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Cancer Cell

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https://www.readbyqxmd.com/read/28416184/tiam1-antagonizes-taz-yap-both-in-the-destruction-complex-in-the-cytoplasm-and-in-the-nucleus-to-inhibit-invasion-of-intestinal-epithelial-cells
#1
Zoi Diamantopoulou, Gavin White, Muhammad Z H Fadlullah, Marcel Dreger, Karen Pickering, Joe Maltas, Garry Ashton, Ruth MacLeod, George S Baillie, Valerie Kouskoff, Georges Lacaud, Graeme I Murray, Owen J Sansom, Adam F L Hurlstone, Angeliki Malliri
Aberrant WNT signaling drives colorectal cancer (CRC). Here, we identify TIAM1 as a critical antagonist of CRC progression through inhibiting TAZ and YAP, effectors of WNT signaling. We demonstrate that TIAM1 shuttles between the cytoplasm and nucleus antagonizing TAZ/YAP by distinct mechanisms in the two compartments. In the cytoplasm, TIAM1 localizes to the destruction complex and promotes TAZ degradation by enhancing its interaction with βTrCP. Nuclear TIAM1 suppresses TAZ/YAP interaction with TEADs, inhibiting expression of TAZ/YAP target genes implicated in epithelial-mesenchymal transition, cell migration, and invasion, and consequently suppresses CRC cell migration and invasion...
April 7, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28262554/target-expression-generation-preclinical-activity-and-pharmacokinetics-of-the-bcma-t-cell-bispecific-antibody-em801-for-multiple-myeloma-treatment
#2
Anja Seckinger, Jose Antonio Delgado, Samuel Moser, Laura Moreno, Brigitte Neuber, Anna Grab, Susanne Lipp, Juana Merino, Felipe Prosper, Martina Emde, Camille Delon, Melanie Latzko, Reto Gianotti, Remo Lüoend, Ramona Murr, Ralf J Hosse, Lydia Jasmin Harnisch, Marina Bacac, Tanja Fauti, Christian Klein, Aintzane Zabaleta, Jens Hillengass, Elisabetta Ada Cavalcanti-Adam, Anthony D Ho, Michael Hundemer, Jesus F San Miguel, Klaus Strein, Pablo Umaña, Dirk Hose, Bruno Paiva, Minh Diem Vu
We identified B cell maturation antigen (BCMA) as a potential therapeutic target in 778 newly diagnosed and relapsed myeloma patients. We constructed an IgG-based BCMA-T cell bispecific antibody (EM801) and showed that it increased CD3(+) T cell/myeloma cell crosslinking, followed by CD4(+)/CD8(+) T cell activation, and secretion of interferon-γ, granzyme B, and perforin. This effect is CD4 and CD8 T cell mediated. EM801 induced, at nanomolar concentrations, myeloma cell death by autologous T cells in 34 of 43 bone marrow aspirates, including those from high-risk patients and patients after multiple lines of treatment, tumor regression in six of nine mice in a myeloma xenograft model, and depletion of BCMA(+) cells in cynomolgus monkeys...
February 27, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28238683/endothelial-notch1-activity-facilitates-metastasis
#3
Elfriede Wieland, Juan Rodriguez-Vita, Sven S Liebler, Carolin Mogler, Iris Moll, Stefanie E Herberich, Elisa Espinet, Esther Herpel, Amitai Menuchin, Jenny Chang-Claude, Michael Hoffmeister, Christoffer Gebhardt, Hermann Brenner, Andreas Trumpp, Christian W Siebel, Markus Hecker, Jochen Utikal, David Sprinzak, Andreas Fischer
Endothelial cells (ECs) provide angiocrine factors orchestrating tumor progression. Here, we show that activated Notch1 receptors (N1ICD) are frequently observed in ECs of human carcinomas and melanoma, and in ECs of the pre-metastatic niche in mice. EC N1ICD expression in melanoma correlated with shorter progression-free survival. Sustained N1ICD activity induced EC senescence, expression of chemokines and the adhesion molecule VCAM1. This promoted neutrophil infiltration, tumor cell (TC) adhesion to the endothelium, intravasation, lung colonization, and postsurgical metastasis...
February 12, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28399412/cell-cycle-targeting-micrornas-as-therapeutic-tools-against-refractory-cancers
#4
Per Hydbring, Yinan Wang, Anne Fassl, Xiaoting Li, Veronica Matia, Tobias Otto, Yoon Jong Choi, Katharine E Sweeney, Jan M Suski, Hao Yin, Roman L Bogorad, Shom Goel, Haluk Yuzugullu, Kevin J Kauffman, Junghoon Yang, Chong Jin, Yingxiang Li, Davide Floris, Richard Swanson, Kimmie Ng, Ewa Sicinska, Lars Anders, Jean J Zhao, Kornelia Polyak, Daniel G Anderson, Cheng Li, Piotr Sicinski
Cyclins and cyclin-dependent kinases (CDKs) are hyperactivated in numerous human tumors. To identify means of interfering with cyclins/CDKs, we performed nine genome-wide screens for human microRNAs (miRNAs) directly regulating cell-cycle proteins. We uncovered a distinct class of miRNAs that target nearly all cyclins/CDKs, which are very effective in inhibiting cancer cell proliferation. By profiling the response of over 120 human cancer cell lines, we derived an expression-based algorithm that can predict the response of tumors to cell-cycle-targeting miRNAs...
April 10, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28399411/inhibition-of-hematopoietic-cell-kinase-activity-suppresses-myeloid-cell-mediated-colon-cancer-progression
#5
Ashleigh R Poh, Christopher G Love, Frederick Masson, Adele Preaudet, Cary Tsui, Lachlan Whitehead, Simon Monard, Yelena Khakham, Lotta Burstroem, Guillaume Lessene, Oliver Sieber, Clifford Lowell, Tracy L Putoczki, Robert J J O'Donoghue, Matthias Ernst
Aberrant activation of the SRC family kinase hematopoietic cell kinase (HCK) triggers hematological malignancies as a tumor cell-intrinsic oncogene. Here we find that high HCK levels correlate with reduced survival of colorectal cancer patients. Likewise, increased Hck activity in mice promotes the growth of endogenous colonic malignancies and of human colorectal cancer cell xenografts. Furthermore, tumor-associated macrophages of the corresponding tumors show a pronounced alternatively activated endotype, which occurs independently of mature lymphocytes or of Stat6-dependent Th2 cytokine signaling...
April 10, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28399410/hoxa9-and-meis1-cooperatively-induce-addiction-to-syk-signaling-by-suppressing-mir-146a-in-acute-myeloid-leukemia
#6
Sebastian Mohr, Carmen Doebele, Federico Comoglio, Tobias Berg, Julia Beck, Hanibal Bohnenberger, Gabriela Alexe, Jasmin Corso, Philipp Ströbel, Astrid Wachter, Tim Beissbarth, Frank Schnütgen, Anjali Cremer, Nadine Haetscher, Stefanie Göllner, Arefeh Rouhi, Lars Palmqvist, Michael A Rieger, Timm Schroeder, Halvard Bönig, Carsten Müller-Tidow, Florian Kuchenbauer, Ekkehard Schütz, Anthony R Green, Henning Urlaub, Kimberly Stegmaier, R Keith Humphries, Hubert Serve, Thomas Oellerich
The transcription factor Meis1 drives myeloid leukemogenesis in the context of Hox gene overexpression but is currently considered undruggable. We therefore investigated whether myeloid progenitor cells transformed by Hoxa9 and Meis1 become addicted to targetable signaling pathways. A comprehensive (phospho)proteomic analysis revealed that Meis1 increased Syk protein expression and activity. Syk upregulation occurs through a Meis1-dependent feedback loop. By dissecting this loop, we show that Syk is a direct target of miR-146a, whose expression is indirectly regulated by Meis1 through the transcription factor PU...
April 10, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28399409/direct-pharmacological-targeting-of-a-mitochondrial-ion-channel-selectively-kills-tumor-cells-in%C3%A2-vivo
#7
Luigi Leanza, Matteo Romio, Katrin Anne Becker, Michele Azzolini, Livio Trentin, Antonella Managò, Elisa Venturini, Angela Zaccagnino, Andrea Mattarei, Luca Carraretto, Andrea Urbani, Stephanie Kadow, Lucia Biasutto, Veronica Martini, Filippo Severin, Roberta Peruzzo, Valentina Trimarco, Jan-Hendrik Egberts, Charlotte Hauser, Andrea Visentin, Gianpietro Semenzato, Holger Kalthoff, Mario Zoratti, Erich Gulbins, Cristina Paradisi, Ildiko Szabo
The potassium channel Kv1.3 is highly expressed in the mitochondria of various cancerous cells. Here we show that direct inhibition of Kv1.3 using two mitochondria-targeted inhibitors alters mitochondrial function and leads to reactive oxygen species (ROS)-mediated death of even chemoresistant cells independently of p53 status. These inhibitors killed 98% of ex vivo primary chronic B-lymphocytic leukemia tumor cells while sparing healthy B cells. In orthotopic mouse models of melanoma and pancreatic ductal adenocarcinoma, the compounds reduced tumor size by more than 90% and 60%, respectively, while sparing immune and cardiac functions...
April 10, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28399408/eradication-of-tumors-through-simultaneous-ablation-of-cd276-b7-h3-positive-tumor-cells-and-tumor-vasculature
#8
Steven Seaman, Zhongyu Zhu, Saurabh Saha, Xiaoyan M Zhang, Mi Young Yang, Mary Beth Hilton, Karen Morris, Christopher Szot, Holly Morris, Deborah A Swing, Lino Tessarollo, Sean W Smith, Sylvia Degrado, Dmitry Borkin, Nareshkumar Jain, Julia Scheiermann, Yang Feng, Yanping Wang, Jinyu Li, Dean Welsch, Gary DeCrescenzo, Amit Chaudhary, Enrique Zudaire, Kimberly D Klarmann, Jonathan R Keller, Dimiter S Dimitrov, Brad St Croix
Targeting the tumor vasculature with antibody-drug conjugates (ADCs) is a promising anti-cancer strategy that in order to be realized must overcome several obstacles, including identification of suitable targets and optimal warheads. Here, we demonstrate that the cell-surface protein CD276/B7-H3 is broadly overexpressed by multiple tumor types on both cancer cells and tumor-infiltrating blood vessels, making it a potentially ideal dual-compartment therapeutic target. In preclinical studies CD276 ADCs armed with a conventional MMAE warhead destroyed CD276-positive cancer cells, but were ineffective against tumor vasculature...
April 10, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28399407/messenger-rna-methylation-regulates-glioblastoma-tumorigenesis
#9
Deobrat Dixit, Qi Xie, Jeremy N Rich, Jing Crystal Zhao
Messenger RNA (mRNA) modification provides an additional layer of gene regulation in cells. In this issue of Cancer Cell, Zhang et al. report that ALKBH5, a demethylase of the mRNA modification N(6)-methyladenosine, regulates proliferation and self-renewal of glioblastoma stem-like cells by modulating pre-mRNA stability and expression of the FOXM1 gene.
April 10, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28399406/not-so-fast-cultivating-mirs-as-kinks-in-the-chain-of-the-cell-cycle
#10
Matthew J Schiewer, Karen E Knudsen
In this issue of Cancer Cell, Hydbring and colleagues define a novel class of microRNAs (miRNAs), deemed "cell-cycle-targeting miRNAs," that target several cyclins/CDKs, reduce tumor cell growth, and induce apoptosis. These miRNAs effectively suppressed chemoresistant patient-derived xenograft growth in vivo, and efficacy could be prospectively predicted with an expression-based algorithm.
April 10, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28399405/a-cd276-antibody-guided-missile-with-one-warhead-and-two-targets-the-tumor-and-its-vasculature
#11
Kabir A Khan, Robert S Kerbel
In this issue of Cancer Cell, Seaman et al. demonstrate that antibody drug conjugates (ADCs) against CD276 expressed by tumor cells and tumor vasculature have promising anti-tumor activity while showing little toxicity. Importantly, these agents have the potential to target both angiogenic vessels and non-angiogenic vessels co-opted by tumor cells.
April 10, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28399404/data-triumph-at-c
#12
Mark Levine, Pierre-Christian Violet
Despite historical controversy, pharmacologic ascorbate is emerging as promising cancer therapy via pro-oxidant chemistry. In this issue of Cancer Cell, Schoenfeld et al. describe how intracellular iron pools and reactive oxygen species drive pharmacologic ascorbate's selective toxicity to cancer cells in vitro, in mice, and in humans.
April 10, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28366679/o2-%C3%A2-and-h2o2-mediated-disruption-of-fe-metabolism-causes-the-differential-susceptibility-of-nsclc-and-gbm-cancer-cells-to-pharmacological-ascorbate
#13
Joshua D Schoenfeld, Zita A Sibenaller, Kranti A Mapuskar, Brett A Wagner, Kimberly L Cramer-Morales, Muhammad Furqan, Sonia Sandhu, Thomas L Carlisle, Mark C Smith, Taher Abu Hejleh, Daniel J Berg, Jun Zhang, John Keech, Kalpaj R Parekh, Sudershan Bhatia, Varun Monga, Kellie L Bodeker, Logan Ahmann, Sandy Vollstedt, Heather Brown, Erin P Shanahan Kauffman, Mary E Schall, Ray J Hohl, Gerald H Clamon, Jeremy D Greenlee, Matthew A Howard, Michael K Shultz, Brian J Smith, Dennis P Riley, Frederick E Domann, Joseph J Cullen, Garry R Buettner, John M Buatti, Douglas R Spitz, Bryan G Allen
Pharmacological ascorbate has been proposed as a potential anti-cancer agent when combined with radiation and chemotherapy. The anti-cancer effects of ascorbate are hypothesized to involve the autoxidation of ascorbate leading to increased steady-state levels of H2O2; however, the mechanism(s) for cancer cell-selective toxicity remain unknown. The current study shows that alterations in cancer cell mitochondrial oxidative metabolism resulting in increased levels of O2(⋅-) and H2O2 are capable of disrupting intracellular iron metabolism, thereby selectively sensitizing non-small-cell lung cancer (NSCLC) and glioblastoma (GBM) cells to ascorbate through pro-oxidant chemistry involving redox-active labile iron and H2O2...
April 10, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28366678/harnessing-the-immunotherapy-revolution-for-the-treatment-of-childhood-cancers
#14
REVIEW
Robbie G Majzner, Sabine Heitzeneder, Crystal L Mackall
Cancer immunotherapies can be classified into agents that amplify natural immune responses (e.g., checkpoint inhibitors) versus synthetic immunotherapies designed to initiate new responses (e.g., monoclonal antibodies [mAbs], chimeric antigen receptors [CARs]). Checkpoint inhibitors mediate unprecedented benefit in some adult cancers, but have not demonstrated significant activity in pediatric cancers, likely due their paucity of neoantigens. In contrast, synthetic immunotherapies such as mAbs and CAR T cells demonstrate impressive effects against childhood cancers...
April 10, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28344040/m-6-a-demethylase-alkbh5-maintains-tumorigenicity-of-glioblastoma-stem-like-cells-by-sustaining-foxm1-expression-and-cell-proliferation-program
#15
Sicong Zhang, Boxuan Simen Zhao, Aidong Zhou, Kangyu Lin, Shaoping Zheng, Zhike Lu, Yaohui Chen, Erik P Sulman, Keping Xie, Oliver Bögler, Sadhan Majumder, Chuan He, Suyun Huang
The dynamic and reversible N(6)-methyladenosine (m(6)A) RNA modification installed and erased by N(6)-methyltransferases and demethylases regulates gene expression and cell fate. We show that the m(6)A demethylase ALKBH5 is highly expressed in glioblastoma stem-like cells (GSCs). Silencing ALKBH5 suppresses the proliferation of patient-derived GSCs. Integrated transcriptome and m(6)A-seq analyses revealed altered expression of certain ALKBH5 target genes, including the transcription factor FOXM1. ALKBH5 demethylates FOXM1 nascent transcripts, leading to enhanced FOXM1 expression...
April 10, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28344039/development-of-peptidomimetic-inhibitors-of-the-erg-gene-fusion-product-in-prostate-cancer
#16
Xiaoju Wang, Yuanyuan Qiao, Irfan A Asangani, Bushra Ateeq, Anton Poliakov, Marcin Cieślik, Sethuramasundaram Pitchiaya, Balabhadrapatruni V S K Chakravarthi, Xuhong Cao, Xiaojun Jing, Cynthia X Wang, Ingrid J Apel, Rui Wang, Jean Ching-Yi Tien, Kristin M Juckette, Wei Yan, Hui Jiang, Shaomeng Wang, Sooryanarayana Varambally, Arul M Chinnaiyan
Transcription factors play a key role in the development of diverse cancers, and therapeutically targeting them has remained a challenge. In prostate cancer, the gene encoding the transcription factor ERG is recurrently rearranged and plays a critical role in prostate oncogenesis. Here, we identified a series of peptides that interact specifically with the DNA binding domain of ERG. ERG inhibitory peptides (EIPs) and derived peptidomimetics bound ERG with high affinity and specificity, leading to proteolytic degradation of the ERG protein...
April 10, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28292443/paradox-breaking-raf-inhibitors-that-also-target-src-are-effective-in-drug-resistant-braf-mutant-melanoma
#17
Maria Romina Girotti, Filipa Lopes, Natasha Preece, Dan Niculescu-Duvaz, Alfonso Zambon, Lawrence Davies, Steven Whittaker, Grazia Saturno, Amaya Viros, Malin Pedersen, Bart M J M Suijkerbuijk, Delphine Menard, Robert McLeary, Louise Johnson, Laura Fish, Sarah Ejiama, Berta Sanchez-Laorden, Juliane Hohloch, Neil Carragher, Kenneth Macleod, Garry Ashton, Anna A Marusiak, Alberto Fusi, John Brognard, Margaret Frame, Paul Lorigan, Richard Marais, Caroline Springer
No abstract text is available yet for this article.
March 13, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28292442/eto2-glis2-hijacks-transcriptional-complexes-to-drive-cellular-identity-and-self-renewal-in-pediatric-acute-megakaryoblastic-leukemia
#18
Cécile Thirant, Cathy Ignacimouttou, Cécile K Lopez, M'Boyba Diop, Lou Le Mouël, Clarisse Thiollier, Aurélie Siret, Phillipe Dessen, Zakia Aid, Julie Rivière, Philippe Rameau, Céline Lefebvre, Mehdi Khaled, Guy Leverger, Paola Ballerini, Arnaud Petit, Hana Raslova, Catherine L Carmichael, Benjamin T Kile, Eric Soler, John D Crispino, Christian Wichmann, Françoise Pflumio, Jürg Schwaller, William Vainchenker, Camille Lobry, Nathalie Droin, Olivier A Bernard, Sébastien Malinge, Thomas Mercher
Chimeric transcription factors are a hallmark of human leukemia, but the molecular mechanisms by which they block differentiation and promote aberrant self-renewal remain unclear. Here, we demonstrate that the ETO2-GLIS2 fusion oncoprotein, which is found in aggressive acute megakaryoblastic leukemia, confers megakaryocytic identity via the GLIS2 moiety while both ETO2 and GLIS2 domains are required to drive increased self-renewal properties. ETO2-GLIS2 directly binds DNA to control transcription of associated genes by upregulation of expression and interaction with the ETS-related ERG protein at enhancer elements...
March 13, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28292441/spop-mutation-drives-prostate-tumorigenesis-in%C3%A2-vivo-through-coordinate-regulation-of-pi3k-mtor-and-ar-signaling
#19
Mirjam Blattner, Deli Liu, Brian D Robinson, Dennis Huang, Anton Poliakov, Dong Gao, Srilakshmi Nataraj, Lesa D Deonarine, Michael A Augello, Verena Sailer, Lalit Ponnala, Michael Ittmann, Arul M Chinnaiyan, Andrea Sboner, Yu Chen, Mark A Rubin, Christopher E Barbieri
Recurrent point mutations in SPOP define a distinct molecular subclass of prostate cancer. Here, we describe a mouse model showing that mutant SPOP drives prostate tumorigenesis in vivo. Conditional expression of mutant SPOP in the prostate dramatically altered phenotypes in the setting of Pten loss, with early neoplastic lesions (high-grade prostatic intraepithelial neoplasia) with striking nuclear atypia and invasive, poorly differentiated carcinoma. In mouse prostate organoids, mutant SPOP drove increased proliferation and a transcriptional signature consistent with human prostate cancer...
March 13, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28292440/a-kinase-inhibitor-targeted-to-mtorc1-drives-regression-in-glioblastoma
#20
QiWen Fan, Ozlem Aksoy, Robyn A Wong, Shirin Ilkhanizadeh, Chris J Novotny, William C Gustafson, Albert Yi-Que Truong, Geraldine Cayanan, Erin F Simonds, Daphne Haas-Kogan, Joanna J Phillips, Theodore Nicolaides, Masanori Okaniwa, Kevan M Shokat, William A Weiss
Although signaling from phosphatidylinositol 3-kinase (PI3K) and AKT to mechanistic target of rapamycin (mTOR) is prominently dysregulated in high-grade glial brain tumors, blockade of PI3K or AKT minimally affects downstream mTOR activity in glioma. Allosteric mTOR inhibitors, such as rapamycin, incompletely block mTORC1 compared with mTOR kinase inhibitors (TORKi). Here, we compared RapaLink-1, a TORKi linked to rapamycin, with earlier-generation mTOR inhibitors. Compared with rapamycin and Rapalink-1, TORKi showed poor durability...
March 13, 2017: Cancer Cell
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