Biology subjects

Edwards, R. A.

Publications and source records attributed to Edwards, R. A..

42 records · Page 3Linked to original sources

bioRxiv2020

Patient-derived xenograft culture-transplant system for investigation of human breast cancer metastasis

Metastasis is a fatal disease where research progress has been hindered by a lack of authentic experimental models. Here, we develop a 3D tumor sphere culture-transplant system that facilitates the expansion and engineering of patient-derived xenograft (PDX) tumor cells for functional metastasis assays in vivo. Orthotopic transplantation and RNA sequencing analyses show that PDX tumor spheres maintain tumorigenic potential, and the molecular marker and global transcriptome signatures of native tumor cells. Tumor spheres display robust capacity for lentiviral engineering and dissemination in spontaneous and experimental metastasis assays in vivo. Inhibition of pathways previously reported to attenuate metastasis also inhibit metastasis after sphere culture, validating our approach for authentic investigations of metastasis. Finally, we demonstrate a new role for the metabolic enzyme NME1 in promoting breast cancer metastasis, providing proof-of-principle that our culture-transplant system can be used for authentic propagation and engineering of patient tumor cells for functional studies of metastasis.

cancer biology↗

bioRxiv2019

Genomics to aid species delimitation and effective conservation of the Sharpnose Guitarfish (Glaucostegus granulatus)

The Sharpnose Guitarfish (Glaucostegus granulatus) is one of fifteen critically endangered Rhino Rays which has been exploited as incidental catch, leading to severe population depletions and localized disappearances. Like many chondrichthyan species, there are no species-specific time-series data available for the Sharpnose Guitarfish that can be used to calculate population reduction, partly due to a lack of species-specific reporting as well as limitations in accurate taxonomic identification. We here present the first complete mitochondrial genome and partial nuclear genome of the species and the first detail phylogenetic assessment of the species. We expect that data presented in the current manuscript will aid in accurate species-specific landing and population assessments of the species in the future and will enable conservation efforts to protect and recover remaining populations.

genomics↗

bioRxiv2019

Disrupting β-catenin dependent Wnt signaling activates an invasive gene program predictive of colon cancer progression

The recent classification of colon cancer into molecular subtypes revealed that patients with the poorest prognosis harbor tumors with the lowest levels of Wnt signaling. This is contrary to the long-standing understanding that overactive Wnt signaling promotes tumor progression from early initiation stages through to the later stages including invasion and metastasis. Here, we lower the levels of Wnt signaling in colon cancer via interference with two different steps in the pathway that lie upstream or downstream of the effector protein {beta}-catenin. We find that these Wnt-reduced cancer cells exhibit a more aggressive disease phenotype, including increased mobility in vitro and localized invasion in an orthotopic mouse model. RNA sequencing reveals that interference with Wnt signaling leads to an upregulation of gene programs that favor cell migration and invasion. We identify a set of upregulated genes common among the Wnt perturbations and find that elevated expression of these genes is strongly predictive of poor patient outcomes in early-invasive colon cancer. These genes may have clinical applications as patient biomarkers or new drug targets to be used in concert with existing therapies.\n\nOne Sentence SummaryLow Wnt Signaling Leads to Invasive Tumor Phenotypes in Colorectal Cancer.

cancer biology↗

bioRxiv2019

multiPhATE: bioinformatics pipeline for functional annotation of phage isolates

SummaryTo address the need for improved phage annotation tools that scale, we created an automated throughput annotation pipeline: multiple-genome Phage Annotation Toolkit and Evaluator (multiPhATE). multiPhATE is a throughput pipeline driver that invokes an annotation pipeline (PhATE) across a user-specified set of phage genomes. This tool incorporates a de novo phage gene-calling algorithm and assigns putative functions to gene calls using protein-, virus-, and phage-centric databases. multiPhATEs modular construction allows the user to implement all or any portion of the analyses by acquiring local instances of the desired databases and specifying the desired analyses in a configuration file. We demonstrate multiPhATE by annotating two newly sequenced Yersinia pestis phage genomes. Within multiPhATE, the PhATE processing pipeline can be readily implemented across multiple processors, making it adaptable for throughput sequencing projects. Software documentation assists the user in configuring the system. Availability and implementationmultiPhATE was implemented in Python 3.7, and runs as a command-line code under Linux or Unix. multiPhATE is freely available under an open-source BSD3 license from https://github.com/carolzhou/multiPhATE. Instructions for acquiring the databases and third-party codes used by multiPhATE are included in the distribution README file. Users may report bugs by submitting to the github issues page associated with the multiPhATE distribution. Contactzhou4@llnl.gov or carol.zhou@comcast.net. Supplementary informationData generated during the current study are included as supplementary files available for download at https://github.com/carolzhou/PhATE_docs.

bioinformatics↗

bioRxiv2017

Genomic, proteomic, and phylogenetic analysis of spounaviruses indicates paraphyly of the order Caudovirales

It is almost a cliche that tailed bacteriophages of the order Caudovirales are the most abundant and diverse viruses in the world. Yet, their taxonomy still consists of a single order with just three families: Myoviridae, Siphoviridae, and Podoviridae. Thousands of newly discovered phage genomes have recently challenged this morphology-based classification, revealing that tailed bacteriophages are genomically even more diverse than once thought. Here, we evaluate a range of methods for bacteriophage taxonomy by using a particularly challenging group as an example, the Bacillus phage SPO1-related viruses of the myovirid subfamily Spounavirinae. Exhaustive phylogenetic and phylogenomic analyses indicate that the spounavirins are consistent with the taxonomic rank of family and should be divided into at least five subfamilies. This work is a case study for virus genomic taxonomy and the first step in an impending massive reorganization of the tailed bacteriophage taxonomy.

microbiology↗

bioRxiv2017

Prophage genomics reveals patterns in phage genome organization and replication

Temperate phage genomes are highly variable mosaic collections of genes that infect a bacterial host, integrate into the hosts genome or replicate as low copy number plasmids, and are regulated to switch from the lysogenic to lytic cycles to generate new virions and escape their host. Genomes from most Bacterial phyla contain at least one or more prophages. We updated our PhiSpy algorithm to improve detection of prophages and to provide a web-based framework for PhiSpy. We have used this algorithm to identify 36,488 prophage regions from 11,941 bacterial genomes, including almost 600 prophages with no known homology to any proteins. Transfer RNA genes were abundant in the prophages, many of which alleviate the limits of translation efficiency due to host codon bias and presumably enable phages to surpass the normal capacity of the hosts translation machinery. We identified integrase genes in 15,765 prophages (43% of the prophages). The integrase was routinely located at either end of the integrated phage genome, and was used to orient and align prophage genomes to reveal their underlying organization. The conserved genome alignments of phages recapitulate early, middle, and late gene order in transcriptional control of phage genes, and demonstrate that gene order, presumably selected by transcription timing and/or coordination among functional modules has been stably conserved throughout phage evolution.

biochemistry↗