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Lloyd Trotman

Jean Albrengues, Mario A Shields, David Ng, Chun Gwon Park, Alexandra Ambrico, Morgan E Poindexter, Priya Upadhyay, Dale L Uyeminami, Arnaud Pommier, Victoria Küttner, Emilis Bružas, Laura Maiorino, Carmelita Bautista, Ellese M Carmona, Phyllis A Gimotty, Douglas T Fearon, Kenneth Chang, Scott K Lyons, Kent E Pinkerton, Lloyd C Trotman, Michael S Goldberg, Johannes T-H Yeh, Mikala Egeblad
Cancer cells from a primary tumor can disseminate to other tissues, remaining dormant and clinically undetectable for many years. Little is known about the cues that cause these dormant cells to awaken, resume proliferating, and develop into metastases. Studying mouse models, we found that sustained lung inflammation caused by tobacco smoke exposure or nasal instillation of lipopolysaccharide converted disseminated, dormant cancer cells to aggressively growing metastases. Sustained inflammation induced the formation of neutrophil extracellular traps (NETs), and these were required for awakening dormant cancer...
September 28, 2018: Science
Adam Naguib, Grinu Mathew, Colleen R Reczek, Kaitlin Watrud, Alexandra Ambrico, Tali Herzka, Irene Casanova Salas, Matthew F Lee, Nour El-Amine, Wu Zheng, M Emilia Di Francesco, Joseph R Marszalek, Darryl J Pappin, Navdeep S Chandel, Lloyd C Trotman
A hallmark of advanced prostate cancer (PC) is the concomitant loss of PTEN and p53 function. To selectively eliminate such cells, we screened cytotoxic compounds on Pten-/- ;Trp53-/- fibroblasts and their Pten-WT reference. Highly selective killing of Pten-null cells can be achieved by deguelin, a natural insecticide. Deguelin eliminates Pten-deficient cells through inhibition of mitochondrial complex I (CI). Five hundred-fold higher drug doses are needed to obtain the same killing of Pten-WT cells, even though deguelin blocks their electron transport chain equally well...
April 3, 2018: Cell Reports
Joan Alexander, Jude Kendall, Jean McIndoo, Linda Rodgers, Robert Aboukhalil, Dan Levy, Asya Stepansky, Guoli Sun, Lubomir Chobardjiev, Michael Riggs, Hilary Cox, Inessa Hakker, Dawid G Nowak, Juliana Laze, Elton Llukani, Abhishek Srivastava, Siobhan Gruschow, Shalini S Yadav, Brian Robinson, Gurinder Atwal, Lloyd C Trotman, Herbert Lepor, James Hicks, Michael Wigler, Alexander Krasnitz
A distinction between indolent and aggressive disease is a major challenge in diagnostics of prostate cancer. As genetic heterogeneity and complexity may influence clinical outcome, we have initiated studies on single tumor cell genomics. In this study, we demonstrate that sparse DNA sequencing of single-cell nuclei from prostate core biopsies is a rich source of quantitative parameters for evaluating neoplastic growth and aggressiveness. These include the presence of clonal populations, the phylogenetic structure of those populations, the degree of the complexity of copy-number changes in those populations, and measures of the proportion of cells with clonal copy-number signatures...
January 15, 2018: Cancer Research
Serif Senturk, Nitin H Shirole, Dawid G Nowak, Vincenzo Corbo, Debjani Pal, Alexander Vaughan, David A Tuveson, Lloyd C Trotman, Justin B Kinney, Raffaella Sordella
The CRISPR/Cas9 system is a powerful tool for studying gene function. Here, we describe a method that allows temporal control of CRISPR/Cas9 activity based on conditional Cas9 destabilization. We demonstrate that fusing an FKBP12-derived destabilizing domain to Cas9 (DD-Cas9) enables conditional Cas9 expression and temporal control of gene editing in the presence of an FKBP12 synthetic ligand. This system can be easily adapted to co-express, from the same promoter, DD-Cas9 with any other gene of interest without co-modulation of the latter...
February 22, 2017: Nature Communications
Muhan Chen, Dawid G Nowak, Navneet Narula, Brian Robinson, Kaitlin Watrud, Alexandra Ambrico, Tali M Herzka, Martha E Zeeman, Matthias Minderer, Wu Zheng, Saya H Ebbesen, Kendra S Plafker, Carlos Stahlhut, Victoria M Y Wang, Lorna Wills, Abu Nasar, Mireia Castillo-Martin, Carlos Cordon-Cardo, John E Wilkinson, Scott Powers, Raffaella Sordella, Nasser K Altorki, Vivek Mittal, Brendon M Stiles, Scott M Plafker, Lloyd C Trotman
Phosphatase and tensin homologue (PTEN) protein levels are critical for tumor suppression. However, the search for a recurrent cancer-associated gene alteration that causes PTEN degradation has remained futile. In this study, we show that Importin-11 (Ipo11) is a transport receptor for PTEN that is required to physically separate PTEN from elements of the PTEN degradation machinery. Mechanistically, we find that the E2 ubiquitin-conjugating enzyme and IPO11 cargo, UBE2E1, is a limiting factor for PTEN degradation...
March 6, 2017: Journal of Cell Biology
David P Labbé, Noriko Uetani, Valérie Vinette, Laurent Lessard, Isabelle Aubry, Eva Migon, Jacinthe Sirois, Jody J Haigh, Louis R Bégin, Lloyd C Trotman, Marilène Paquet, Michel L Tremblay
Diet affects the risk and progression of prostate cancer, but the interplay between diet and genetic alterations in this disease is not understood. Here we present genetic evidence in the mouse showing that prostate cancer progression driven by loss of the tumor suppressor Pten is mainly unresponsive to a high-fat diet (HFD), but that coordinate loss of the protein tyrosine phosphatase Ptpn1 (encoding PTP1B) enables a highly invasive disease. Prostate cancer in Pten(-/-)Ptpn1(-/-) mice was characterized by increased cell proliferation and Akt activation, interpreted to reflect a heightened sensitivity to IGF-1 stimulation upon HFD feeding...
June 1, 2016: Cancer Research
Adam Naguib, Gyula Bencze, Hyejin Cho, Wu Zheng, Ante Tocilj, Elad Elkayam, Christopher R Faehnle, Nadia Jaber, Christopher P Pratt, Muhan Chen, Wei-Xing Zong, Michael S Marks, Leemor Joshua-Tor, Darryl J Pappin, Lloyd C Trotman
PTEN is proposed to function at the plasma membrane, where receptor tyrosine kinases are activated. However, the majority of PTEN is located throughout the cytoplasm. Here, we show that cytoplasmic PTEN is distributed along microtubules, tethered to vesicles via phosphatidylinositol 3-phosphate (PI(3)P), the signature lipid of endosomes. We demonstrate that the non-catalytic C2 domain of PTEN specifically binds PI(3)P through the CBR3 loop. Mutations render this loop incapable of PI(3)P binding and abrogate PTEN-mediated inhibition of PI 3-kinase/AKT signaling...
April 16, 2015: Molecular Cell
Dawid G Nowak, Hyejin Cho, Tali Herzka, Kaitlin Watrud, Daniel V DeMarco, Victoria M Y Wang, Serif Senturk, Christof Fellmann, David Ding, Tumas Beinortas, David Kleinman, Muhan Chen, Raffaella Sordella, John E Wilkinson, Mireia Castillo-Martin, Carlos Cordon-Cardo, Brian D Robinson, Lloyd C Trotman
UNLABELLED: We have recently recapitulated metastasis of human PTEN/TP53-mutant prostate cancer in the mouse using the RapidCaP system. Surprisingly, we found that this metastasis is driven by MYC, and not AKT, activation. Here, we show that cell-cell communication by IL6 drives the AKT-MYC switch through activation of the AKT-suppressing phosphatase PHLPP2, when PTEN and p53 are lost together, but not separately. IL6 then communicates a downstream program of STAT3-mediated MYC activation, which drives cell proliferation...
June 2015: Cancer Discovery
Hyejin Cho, Tali Herzka, Carlos Stahlhut, Kaitlin Watrud, Brian D Robinson, Lloyd C Trotman
Human genome analyses have revealed that increasing gene copy number alteration is a driving force of incurable cancer of the prostate (CaP). Since most of the affected genes are hidden within large amplifications or deletions, there is a need for fast and faithful validation of drivers. However, classic genetic CaP engineering in mouse makes this a daunting task because generation, breeding based combination of alterations and non-invasive monitoring of disease are too time consuming and costly. To address the unmet need, we recently developed RapidCaP mice, which endogenously recreate human PTEN-mutant metastatic CaP based on Cre/Luciferase expressing viral infection, that is guided to Pten(loxP)/Trp53(loxP) prostate...
May 2015: Methods: a Companion to Methods in Enzymology
Adam Naguib, Gyula Bencze, Dannielle D Engle, Iok I C Chio, Tali Herzka, Kaitlin Watrud, Szilvia Bencze, David A Tuveson, Darryl J Pappin, Lloyd C Trotman
Phosphatidylinositol phosphate (PIP) second messengers relay extracellular growth cues through the phosphorylation status of the inositol sugar, a signal transduction system that is deregulated in cancer. In stark contrast to PIP inositol head-group phosphorylation, changes in phosphatidylinositol (PI) lipid acyl chains in cancer have remained ill-defined. Here, we apply a mass-spectrometry-based method capable of unbiased high-throughput identification and quantification of cellular PI acyl chain composition...
January 6, 2015: Cell Reports
Gloria Reyes, Matt Niederst, Ksenya Cohen-Katsenelson, Joshua D Stender, Maya T Kunkel, Muhan Chen, John Brognard, Emma Sierecki, Tianyan Gao, Dawid G Nowak, Lloyd C Trotman, Christopher K Glass, Alexandra C Newton
Growth factor receptor levels are aberrantly high in diverse cancers, driving the proliferation and survival of tumor cells. Understanding the molecular basis for this aberrant elevation has profound clinical implications. Here we show that the pleckstrin homology domain leucine-rich repeat protein phosphatase (PHLPP) suppresses receptor tyrosine kinase (RTK) signaling output by a previously unidentified epigenetic mechanism unrelated to its previously described function as the hydrophobic motif phosphatase for the protein kinase AKT, protein kinase C, and S6 kinase...
September 23, 2014: Proceedings of the National Academy of Sciences of the United States of America
Rafael Pulido, Suzanne J Baker, Joao T Barata, Arkaitz Carracedo, Victor J Cid, Ian D Chin-Sang, Vrushank Davé, Jeroen den Hertog, Peter Devreotes, Britta J Eickholt, Charis Eng, Frank B Furnari, Maria-Magdalena Georgescu, Arne Gericke, Benjamin Hopkins, Xeujun Jiang, Seung-Rock Lee, Mathias Lösche, Prerna Malaney, Xavier Matias-Guiu, María Molina, Pier Paolo Pandolfi, Ramon Parsons, Paolo Pinton, Carmen Rivas, Rafael M Rocha, Manuel S Rodríguez, Alonzo H Ross, Manuel Serrano, Vuk Stambolic, Bangyan Stiles, Akira Suzuki, Seong-Seng Tan, Nicholas K Tonks, Lloyd C Trotman, Nicolas Wolff, Rudiger Woscholski, Hong Wu, Nicholas R Leslie
The tumor suppressor PTEN is a major brake for cell transformation, mainly due to its phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P3] phosphatase activity that directly counteracts the oncogenicity of phosphoinositide 3-kinase (PI3K). PTEN mutations are frequent in tumors and in the germ line of patients with tumor predisposition or with neurological or cognitive disorders, which makes the PTEN gene and protein a major focus of interest in current biomedical research. After almost two decades of intense investigation on the 403-residue-long PTEN protein, a previously uncharacterized form of PTEN has been discovered that contains 173 amino-terminal extra amino acids, as a result of an alternate translation initiation site...
July 1, 2014: Science Signaling
Muhan Chen, Dawid G Nowak, Lloyd C Trotman
Cancer research has seen tremendous changes over the past decade. Fast progress in sequencing technology has afforded us with landmark genetic alterations, which had immediate impact on clinical science and practice by pointing to new kinase targets, such as phosphoinositide 3-kinase (PI3K), the EGF receptor, or BRAF. The PI3K pathway for growth control has emerged as a prime example for both oncogene activation and tumor suppressor loss in cancer. Here, we discuss how therapy using PI3K pathway inhibitors could benefit from information on specific phosphatases, which naturally antagonize the kinase targets...
June 15, 2014: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Hyejin Cho, Tali Herzka, Wu Zheng, Jun Qi, John E Wilkinson, James E Bradner, Brian D Robinson, Mireia Castillo-Martin, Carlos Cordon-Cardo, Lloyd C Trotman
Genetically engineered mouse (GEM) models are a pillar of functional cancer research. Here, we developed RapidCaP, a GEM modeling system that uses surgical injection for viral gene delivery to the prostate. We show that in Pten deficiency, loss of p53 suffices to trigger metastasis to distant sites at greater than 50% penetrance by four months, consistent with results from human prostate cancer genome analysis. Live bioluminescence tracking showed that endogenous primary and metastatic disease responds to castration before developing lethal castration resistance...
March 2014: Cancer Discovery
Alexandra C Newton, Lloyd C Trotman
Precise control of the balance between protein phosphorylation, catalyzed by protein kinases, and protein dephosphorylation, catalyzed by protein phosphatases, is essential for cellular homeostasis. Dysregulation of this balance leads to pathophysiological states, driving diseases such as cancer, heart disease, and diabetes. Aberrant phosphorylation of components of the pathways that control cell growth and cell survival are particularly prevalent in cancer. One of the most studied tumor suppressors in these pathways is the lipid phosphatase PTEN (phosphatase and tensin homolog deleted on chromosome ten), which dephosphorylates the lipid second messenger phosphatidylinositol 3,4,5-trisphosphate (PIP3), thus preventing activation of the oncogenic kinase AKT (v-akt murine thymoma viral oncogene homolog)...
2014: Annual Review of Pharmacology and Toxicology
David P Labbé, Dawid G Nowak, Geneviève Deblois, Laurent Lessard, Vincent Giguère, Lloyd C Trotman, Michel L Tremblay
UNLABELLED: The 20q13 chromosomal region has been previously identified as the hereditary prostate cancer genetic-susceptibility locus on chromosome 20 (HPC20). In this study, the 20q13 region was shown to be frequently co-amplified with the androgen receptor (AR) in metastatic prostate cancer. Furthermore, the AR signaling axis, which plays an essential role in the pathogenesis of prostate cancer, was demonstrated to be central to the regulation of the 20q13 common amplified region (CAR)...
February 2014: Molecular Cancer Research: MCR
Adam Naguib, Lloyd C Trotman
PTEN loss drives many cancers and recent genetic studies reveal that often PTEN is antagonised at the protein level without alteration of DNA or RNA expression. This scenario can already cause malignancy, because PTEN is haploinsufficient. We here review normally occurring mechanisms of PTEN protein regulation and discuss three processes where PTEN plasticity is needed: ischaemia, development, and wound healing. These situations demand transient PTEN suppression, whereas cancer exploits them for continuous proliferation and survival advantages...
August 2013: Trends in Cell Biology
Qiaojie Xiong, Hysell V Oviedo, Lloyd C Trotman, Anthony M Zador
Autism spectrum disorders (ASDs) are highly heritable developmental disorders caused by a heterogeneous collection of genetic lesions. Here we use a mouse model to study the effect on cortical connectivity of disrupting the ASD candidate gene PTEN (phosphatase and tensin homolog deleted on chromosome 10). Through Cre-mediated recombination, we conditionally knocked out PTEN expression in a subset of auditory cortical neurons. Analysis of long-range connectivity using channelrhodopsin-2 revealed that the strength of synaptic inputs from both the contralateral auditory cortex and from the thalamus onto PTEN-cko neurons was enhanced compared with nearby neurons with normal PTEN expression...
February 1, 2012: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Laurent Lessard, David P Labbé, Geneviève Deblois, Louis R Bégin, Serge Hardy, Anne-Marie Mes-Masson, Fred Saad, Lloyd C Trotman, Vincent Giguère, Michel L Tremblay
The androgen receptor (AR) signaling axis plays a key role in the pathogenesis of prostate cancer. In this study, we found that the protein tyrosine phosphatase PTP1B, a well-established regulator of metabolic signaling, was induced after androgen stimulation of AR-expressing prostate cancer cells. PTP1B induction by androgen occurred at the mRNA and protein levels to increase PTP1B activity. High-resolution chromosome mapping revealed AR recruitment to two response elements within the first intron of the PTP1B encoding gene PTPN1, correlating with an AR-mediated increase in RNA polymerase II recruitment to the PTPN1 transcriptional start site...
March 15, 2012: Cancer Research
Jason Howitt, Jenny Lackovic, Ley-Hian Low, Adam Naguib, Alison Macintyre, Choo-Peng Goh, Jennifer K Callaway, Vicki Hammond, Tim Thomas, Matthew Dixon, Ulrich Putz, John Silke, Perry Bartlett, Baoli Yang, Sharad Kumar, Lloyd C Trotman, Seong-Seng Tan
PTEN (phosphatase and tensin homologue deleted on chromosome TEN) is the major negative regulator of phosphatidylinositol 3-kinase signaling and has cell-specific functions including tumor suppression. Nuclear localization of PTEN is vital for tumor suppression; however, outside of cancer, the molecular and physiological events driving PTEN nuclear entry are unknown. In this paper, we demonstrate that cytoplasmic Pten was translocated into the nuclei of neurons after cerebral ischemia in mice. Critically, this transport event was dependent on a surge in the Nedd4 family-interacting protein 1 (Ndfip1), as neurons in Ndfip1-deficient mice failed to import Pten...
January 9, 2012: Journal of Cell Biology
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