Top 8 Biorxiv Papers Today in Cancer Biology


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#1. Tyrosine phosphorylation of ACLY regulates lipid metabolism and oncogenesis in ALK positive Anaplastic Large Cell Lymphoma
Johnvesly Basappa, Mahmoud ElAzzouny, Delphine Rolland, Anagh Sahasrabuddhe, Kaiyu Ma, Gleb Bazilevsky, Steven R Hwang, Venkatesh Basrur, Kevin Conlon, Nathanael Bailey, John Frederiksen, Santiago Schnell, Yeqiao Zhou, David Cookmeyer, Jan Pawlicki, Amit Dipak Amin, James Riley, Robert Faryabi, Jonathan Schatz, Kathryn Wellen, Ronen Marmorstein, Charles Burant, Kojo SJ Elenitoba-Johnson, Megan Lim
A fundamental requirement for growth of rapidly proliferating cells is metabolic adaptation to promote synthesis of biomass. ATP citrate lyase (ACLY) is a critical enzyme responsible for synthesis of cytosolic acetyl-CoA, the key building component for de novo fatty acid synthesis and links vital pathways such as carbohydrate and lipid metabolism. The mechanisms of ACLY regulation are not completely understood and the regulation of ACLY function by tyrosine phosphorylation is unknown. Here we show using mass-spectrometry-driven phosphoproteomics and metabolomics that ACLY is phosphorylated and functionally regulated at an evolutionary conserved residue, Y682 in ALK+ lymphoma. Physiologic signals promoting rapid cell growth such as epidermal growth factor stimulation in epithelial cells and T-cell receptor activation in primary human T-cells result in rapid phosphorylation of ACLY at Y682. In vitro kinase assays demonstrate that Y682 is directly phosphorylated by multiple tyrosine kinases, including ALK, ROS1, SRC, JAK2 and LTK....
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#2. Use of Transabdominal Ultrasound for the Detection of Intra-Peritoneal Tumor Engraftment and Growth in Mouse Xenografts of Epithelial Ovarian Cancer
Laura Chambers, Emily Esakov, Chad Braley, Mariam AlHilli, Chad Michener, Ofer Reizes
Objective:  To evaluate intraperitoneal (IP) tumor engraftment, metastasis and growth in a pre-clinical murine epithelial ovarian cancer (EOC) model using both transabdominal ultrasound (TAUS) and bioluminescence in vivo imaging system (IVIS).  Methods: Ten female C57Bl/6J mice at six weeks of age were included in this study. Five mice underwent IP injection of 5x10 6 ID8-luc cells (+ D- luciferin) and the remaining five mice underwent IP injection of ID8-VEGF cells. Monitoring of tumor growth and ascites was performed weekly starting at seven days post-injection until study endpoint. ID8-luc mice were monitored using both TAUS and IVIS, and ID8-VEGF mice underwent TAUS monitoring only. Individual tumor implant dimension and total tumor volume were calculated. Average luminescent intensity was calculated and reported per mouse abdomen. Tumor detection was confirmed by gross evaluation and histopathology. All data are presented as mean +/- standard deviation. Results: Overall, tumors were successfully detected in all ten mice using...
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#3. High Content Phenotypic Profiling in Oesophageal Adenocarcinoma Identifies Selectively Active Pharmacological Classes of Drugs for Repurposing and Chemical Starting Points for Novel Drug Discovery
Rebecca E Hughes, Richard J R Elliott, Alison F Munro, Ashraff Makda, J Robert O'Neill, Ted Hupp, Neil O Carragher
Oesophageal adenocarcinoma (OAC) is a highly heterogeneous disease, dominated by large-scale genomic rearrangements and copy number alterations. Such characteristics have hampered conventional target-directed drug discovery and personalized medicine strategies contributing to poor outcomes for patients diagnosed with OAC. We describe the development and application of a phenotypic-led OAC drug discovery platform incorporating image-based, high-content cell profiling and associated image-informatics tools to classify drug mechanism-of-action (MoA). We applied a high-content Cell Painting assay to profile the phenotypic response of 19,555 compounds across a panel of six OAC cell lines representing the genetic heterogeneity of disease, a pre-neoplastic Barrett's oesophagus line and a non-transformed squamous oesophageal line. We built an automated phenotypic screening and high-content image analysis pipeline to identify compounds that selectively modified the phenotype of OAC cell lines. We further trained a machine-learning model to...
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#4. Hotspots of aberrant enhancer activity in fibrolamellar carcinoma reveal molecular mechanisms of oncogenesis and intrinsic drug resistance
Timothy A Dinh, Ramja Sritharan, F Donelson Smith, Adam B Francisco, Rosanna K Ma, Rodica P Bunaciu, Matt Kanke, Charles G Danko, Andrew P Massa, John D Scott, Praveen Sethupathy
Fibrolamellar carcinoma (FLC) is a rare, therapeutically intractable liver cancer that disproportionately affects youth. Although FLC tumors exhibit a distinct gene expression profile, the causative transcriptional mechanisms remain unclear. Here we used chromatin run-on sequencing to discover approximately 7,000 enhancers and 141 enhancer hotspots activated in FLC relative to non-malignant liver. Detailed bioinformatic analyses revealed aberrant ERK/MEK signaling and candidate master transcriptional regulators. We also defined the genes most strongly associated with aberrant FLC enhancer activity, including CA12 and SLC16A14. Treatment of FLC cell models with inhibitors of CA12 or SLC16A14 independently reduced cell viability and/or significantly enhanced the effect of MEK inhibitor cobimetinib. These findings highlight new molecular targets for drug development as well as novel drug combination approaches.
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#5. Mechanical-control of cell proliferation increases resistance to chemotherapeutic agents
Ilaria Rizzuti, Pietro Mascheroni, Silvia Arcucci, Zacchari Ben-Meriem, Audrey Prunet, Catherine Barentin, Charlotte Riviere, Helene Delanoe-Ayari, Haralampos Hatzirikou, Julie Julie Guillermet-Guibert, Morgan Delarue
While many cellular mechanisms leading to chemotherapeutic resistance have been identified, there is an increasing realization that tumor-stroma interactions also play an important role. In particular, mechanical alterations are inherent to solid cancer progression and profoundly impact cell physiology. Here, we explore the impact of compressive stress on the efficacy of chemotherapeutics in pancreatic cancer spheroids. We find that increased compressive stress leads to decreased drug efficacy. Theoretical modeling and experiments suggest that mechanical stress leads to decreased cell proliferation which in turn reduces the efficacy of chemotherapeutics that target proliferating cells. Our work highlights a mechanical-form of drug resistance, and suggests new strategies for therapy.
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AgataNyga: RT @biorxivpreprint: Mechanical-control of cell proliferation increases resistance to chemotherapeutic agents https://t.co/sKSdP5xXH2 #bio…
SineadAphrodite: RT @biorxivpreprint: Mechanical-control of cell proliferation increases resistance to chemotherapeutic agents https://t.co/sKSdP5xXH2 #bio…
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#6. Finding new cancer epigenetic and genetic biomarkers from cell-free DNA by combining SALP-seq and machine learning:esophageal cancer as an example
Shicai Liu, Jian Wu, Qiang Xia, Hongde Liu, Weiwei Li, Xinyi Xia, Jinke Wang
Background: Cancer is an important public health problem worldwide and its early diagnosis and effective prognosis are critical for its treatment. In recent years, as a good material for cancer liquid biopsy, plasma cell-free DNA (cfDNA) has been widely analyzed by next generation sequencing (NGS) for finding new molecular markers for cancer diagnosis such as size, methylation and end coordinate. However, the current studies did not still involve esophageal cancer (ESCA), a main cancer that seriously threatens human health and life in China. Here we therefore tried to find new biomarkers for this cancer from cfDNA. Materials & methods: Thirty cfDNA samples from 26 ESCA patients and 4 healthy people were used to construct the NGS libraries and sequenced by using SALP-seq. The sequencing data were analyzed with variant bioinformatics methods for finding ESCA molecular biomarkers. Results & conclusion: We identified 103 epigenetic markers (including 54 genome-wide and 49 promoter markers) and 37 genetic markers for ESCA. These...
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#7. Limiting Self-Renewal of the Basal Compartment Induces Differentiation and Alters Evolution of Mammary Tumors
Nevena B Ognjenovic, Meisam Bagheri, Gadisti Aisha Mohamed, Ke Xu, Meredith S Brown, Youdinghuan Chen, Mohamed Ashick Mohamed Saleem, Shivashankar H Nagaraj, Kristen E Muller, Brock Christensen, Diwakar R Pattabiraman
Differentiation therapy is an approach that utilizes our understanding of the hierarchy of cellular systems to pharmacologically induce a shift towards terminal commitment. While this approach has been a paradigm in treating certain hematological malignancies, efforts to translate this success to solid tumors have proven challenging. In this study we show that activation of PKA drives aberrant mammary differentiation by diminishing the self-renewing potential of the basal compartment. PKA activation results in tumors that are more benign, exhibiting reduced metastatic propensity, loss of tumor-initiating potential and increased sensitivity to chemotherapy. Analysis of tumor histopathology revealed features of overt differentiation with papillary characteristics. Longitudinal single cell profiling at the hyperplasia and tumor stages uncovered an altered path of tumor evolution whereby PKA curtails the emergence of aggressive subpopulations. PKA activation represents a promising approach as an adjuvant to chemotherapy for certain...
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#8. Neutralizing PD-L1 and PD-L2 Enhances the Efficacy of Immune Checkpoint Inhibitors in Ovarian Cancer.
Yu Rebecca Miao, Kaushik N Thakkar, Jin Qian, Mihalis S Kariolis, Wei Huang, Saravanan A Nandagopal, Teddy Yang, Anh N Diep, Gerald Maxwell Cherf, Yu Xu, Eui Jung Moon, Yiren Xiao, Haizea Alemany, Tiane Li, Wenhua Yu, Bo Wei, Erinn B Rankin, Amato J. Giaccia
Immune checkpoint inhibitors targeting the PD-1/PD-L1 pathway have improved for a number of solid tumors. Unfortunately, ovarian cancer represents a major clinical hurdle for immune checkpoint blockade (ICB) with reported low patient response rates. Using IHC staining, we find that PD-L2 is highly expressed in ovarian cancers and other malignancies with sub-optimal response to ICB, and is expressed at low levels in cancers responsive to ICB. Based on this observation, we hypothesized that the elevated expression of PD-L2 produced by both tumor and surrounding stromal cells contributes to immune-suppression. Since PD-L2 has been reported to have a 6- to10-fold higher native binding affinity to PD-1 compared with PD-L1, we hypothesized that high levels of PD-L2 can lead to insufficient blockade of the PD-1 signaling pathway. To overcome the immune repressive activity of PD-L2, we engineered a soluble PD-1 decoy molecule (sPD-1 mutant) that binds and neutralizes both PD-L1 and PD-L2 with a 10,000- and 200- fold improvement in binding...
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