disruption of the ‘foot’ of kinesin, released from its C-terminus contact by ATP (10-19 Joules). The final phase of the walk is driven by thermal buffeting of the forward foot randomly positioning it near enough to the C-terminus for electrostatic forces to bind it. A stall force ~10-19 - 10-16 N from TTFields would prevent diffusion and disrupt the kinesin walk. A recent clinical study segregating patient cohorts treated vs. not treated with dexamethasone found overall survival indefinitely for the non-dexamethosone cohort, leading us to hypothesize that TTFields activate the intrinsic Bcl2-mediated apoptotic signaling pathway. Future modeling will seek to tie disruption of motor protein transport along MTs to activating intrinsic apoptosis, e.g. via failure to silence the G2 cell cycle checkpoint. CONCLUSION: Our modeling predicts that TTFields in cytosol induce electric currents along MTs that are strong enough to disrupt key cellular functions such as the kinesin walk and C-termini transitions, both of which are crucial for motor protein transport. Hence, TTFields disrupt the most delicate mechanisms involved in the carefully-orchestrated succession of steps in mitosis.
Citation Format: Kristen W. Carlson, Nirmal Paudel, Jack A. Tuszynski, Zeev Bomzon. Numerical simulation of tumor treating fields effects on cell structures: Mechanism and signaling pathway candidates [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3725.
Abstract 373: Dysregulated RPB1 is a key driver of overgrowth and drug resistance in acute myeloid leukemia
Authors: Yu Qingfeng , Zheng Shu , Xu Ying , Xu Rongzhen 
Published: August 2019

Abstract
Acute myeloid leukemia (AML) is a group of highly aggressive malignancies with a 5-year overall survival (OS) of &lt;40%. Cell overgrowth with apoptosis resistance is a hallmark of AML, but little is known about how it occurs. In this study, we show that dysregulated the largest subunit of RNA polymerase II (RPB1) encoded by POLR2A gene is critically involved in this hallmark in AML. qRT-PCR and RNA-seq results showed that POLR2A mRNA were significantly overexpressed in 76.87% (113/147) compared with normal hematopoietic cells(1.5526 versus 0.8447, P&lt;0.001). Western blotting analysis revealed that RPB1 protein is also aberrantly activated in 68.14%(67/113) of AML patients but rare or even absent in normal hematopoietic cells, (0.7889 versus 0.0509, P&lt;0.01). TCGA data analysis indicated that aberrant activation of POLR2A mRNA occurred predominantly in AML, CHOL and THYM, but not in most other types of cancers. Importantly, we observed that RPB1 expression levels were closely associated with tumor burden and poor prognosis. Notably, we found that POLR2A inhibition induced potent apoptosis and growth inhibition of refractory AML cells. Global transcriptomic analysis reveals that POLR2A knockout selectively depleted an array of AML-related oncogenic and anti-apoptosis genes such as c-MYC, RUNX2, MEIS1, FLT3, CDC25A and BCL-2. Conversely, enforced overexpression of RPB1 exhibits robust enrichment of oncogenes and anti-apoptosis genes, leading to cell overgrowth and drug resistance. Of particular interesting, targeting RPB1 by both genetic and pharmacological molecules could lead complete regression of refractory human AML in mouse models. In conclusion, our findings for the first time reveal that dysregulated RPB1 is a central oncogenic hub that drives overgrowth and drug resistance by coordinately hijacking an array of oncogenic genes and anti-apoptosis factors. Importantly, RPB1 is not absolutely required for the survival of normal hematopoietic cells, which is contrary to the commonly accepted belief that RPB1, the heart of the cellular transcription machinery, is required for all protein-coding genes. These data suggest that targeting RPB1 might be a potential therapeutics for treating refractory/relapse AML.
Note: This abstract was not presented at the meeting.
Citation Format: Qingfeng Yu, Shu Zheng, Ying Xu, Rongzhen Xu. Dysregulated RPB1 is a key driver of overgrowth and drug resistance in acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 373.
Abstract 3742: Exosome-mediated EGR1 transportation controls the radiation-induced abscopal effect in head and neck cancer
Authors: Akbor Mohammady , Lin Liang-Ting 
Published: August 2019

Abstract
Head and neck cancer (HNC) are one of the vital types of metastatic cancer, and radiotherapy (RT) is the convincing treatment regarding its location. RT can regulate cancer growth in not only directly irradiated cells but also non-irradiated remote cells by abscopal or bystander effects. It is evident that radiation-induced Early Growth Response 1 (EGR1) is involved in the control of such type cancer progression. Also, exosomes are established carriers for biological factors basically in cell communication. In this study, we would like to identify the EGR1 as a functional molecule that carried by the radiation-induced exosome to control the HNC growth to disclose the molecular mechanism of the abscopal effect. In this case, we used FaDu cell, a hypopharyngeal cancer, for in vitro experiments. Irradiation was given to the cells in a dose-dependent manner from 0 to 12 Gy followed by exosome isolation using miRCURY Exosome Cell Kit. Characterization of the isolated exosomes was performed by Nanoparticle Tracking Analysis (NTA) for vesicle sizes and concentration, and by transmembrane markers CD63 and CD9 through western blot. We treated unirradiated FaDu cells with isolated exosomes to address the phenotypic changes. MTT assay and colony-forming assay observed the cell viability and survival. Moreover, the expression of EGR1 in both radiation-induced exosome and the exosome-treated cells were determined by western blot. To validate the causal effect of exosomal transportation of EGR1, we assessed the viability changes in EGR1-silenced FaDu cells with exosome treatment. Our results indicated that the number of exosomes was increased while the amounts of protein in each isolated exosome were also increased in a radiation dose-dependent manner. CD63 and CD9 had been identified through western blotting. Moreover, the enhanced expression of EGR1 was observed in both radiation-induced exosomes and the cells treated with isolated exosomes. The possible abscopal effect was evident by the significant decrease of the viability of unirradiated FaDu cells treated with radiation-induced exosomes. Besides, elevated expression of EGR1 was noticed in the radiation-induced exosomes comparing to non-irradiated cohorts. Notably, EGR1-containing exosomes can suppress the proliferation of the unirradiated FaDu cells. Alternatively, radiation-induced EGR1-containing exosome failed to inhibit the proliferation of EGR1 knockdown FaDu cells. In conclusion, radiation-induced EGR1 via exosome transportation contributes to the mechanism of the abscopal effect for metastatic head and neck cancer.
Citation Format: Mohammady Akbor, Liang-Ting Lin. Exosome-mediated EGR1 transportation controls the radiation-induced abscopal effect in head and neck cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3742.
Abstract 3757: Probing glioblastoma and its microenvironment at single cell resolution
Authors: Peng Sen , Rath Sanhita , Bollam Saumya , Eschbacher Jenny , Mehta Shwetal , Sanai Nader , Berens Michael , Kim Seungchan , Dhruv Harshil 
Published: August 2019

Abstract
Single-cell sequencing (scSeq) is a powerful tool to investigate cancer genomics at single cell resolution. Multiple studies have recently illuminated intratumoral heterogeneity in glioblastoma, however, the majority focused on molecular complexity of tumor cells, without taking into account unexplored host cell types that contribute to the microenvironment around GBM tumor. To address the glioblastoma microenvironment composition and potential tumor-host interactions, we performed deep coverage (176k average reads per cell) scSeq of freshly resected primary GBM patient tissue without implementing any tumor cell enrichment strategies. scSeq libraries for 902 cells were prepared using 10X Gemcode platform and sequenced on Illumina NextSeq 500. This run was of high quality with 2,663 median genes per cell and low mitochondrial gene percentage (median &lt; 5%). We used Cell Ranger analysis pipelines and Seurat packages to classify individual cells into 10 clusters and visualize them using t-SNE two-dimensional projections. We then identified the signature gene set for each cluster, relative to all other cells. Pathway analysis of each cluster signature along with known GBM microenvironment cell signatures revealed glioma tumor population along with surrounding microglia/marcophages, astrocytes, pericytes, oligodendrocytes, T cells and endothelial cells. Cell type markers identified by single cell transcriptomics were validated by IHC analysis. Microenvironmental composition and single cell signature will be confirmed through single nuclei sequencing of preserved (Frozen) tumor sample. Our results demonstrate the cellular diversity of brain tumor microenvironment and lay a foundation to further investigate the individual tumor and host cell transcriptomes that are influenced not only by their cell identity but also by their interaction with surrounding microenvironment.
Citation Format: Sen Peng, Sanhita Rath, Saumya Bollam, Jenny Eschbacher, Shwetal Mehta, Nader Sanai, Michael Berens, Seungchan Kim, Harshil Dhruv. Probing glioblastoma and its microenvironment at single cell resolution [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3757.
Abstract 3759: Host and neoplastic cell secretions of proteolytic enzymes potentiate metastasis
Authors: Dykes Samantha S. , Fasanya Henrietta O. , Siemann Dietmar W. 
Published: August 2019

Abstract
The presence of macrophages within breast tumors is associated with metastatic potential. Tumor-associated macrophages are often stimulated by Interleukin-4, resulting in a pro-tumorigenic (M2-like) phenotype and the secretion of growth factors and proteases, including the lysosomal protease cathepsin L (CTSL). CTSL is often secreted by breast cancer cells and stromal cells and contributes to tumor invasion, metastasis, and angiogenesis. We hypothesized that secretion of the proteolytic enzyme cathepsin L by both tumor-associated macrophages and neoplastic cells facilitate tumor invasion and dissemination. Initial studies found that inhibiting CTSL using the novel cathepsin L/K inhibitors KGP94 and KGP207 prevented in vitro M2 macrophage invasion and reduced macrophage-stimulated invasion of 4T1 murine breast cancer cells. Interestingly, KGP94 and KGP207 also reduced the expression of several M2-associated markers, suggesting that CTSL activity may be important for Interleukin-4-driven M0 to M2 differentiation. Furthermore, CTSL shRNA knockdowns revealed that CTSL supplied from both the tumor cell and the macrophage population is important for tumor cell invasion. These data suggest that tumor cells and macrophages may both contribute to the CTSL-driven metastatic phenotype of breast cancer. Taken together, these studies highlight the importance of CTSL in macrophage functions and suggest that cathepsin inhibition strategies may be therapeutically beneficial by impairing the progression of tumors with high infiltration of M2 macrophages.
Citation Format: Samantha S. Dykes, Henrietta O. Fasanya, Dietmar W. Siemann. Host and neoplastic cell secretions of proteolytic enzymes potentiate metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3759.
Abstract 3768: Single-cell characterization and lineage tracking of recurrent pediatric rhabdomyosarcoma
Authors: Patel Anand G. , Stewart Elizabeth , Clay Michael , Chen Xiang , Dyer Michael 
Published: August 2019

Abstract
A critical challenge for the effective treatment of pediatric solid tumors is tumor recurrence. In pediatric rhabdomyosarcoma (RMS), 70% of patients with metastatic disease will experience relapse despite treatment with chemotherapy, radiation and/or surgery. Those patients with relapse have particularly dismal outcomes with less than 20% survival over 5 years. These poor outcomes underscore the need for a better understanding of RMS, particularly the biologic processes responsible for recurrence and progression. Currently, a major obstacle towards improving RMS treatment has been that we, as a field, do not know which cells within RMS tumors evade treatment toxicity, and how these cells are selected for in the presence of chemotherapy.
We have previously developed a panel of orthotopic patient-derived xenografts (O-PDXs) that encompass the clinical and molecular diversity of RMS. In this study, we have leveraged single-cell RNA-sequencing (scRNA-seq) of our O-PDX system to characterize the intratumoral heterogeneity within this panel. Analysis of single-cell transcriptomic data demonstrate that fusion-negative RMS O-PDXs bear two distinct subpopulations: (1) a major subpopulation encompassing approximately 99% of the tumor cells, and (2) a minor population that are non-cycling and express genes from a variety of mesenchymal lineages. This two-population intratumoral structure is stable within O-PDXs during passaging of xenografts.
To extend these findings, we have developed a workflow using lentiviral transduction of O-PDX cells with a high complexity barcode library. This library integrates a unique 18-mer oligonucleotide barcode into each transduced cell within the 3’-untranslated region of blue fluorescent protein. Thus, all cells within an O-PDX with the same barcode are progeny of the same ancestral cell. We have validated longitudinal tracking of barcode diversity using genomic DNA and within the libraries generated during scRNA-seq. Mice bearing barcoded O-PDXs have undergone chemotherapy dosed to pharmacokinetically mimic pediatric therapy regimens; O-PDXs regress during treatment and ultimately recur following completion of therapy, akin to the clinical experience with RMS. Recurrent O-PDXs bear divergent barcodes, indicating that chemotherapy selects for tumor cells independent of the originating lineage of those cells. Further studies to evaluate the changes that occur in recurrent O-PDXs cells are underway.
Citation Format: Anand G. Patel, Elizabeth Stewart, Michael Clay, Xiang Chen, Michael Dyer. Single-cell characterization and lineage tracking of recurrent pediatric rhabdomyosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3768.