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Christopher Dravis, Chi-Yeh Chung, Nikki K Lytle, Jaslem Herrera-Valdez, Gidsela Luna, Christy L Trejo, Tannishtha Reya, Geoffrey M Wahl
Cell state reprogramming during tumor progression complicates accurate diagnosis, compromises therapeutic effectiveness, and fuels metastatic dissemination. We used chromatin accessibility assays and transcriptional profiling during mammary development as an agnostic approach to identify factors that mediate cancer cell state interconversions. We show that fetal and adult basal cells share epigenetic features consistent with multi-lineage differentiation potential. We find that DNA-binding motifs for SOX transcription factors are enriched in chromatin that is accessible in stem/progenitor cells and inaccessible in differentiated cells...
September 10, 2018: Cancer Cell
Rajshekhar R Giraddi, Chi-Yeh Chung, Richard E Heinz, Ozlen Balcioglu, Mark Novotny, Christy L Trejo, Christopher Dravis, Berhane M Hagos, Elnaz Mirzaei Mehrabad, Luo Wei Rodewald, Jae Y Hwang, Cheng Fan, Roger Lasken, Katherine E Varley, Charles M Perou, Geoffrey M Wahl, Benjamin T Spike
The mammary gland consists of cells with gene expression patterns reflecting their cellular origins, function, and spatiotemporal context. However, knowledge of developmental kinetics and mechanisms of lineage specification is lacking. We address this significant knowledge gap by generating a single-cell transcriptome atlas encompassing embryonic, postnatal, and adult mouse mammary development. From these data, we map the chronology of transcriptionally and epigenetically distinct cell states and distinguish fetal mammary stem cells (fMaSCs) from their precursors and progeny...
August 7, 2018: Cell Reports
Maya Saison-Ridinger, Kathleen E DelGiorno, Tejia Zhang, Annabelle Kraus, Randall French, Dawn Jaquish, Crystal Tsui, Galina Erikson, Benjamin T Spike, Maxim N Shokhirev, Christopher Liddle, Ruth T Yu, Michael Downes, Ronald M Evans, Alan Saghatelian, Andrew M Lowy, Geoffrey M Wahl
Pancreatic ductal adenocarcinoma (PDAC) is characterized by an extremely dense fibrotic stroma, which contributes to tumor growth, metastasis, and drug resistance. During tumorigenesis, quiescent pancreatic stellate cells (PSCs) are activated and become major contributors to fibrosis, by increasing growth factor signaling and extracellular matrix deposition. The p53 tumor suppressor is known to restrict tumor initiation and progression through cell autonomous mechanisms including apoptosis, cell cycle arrest, and senescence...
2017: PloS One
Christy L Trejo, Gidsela Luna, Christopher Dravis, Benjamin T Spike, Geoffrey M Wahl
The search for the bipotent mammary stem cells that drive mammary development requires markers to enable their prospective isolation. There is general agreement that bipotent mouse mammary stem cells are abundant in late fetal development, but their existence in the adult is vigorously debated. Among markers useful for mammary stem cell identification, the Wnt co-receptor Lgr5 has been suggested by some to be both "necessary and sufficient" for bipotency and transplantation of adult mammary stem cell activity, though other studies disagree...
2017: NPJ Breast Cancer
Geoffrey M Wahl, Benjamin T Spike
Cellular heterogeneity in cancer represents a significant challenge. In order to develop effective and lasting therapies, it is essential to understand the source of this heterogeneity, and its role in tumor progression and therapy resistance. Here, we consider not only genetic and epigenetic mechanisms, but also inflammation and cell state reprogramming in creating tumor heterogeneity. We discuss similarities between normal mammary epithelial developmental states and various breast cancer molecular sub-types, and the cells that are thought to propagate them...
2017: NPJ Breast Cancer
Kristen M Turner, Viraj Deshpande, Doruk Beyter, Tomoyuki Koga, Jessica Rusert, Catherine Lee, Bin Li, Karen Arden, Bing Ren, David A Nathanson, Harley I Kornblum, Michael D Taylor, Sharmeela Kaushal, Webster K Cavenee, Robert Wechsler-Reya, Frank B Furnari, Scott R Vandenberg, P Nagesh Rao, Geoffrey M Wahl, Vineet Bafna, Paul S Mischel
Human cells have twenty-three pairs of chromosomes. In cancer, however, genes can be amplified in chromosomes or in circular extrachromosomal DNA (ecDNA), although the frequency and functional importance of ecDNA are not understood. We performed whole-genome sequencing, structural modelling and cytogenetic analyses of 17 different cancer types, including analysis of the structure and function of chromosomes during metaphase of 2,572 dividing cells, and developed a software package called ECdetect to conduct unbiased, integrated ecDNA detection and analysis...
March 2, 2017: Nature
Anthony N Habgood, Amanda L Tatler, Joanne Porte, Sharon M Wahl, Geoffrey J Laurent, Alison E John, Simon R Johnson, Gisli Jenkins
Idiopathic pulmonary fibrosis is a progressive, fatal disease with limited treatment options. Protease-mediated transforming growth factor-β (TGF-β) activation has been proposed as a pathogenic mechanism of lung fibrosis. Protease activity in the lung is tightly regulated by protease inhibitors, particularly secretory leukocyte protease inhibitor (SLPI). The bleomycin model of lung fibrosis was used to determine the effect of increased protease activity in the lungs of Slpi(-/-) mice following injury. Slpi(-/-), and wild-type, mice received oropharyngeal administration of bleomycin (30 IU) and the development of pulmonary fibrosis was assessed...
June 2016: Laboratory Investigation; a Journal of Technical Methods and Pathology
Ignacio Sancho-Martinez, Emmanuel Nivet, Yun Xia, Tomoaki Hishida, Aitor Aguirre, Alejandro Ocampo, Li Ma, Robert Morey, Marie N Krause, Andreas Zembrzycki, Olaf Ansorge, Eric Vazquez-Ferrer, Ilir Dubova, Pradeep Reddy, David Lam, Yuriko Hishida, Min-Zu Wu, Concepcion Rodriguez Esteban, Dennis O'Leary, Geoffrey M Wahl, Inder M Verma, Louise C Laurent, Juan Carlos Izpisua Belmonte
Glioma tumour-initiating cells (GTICs) can originate upon the transformation of neural progenitor cells (NPCs). Studies on GTICs have focused on primary tumours from which GTICs could be isolated and the use of human embryonic material. Recently, the somatic genomic landscape of human gliomas has been reported. RTK (receptor tyrosine kinase) and p53 signalling were found dysregulated in ∼90% and 86% of all primary tumours analysed, respectively. Here we report on the use of human-induced pluripotent stem cells (hiPSCs) for modelling gliomagenesis...
February 22, 2016: Nature Communications
Christopher Dravis, Benjamin T Spike, J Chuck Harrell, Claire Johns, Christy L Trejo, E Michelle Southard-Smith, Charles M Perou, Geoffrey M Wahl
To discover mechanisms that mediate plasticity in mammary cells, we characterized signaling networks that are present in the mammary stem cells responsible for fetal and adult mammary development. These analyses identified a signaling axis between FGF signaling and the transcription factor Sox10. Here, we show that Sox10 is specifically expressed in mammary cells exhibiting the highest levels of stem/progenitor activity. This includes fetal and adult mammary cells in vivo and mammary organoids in vitro. Sox10 is functionally relevant, as its deletion reduces stem/progenitor competence whereas its overexpression increases stem/progenitor activity...
September 29, 2015: Cell Reports
Cassandra J Adams, Jennifer S Yu, Jian-Hua Mao, Kuang-Yu Jen, Sylvain V Costes, Mark Wade, Jocelyn Shoemake, Olulanu H Aina, Reyno Del Rosario, Phuong Thuy Menchavez, Robert D Cardiff, Geoffrey M Wahl, Allan Balmain
The tumor suppressor TP53 can initiate a plethora of anti-proliferative effects to maintain genomic integrity under conditions of genotoxic stress. The N-terminal proline-rich domain (PRD) of TP53 is important in the regulation of TP53 activity and stability. A common polymorphism at codon 72 in this region has been associated with altered cancer risk in humans. The Trp53ΔP mouse, which carries a germline homozygous deletion of a region of the PRD, does not develop spontaneous tumors in a mixed 129/Sv and C57BL/6 genetic background, but is highly susceptible to a broad range of tumor types following total body exposure to 4 Gy gamma (γ) radiation...
September 2016: Molecular Carcinogenesis
Andrii I Rozhok, Geoffrey M Wahl, James DeGregori
Tomasetti and Vogelstein (1) argue that lifetime cancer risk for particular tissues is mostly determined by the total number of stem cell (SC) divisions within the tissue, whereby most cancers arise due to "bad luck"—mutations occurring during DNA replication. We argue that the poorly substantiated estimations of SC division parameters and assumptions that oversimplify somatic evolution prevent such a conclusion from being drawn.
September 2015: Cancer Prevention Research
Yao-Cheng Li, Luo Wei Rodewald, Christian Hoppmann, Ee Tsin Wong, Sylvain Lebreton, Pavel Safar, Marcel Patek, Lei Wang, Kenneth F Wertman, Geoffrey M Wahl
Protein-protein interactions (PPIs) play central roles in orchestrating biological processes. While some PPIs are stable, many important ones are transient and hard to detect with conventional approaches. We developed ReBiL, a recombinase enhanced bimolecular luciferase complementation platform, to enable detection of weak PPIs in living cells. ReBiL readily identified challenging transient interactions between an E3 ubiquitin ligase and an E2 ubiquitin-conjugating enzyme. ReBiL's ability to rapidly interrogate PPIs in diverse conditions revealed that some stapled α-helical peptides, a class of PPI antagonists, induce target-independent cytosolic leakage and cytotoxicity that is antagonized by serum...
December 11, 2014: Cell Reports
Mara H Sherman, Ruth T Yu, Dannielle D Engle, Ning Ding, Annette R Atkins, Herve Tiriac, Eric A Collisson, Frances Connor, Terry Van Dyke, Serguei Kozlov, Philip Martin, Tiffany W Tseng, David W Dawson, Timothy R Donahue, Atsushi Masamune, Tooru Shimosegawa, Minoti V Apte, Jeremy S Wilson, Beverly Ng, Sue Lynn Lau, Jenny E Gunton, Geoffrey M Wahl, Tony Hunter, Jeffrey A Drebin, Peter J O'Dwyer, Christopher Liddle, David A Tuveson, Michael Downes, Ronald M Evans
The poor clinical outcome in pancreatic ductal adenocarcinoma (PDA) is attributed to intrinsic chemoresistance and a growth-permissive tumor microenvironment. Conversion of quiescent to activated pancreatic stellate cells (PSCs) drives the severe stromal reaction that characterizes PDA. Here, we reveal that the vitamin D receptor (VDR) is expressed in stroma from human pancreatic tumors and that treatment with the VDR ligand calcipotriol markedly reduced markers of inflammation and fibrosis in pancreatitis and human tumor stroma...
September 25, 2014: Cell
Benjamin T Spike, Jonathan A Kelber, Evan Booker, Madhuri Kalathur, Rose Rodewald, Julia Lipianskaya, Justin La, Marielle He, Tracy Wright, Richard Klemke, Geoffrey M Wahl, Peter C Gray
Little is known about the extracellular signaling factors that govern mammary stem cell behavior. Here, we identify CRIPTO and its cell-surface receptor GRP78 as regulators of stem cell behavior in isolated fetal and adult mammary epithelial cells. We develop a CRIPTO antagonist that promotes differentiation and reduces self-renewal of mammary stem cell-enriched populations cultured ex vivo. By contrast, CRIPTO treatment maintains the stem cell phenotype in these cultures and yields colonies with enhanced mammary gland reconstitution capacity...
April 8, 2014: Stem Cell Reports
Adam D Pfefferle, Jason I Herschkowitz, Jerry Usary, Joshua Chuck Harrell, Benjamin T Spike, Jessica R Adams, Maria I Torres-Arzayus, Myles Brown, Sean E Egan, Geoffrey M Wahl, Jeffrey M Rosen, Charles M Perou
BACKGROUND: Human breast cancer is a heterogeneous disease consisting of multiple molecular subtypes. Genetically engineered mouse models are a useful resource for studying mammary cancers in vivo under genetically controlled and immune competent conditions. Identifying murine models with conserved human tumor features will facilitate etiology determinations, highlight the effects of mutations on pathway activation, and should improve preclinical drug testing. RESULTS: Transcriptomic profiles of 27 murine models of mammary carcinoma and normal mammary tissue were determined using gene expression microarrays...
2013: Genome Biology
Guifen He, Yi-Wei Zhang, Jun-Ho Lee, Shelya X Zeng, Yunyuan V Wang, Zhijun Luo, X Charlie Dong, Benoit Viollet, Geoffrey M Wahl, Hua Lu
AMP-activated protein kinase (AMPK) has been shown to activate p53 in response to metabolic stress. However, the underlying mechanisms remain unclear. Here we show that metabolic stresses induce AMPK-mediated phosphorylation of human MDMX on Ser342 in vitro and in cells, leading to enhanced association between MDMX and 14-3-3. This markedly inhibits p53 ubiquitylation and significantly stabilizes and activates p53. By striking contrast, no phosphorylation of MDM2 by AMPK was noted. AMPK-mediated MDMX phosphorylation, MDMX-14-3-3 binding, and p53 activation were drastically reduced in mouse embryo fibroblasts harboring endogenous MDMX with S341A (mouse homologue of human serine 342), S367A, and S402A (mouse homologue of human serine 403) mutations...
January 2014: Molecular and Cellular Biology
Neal R Rasmussen, Tricia M Wright, Samira A Brooks, Kathryn E Hacker, Zufan Debebe, Adam B Sendor, Matthew P Walker, Michael Ben Major, Jennifer Green, Geoffrey M Wahl, W Kimryn Rathmell
Expression of the receptor tyrosine kinase-like orphan receptor 2 (Ror2) has been identified in an increasing array of tumor types and is known to play a role as an important mediator of Wnt signaling cascades. In this study, we aimed to clarify Ror2 interactions with the Wnt pathways within the context of renal cell carcinoma (RCC). An examination of Ror2 expression in primary human RCC tumors showed a significant correlation with several Wnt signaling genes, including the classical feedback target gene Axin2...
September 6, 2013: Journal of Biological Chemistry
Maisam Makarem, Benjamin T Spike, Christopher Dravis, Nagarajan Kannan, Geoffrey M Wahl, Connie J Eaves
The mammary gland undergoes dynamic changes throughout life. In the mouse, these begin with initial morphogenesis of the gland in the mid-gestation embryo followed by hormonally regulated changes during puberty and later in adulthood. The adult mammary gland contains a hierarchy of cell types with varying potentials for self-maintenance and differentiation. These include cells able to produce complete, functional mammary glands in vivo and that contain daughter cells with the same remarkable regenerative potential, as well as cells with more limited clonogenic activity in vitro...
June 2013: Journal of Mammary Gland Biology and Neoplasia
Jennifer L Green, Justin La, Kyu W Yum, Payal Desai, Luo-Wei Rodewald, Xiaomei Zhang, Mathias Leblanc, Roeland Nusse, Michael T Lewis, Geoffrey M Wahl
Wnt signaling in mouse mammary development and tumorigenesis has been heavily studied and characterized, but its role in human breast cancer remains elusive. Although Wnt inhibitors are in early clinical development, it is unclear whether they will be of therapeutic benefit to breast cancer patients, and subsequently, to which ones. To address this, we generated a panel of Wnt reporting human breast cancer cell lines and identified a previously unrecognized enrichment for the ability to respond to Wnt in the basal B or claudin-low subtype, which has a poor prognosis and no available targeted therapies...
April 23, 2013: Proceedings of the National Academy of Sciences of the United States of America
Jennifer L Green, Matthieu Bauer, Kyu Won Yum, Yao-Cheng Li, Miranda L Cox, Karl Willert, Geoffrey M Wahl
Functional and mechanistic studies of Wnt signaling have been severely hindered by the inaccessibility of bioactive proteins. To overcome this long-standing barrier, we engineered and characterized a panel of Chinese hamster ovary (CHO) cell lines with inducible transgenes encoding tagged and un-tagged human WNT1, WNT3A, WNT5A, WNT7A, WNT11, WNT16 or the soluble Wnt antagonist Fzd8CRD, all integrated into an identical genomic locus. Using a quantitative real-time bioluminescence assay, we show that cells expressing WNT1, 3A and 7A stimulate Wnt/beta-catenin reporter activity, while the other WNT expressing cell lines interfere with this activation...
2013: PloS One
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