DOCSLIB.ORG

The Rac Gtpase in Cancer: from Old Concepts to New Paradigms Marcelo G

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
The Rac Gtpase in Cancer: from Old Concepts to New Paradigms Marcelo G Published OnlineFirst August 14, 2017; DOI: 10.1158/0008-5472.CAN-17-1456 Cancer Review Research The Rac GTPase in Cancer: From Old Concepts to New Paradigms Marcelo G. Kazanietz1 and Maria J. Caloca2 Abstract Rho family GTPases are critical regulators of cellular func- mislocalization of Rac signaling components. The unexpected tions that play important roles in cancer progression. Aberrant pro-oncogenic functions of Rac GTPase-activating proteins also activity of Rho small G-proteins, particularly Rac1 and their challenged the dogma that these negative Rac regulators solely regulators, is a hallmark of cancer and contributes to the act as tumor suppressors. The potential contribution of Rac tumorigenic and metastatic phenotypes of cancer cells. This hyperactivation to resistance to anticancer agents, including review examines the multiple mechanisms leading to Rac1 targeted therapies, as well as to the suppression of antitumor hyperactivation, particularly focusing on emerging paradigms immune response, highlights the critical need to develop ther- that involve gain-of-function mutations in Rac and guanine apeutic strategies to target the Rac pathway in a clinical setting. nucleotide exchange factors, defects in Rac1 degradation, and Cancer Res; 77(20); 5445–51. Ó2017 AACR. Introduction directed toward targeting Rho-regulated pathways for battling cancer. Exactly 25 years ago, two seminal papers by Alan Hall and Nearly all Rho GTPases act as molecular switches that cycle colleagues illuminated us with one of the most influential dis- between GDP-bound (inactive) and GTP-bound (active) forms. coveries in cancer signaling: the association of Ras-related small Activation is promoted by guanine nucleotide exchange factors GTPases of the Rho family with actin cytoskeleton reorganization (GEF) responsible for GDP dissociation, a process that normally (1, 2). Those findings set the mechanistic basis for the control of occurs very slowly, thereby facilitating the exchange for GTP that is cell motility, invasiveness, and metastasis in response to extra- present at much higher cytosolic concentrations. On the other cellular receptors. The Rho small (21 kDa) G-protein family hand, GTPase-activating proteins (GAP) inactivate Rho proteins comprises 20 members categorized into Rac (Rac1, Rac2, Rac3, by accelerating their intrinsic rate of GTP hydrolysis. Once in the and RhoG), Rho (RhoA, RhoB, and RhoC), and Cdc42 (Cdc42, inactive conformation, Rho GTPases associate with guanine TC10, Chip, TCL, and Wrch-1) subfamilies, and other less studied nucleotide dissociation inhibitors (GDI), a step that contributes GTPases that include RhoD, RhoE, and RhoH (3). Rho GTPases to their stabilization and precludes them from getting activated control a variety of cellular functions through regulation of actin (3, 4). In cancer, changes in abundance of Rho GTPases and their contractility and peripheral actin structures, including cell mor- regulators, or excessive input signals leading to their activation, phology, locomotion, and polarity. Accordingly, they are key have been associated with disease progression (3–5). More recent- players in physiologic processes such as embryonic development, ly, point mutations and deregulated stability or localization of neuronal plasticity, phagocytosis, and stem cell formation. Dereg- these proteins have been identified as mechanisms that contribute ulation of Rho GTPase function in cancer is associated with to tumorigenesis and metastasis, which will be discussed in this fundamental hallmarks of progression, including changes in gene review particularly for the GTPase Rac (summarized in Fig. 1 expression, cell survival, oncogenic transformation, tumor metab- and Table 1). olism, and invasiveness (3–5). Deciphering the key effectors and regulators of Rho family members became a crucial undertaking in cancer cell biology, and significant research efforts have been Distinctive Roles for Rho GTPases in Cancer Initiation and Progression The initial evidence that Rho GTPases are positively involved in cancer cell growth arised from studies showing transforming 1Department of Systems Pharmacology and Translational Therapeutics, Perel- man School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. activity by active forms and inhibition by dominant-negative 2Instituto de Biología y Genetica Molecular, Consejo Superior de Investigaciones forms (see for example ref. 6). Elevated expression of Rac1, the Científicas, Universidad de Valladolid, Valladolid, Spain. active splice variant Rac1b, and other related GTPases has been Corresponding Authors: Marcelo G. Kazanietz, Perelman School of Medicine, frequently observed in human cancer, which in some cases University of Pennsylvania, 1256 Biomedical Research Building II/III, 421 Curie correlated with aggressiveness and poor prognosis (3). Consis- Blvd., Philadelphia, PA 19104-6160. Phone: 215-898-0253; Fax: 215-746-8941; tently, studies in mouse models supported the requirement of Rac E-mail: [email protected]; and Maria J. Caloca, Instituto de Biología y for tumor growth. For example, genetic deletion of the Rac1 gene Genetica Molecular, Consejo Superior de Investigaciones Científicas, Universi- in mice impairs the development of mutant KRas-driven cancer in dad de Valladolid, 47003 Valladolid, Spain. E-mail: [email protected] skin, lung, and pancreas (7–9). Loss of Rac2, but not Rac1, delays doi: 10.1158/0008-5472.CAN-17-1456 the initiation of acute myeloid leukemia, although the survival of Ó2017 American Association for Cancer Research. fully transformed leukemia cells is dependent on Rac1 and Rac2 www.aacrjournals.org 5445 Downloaded from cancerres.aacrjournals.org on October 2, 2021. © 2017 American Association for Cancer Research. Published OnlineFirst August 14, 2017; DOI: 10.1158/0008-5472.CAN-17-1456 Kazanietz and Caloca Activating Active Rac1 Defective Rac Rac-GEF Rac-GAP mutations splice variant degradation hyperactivation downregulation GTP GTP GTP GDP GTP GDP Rac Rac1b Rac Rac Rac Rac GEF GAPs GEF HACE1 GEF GTP GEF Rac GDI Ub Protumorigenic Ub Ub Rac-GAPs Ub GDP GAP Rac GAP Proteasome GAP GAP GAP-independent Altered functions Rac/Rho balance GTP GTP Nucleolus Rac Rac GDP Ect2 GTP Rac Rac Rac GTP mislocalization Rho rDNA transcription Actin polymerization Nuclear plasticity Actomyosin contractility © 2017 American Association for Cancer Research Figure 1. Mechanisms of Rac deregulation in cancer. Activating mutations in Rac1 have been recently found in various cancers, including Rac1P29S, identified as a driver mutation in melanomas. Another hyperactive form is the splice variant Rac1b present in a number of cancers. Degradation of Rac1 by the proteasome contributes to the control of Rac protein expression levels, and it could be impaired in tumors as a consequence of missense mutations in the ubiquitin ligase HACE1. Hyperactivation of Rac-GEFs as a consequence of overexpression or mutation is also a prominent cause of Rac1 deregulation in cancer. Rac-GAPs have a complex role in cancer, as their reduced expression contributes to Rac1 hyperactivation in some tumors; however, overexpression of specific GAPs has been also linked to aggressiveness, most likely through GAP-independent functions. Abnormal nuclear Rac1 localization is also common in cancer, an effect that has been associated with improper nucleocytoplasmic shuttling. Deregulated GEF activity in nuclear compartments, such as the nucleolus, may lead to localized Rac1 activation and enhanced rRNA synthesis. (10). Similarly, deletion of Rac3 resulted in increased survival of a ablation of the RhoB gene in mice (a gene deleted in many human À À transgenic mouse model of acute lymphoblastic leukemia (11). cancers) enhances carcinogen-induced skin cancer (15). Rhob / The involvement of Rac1 in cancer progression has also been mice are less prone to form squamous cell carcinomas following strengthened by means of genetic deletion or silencing of Rac- chronic exposure to UVB, arguing that RhoB favors early stages of specific GEFs such as P-Rex1 and Tiam1 in mouse models, oncogenesis; however, RhoB could also limit the progression to resulting in impaired tumorigenic and metastatic phenotypes highly aggressive tumors (16). Deletion of the RhoC gene in the (12–14). It became increasingly evident, however, that unlike MMTV-PyVT mouse model of breast cancer significantly reduces Rac, Rho could exert either pro- or antioncogenic actions in vivo lung metastasis of mammary tumors (17). However, deletion of in different contexts. For example, early studies revealed that RhoC or RhoA genes failed to suppress KRas-mediated lung 5446 Cancer Res; 77(20) October 15, 2017 Cancer Research Downloaded from cancerres.aacrjournals.org on October 2, 2021. © 2017 American Association for Cancer Research. Published OnlineFirst August 14, 2017; DOI: 10.1158/0008-5472.CAN-17-1456 Rac GTPases in Cancer Table 1. Common cancer-associated alterations in Rac1, Rac-GEFs, and mutants in KRas) and Rac1Q61R (paralogous to Q61 mutants in Rac-GAPs KRas) have been also identified in head and neck, and prostate Alteration Examples cancer, respectively (22). It should not be assumed that the same Rac1 Upregulation Lung and breast cancer scenario is true for other Rho GTPases, because RhoA mutations Point mutations Rac1Q61R (prostate cancer) Rac1P29S (melanoma) found in gastric adenocarcinomas, head and neck cancer, and Rac1G12V/G12R/P34R/Q61R/Q61K (germ cell lymphomas could be either gain-of-function (for example, Y42C G17V testicular
Load more

Recommended publications
  • Cytoplasmic Expression of Epithelial Cell Transforming Sequence 2 in Lung Adenocarcinoma and Its Implications for Malignant Progression
    Laboratory Investigation (2019) 99:551–567 https://doi.org/10.1038/s41374-018-0142-4 ARTICLE Cytoplasmic expression of epithelial cell transforming sequence 2 in lung adenocarcinoma and its implications for malignant progression 1 2 3 1 2 2 Zeinab Kosibaty ● Yoshihiko Murata ● Yuko Minami ● Tomoko Dai ● Junko Kano ● Ryota Matsuoka ● 2 2 Noriyuki Nakano ● Masayuki Noguchi Received: 8 March 2018 / Revised: 14 August 2018 / Accepted: 20 August 2018 / Published online: 12 December 2018 © United States & Canadian Academy of Pathology 2018 Abstract Epithelial cell transforming sequence 2 (ECT2), a guanine nucleotide exchange factor, is predominantly localized in the nucleus of non-transformed cells and functions to regulate cytokinesis. ECT2 is also localized in the cytoplasm of cancer cells. Aberrant cytoplasmic expression of ECT2 is thought to drive tumor growth and invasion. In this study, we investigated the cytoplasmic expression of ECT2 and its prognostic and biological significance in lung adenocarcinoma. Western blotting of cellular fractions from the nucleus and cytoplasm was performed to determine the subcellular localization of ECT2 in lung adenocarcinoma cell lines. The cytoplasmic expression of ECT2 in 167 lung fi 1234567890();,: 1234567890();,: adenocarcinomas was evaluated by immunohistochemistry and its clinical signi cance was examined using Kaplan–Meier curves and Cox regression analysis. Scraping cytology specimens of 13 fresh lung adenocarcinomas were used to assess the subcellular localization of ECT2 and its phosphorylation at Thr790 (P-ECT2(T790)). We found that ECT2 was localized in both the nucleus and cytoplasm of lung adenocarcinoma cell lines and tumor tissues. Cytoplasmic expression of ECT2 was detected by immunohistochemistry in 83 (50%) of the lung adenocarcinomas, and was found to increase during cancer progression.
    [Show full text]
  • Cell Division Symmetry Control and Cancer Stem Cells
    AIMS Molecular Science, 7(2): 82–98. DOI: 10.3934/molsci.2020006 Received: 15 February 2020 Accepted: 26 April 2020 Published: 06 May 2020 http://www.aimspress.com/journal/Molecular Review Cell division symmetry control and cancer stem cells Sreemita Majumdar and Song-Tao Liu* Department of Biological Sciences, University of Toledo, Toledo, OH 43606, USA * Correspondence: Email: [email protected]; Tel: +14195307853. Table S1. Genes encoding polarity and fate-determinant proteins involved in asymmetric cell division. C. elegans1 D. melanogaster 1 Mammals1 Description2 Associated with/ Interactors 3 Cellular Localization (mammalian cell)4 Serine/threonine protein microtubule-associated protein cell membrane, peripheral and lateral, par-1 par-1 MARK1/2/3/4 kinase MAPT/TAU cytoplasm, dendrite RING, Lipid binding par-2 - - domain PDZ for membrane, cell junction, adherens junction, cell cortex, par-3 baz PARD3 Oligomerization domain at actin, PARD6 endomembrane system, NTD Continued on next page 2 C. elegans1 D. melanogaster 1 Mammals1 Description2 Associated with/ Interactors 3 Cellular Localization (mammalian cell)4 Serine/threonine-protein nucleus, mitochondria, cytoplasm, par-4 Lkb1 STK11/LKB1 STRAD complex kinase membrane 14-3-3 domain binding par-5 14-3-3 YWHAB phosphoserine/ adapter to many proteins cytoplasm phosphothreonine motif cell membrane, centriolar satellite, actin par-6 par-6 PARD6A/B/G PB1, CRIB, PDZ PARD3 cytoskeleton,centrosome, cytoplasm ,ruffles PARD3, and a PARD6 protein PB1, AGC-Kinase (PARD6A, PARD6B or PARD6G) pkc-3 aPKC PRKCI/Z domain, DAG binding, cytoplasm, nucleus, membrane and a GTPase protein (CDC42 or Zinc finger domain RAC1), LLGL1,ECT2 LRR and PDZ protein Cadherin, Scrib-APC-beta-catenin nucleoplasm, basolateral plasma membrane, let-413 scrib SCRIB family.
    [Show full text]
  • A GTP-State Specific Cyclic Peptide Inhibitor of the Gtpase Gαs
    bioRxiv preprint doi: https://doi.org/10.1101/2020.04.25.054080; this version posted April 27, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. A GTP-state specific cyclic peptide inhibitor of the GTPase Gαs Shizhong A. Dai1,2†, Qi Hu1,2†, Rong Gao3†, Andre Lazar1,4†, Ziyang Zhang1,2, Mark von Zastrow1,4, Hiroaki Suga3*, Kevan M. Shokat1,2* 5 1Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, 94158, USA 2Howard Hughes Medical Institute 3Department of Chemistry, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan 10 4Department of Psychiatry, University of California, San Francisco, San Francisco, CA, 94158, USA *Correspondence to: [email protected], [email protected] †These authors contributed equally. 15 20 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.04.25.054080; this version posted April 27, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Abstract: The G protein-coupled receptor (GPCR) cascade leading to production of the second messenger cAMP is replete with pharmacologically targetable receptors and enzymes with the exception of the stimulatory G protein α subunit, Gαs.
    [Show full text]
  • 1 Metabolic Dysfunction Is Restricted to the Sciatic Nerve in Experimental
    Page 1 of 255 Diabetes Metabolic dysfunction is restricted to the sciatic nerve in experimental diabetic neuropathy Oliver J. Freeman1,2, Richard D. Unwin2,3, Andrew W. Dowsey2,3, Paul Begley2,3, Sumia Ali1, Katherine A. Hollywood2,3, Nitin Rustogi2,3, Rasmus S. Petersen1, Warwick B. Dunn2,3†, Garth J.S. Cooper2,3,4,5* & Natalie J. Gardiner1* 1 Faculty of Life Sciences, University of Manchester, UK 2 Centre for Advanced Discovery and Experimental Therapeutics (CADET), Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, UK 3 Centre for Endocrinology and Diabetes, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, UK 4 School of Biological Sciences, University of Auckland, New Zealand 5 Department of Pharmacology, Medical Sciences Division, University of Oxford, UK † Present address: School of Biosciences, University of Birmingham, UK *Joint corresponding authors: Natalie J. Gardiner and Garth J.S. Cooper Email: [email protected]; [email protected] Address: University of Manchester, AV Hill Building, Oxford Road, Manchester, M13 9PT, United Kingdom Telephone: +44 161 275 5768; +44 161 701 0240 Word count: 4,490 Number of tables: 1, Number of figures: 6 Running title: Metabolic dysfunction in diabetic neuropathy 1 Diabetes Publish Ahead of Print, published online October 15, 2015 Diabetes Page 2 of 255 Abstract High glucose levels in the peripheral nervous system (PNS) have been implicated in the pathogenesis of diabetic neuropathy (DN). However our understanding of the molecular mechanisms which cause the marked distal pathology is incomplete. Here we performed a comprehensive, system-wide analysis of the PNS of a rodent model of DN.
    [Show full text]
  • Involvement of the Rho/Rac Family Member Rhog in Caveolar Endocytosis
    Oncogene (2006) 25, 2961–2973 & 2006 Nature Publishing Group All rights reserved 0950-9232/06 $30.00 www.nature.com/onc ORIGINAL ARTICLE Involvement of the Rho/Rac family member RhoG in caveolar endocytosis RM Prieto-Sa´ nchez1, IM Berenjeno1 and XR Bustelo Centro de Investigacio´n del Ca´ncer, Instituto de Biologı´a Molecular y Celular del Ca´ncer (IBMCC), and Red Tema´tica Cooperativa de Centros de Ca´ncer, CSIC-University of Salamanca, Campus Unamuno, Salamanca, Spain We show here that the GTPase RhoG is involved in transduction, cell polarity, and intercellular communi- caveolar trafficking. Wild-type RhoG moves sequentially cations (Gruenberg, 2001; Conner and Schmid, 2003; Di to the plasma membrane, intracellular vesicles, and the Guglielmo et al., 2003; Felberbaum-Corti et al., 2003; Golgi apparatus along markers of this endocytic pathway. Gonzalez-Gaitan, 2003). The best-known endocytic Such translocation is associated with changes in RhoG pathway is that composed of clathrin-coated vesicles GDP/GTP levels and is highly dependent on lipid raft (Zerial and McBride, 2001; Conner and Schmid, 2003). integrity and on the function of the GTPase dynamin2. In In this case, we have information regarding the addition, the constitutively active RhoGQ61L mutant is internalization, sorting, recycling, fusion, and delivery preferentially located in endocytic vesicles that can be events that participate in this type of endocytosis (Zerial decorated with markers of the caveola-derived endocytic and McBride, 2001; Conner and Schmid, 2003). This pathway. RhoGQ61L, but not the analogous Rac1 mutant pathway has also been molecularly dissected, resulting protein, affects caveola internalization and the subsequent in the characterization of a large number of regulatory delivery of endocytic vesicles to the Golgi apparatus.
    [Show full text]
  • Clinical Utility of Recently Identified Diagnostic, Prognostic, And
    Modern Pathology (2017) 30, 1338–1366 1338 © 2017 USCAP, Inc All rights reserved 0893-3952/17 $32.00 Clinical utility of recently identified diagnostic, prognostic, and predictive molecular biomarkers in mature B-cell neoplasms Arantza Onaindia1, L Jeffrey Medeiros2 and Keyur P Patel2 1Instituto de Investigacion Marques de Valdecilla (IDIVAL)/Hospital Universitario Marques de Valdecilla, Santander, Spain and 2Department of Hematopathology, MD Anderson Cancer Center, Houston, TX, USA Genomic profiling studies have provided new insights into the pathogenesis of mature B-cell neoplasms and have identified markers with prognostic impact. Recurrent mutations in tumor-suppressor genes (TP53, BIRC3, ATM), and common signaling pathways, such as the B-cell receptor (CD79A, CD79B, CARD11, TCF3, ID3), Toll- like receptor (MYD88), NOTCH (NOTCH1/2), nuclear factor-κB, and mitogen activated kinase signaling, have been identified in B-cell neoplasms. Chronic lymphocytic leukemia/small lymphocytic lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, Burkitt lymphoma, Waldenström macroglobulinemia, hairy cell leukemia, and marginal zone lymphomas of splenic, nodal, and extranodal types represent examples of B-cell neoplasms in which novel molecular biomarkers have been discovered in recent years. In addition, ongoing retrospective correlative and prospective outcome studies have resulted in an enhanced understanding of the clinical utility of novel biomarkers. This progress is reflected in the 2016 update of the World Health Organization classification of lymphoid neoplasms, which lists as many as 41 mature B-cell neoplasms (including provisional categories). Consequently, molecular genetic studies are increasingly being applied for the clinical workup of many of these neoplasms. In this review, we focus on the diagnostic, prognostic, and/or therapeutic utility of molecular biomarkers in mature B-cell neoplasms.
    [Show full text]
  • P2Y Purinergic Receptors, Endothelial Dysfunction, and Cardiovascular Diseases
    International Journal of Molecular Sciences Review P2Y Purinergic Receptors, Endothelial Dysfunction, and Cardiovascular Diseases Derek Strassheim 1, Alexander Verin 2, Robert Batori 2 , Hala Nijmeh 3, Nana Burns 1, Anita Kovacs-Kasa 2, Nagavedi S. Umapathy 4, Janavi Kotamarthi 5, Yash S. Gokhale 5, Vijaya Karoor 1, Kurt R. Stenmark 1,3 and Evgenia Gerasimovskaya 1,3,* 1 The Department of Medicine Cardiovascular and Pulmonary Research Laboratory, University of Colorado Denver, Aurora, CO 80045, USA; [email protected] (D.S.); [email protected] (N.B.); [email protected] (V.K.); [email protected] (K.R.S.) 2 Vascular Biology Center, Augusta University, Augusta, GA 30912, USA; [email protected] (A.V.); [email protected] (R.B.); [email protected] (A.K.-K.) 3 The Department of Pediatrics, Division of Critical Care Medicine, University of Colorado Denver, Aurora, CO 80045, USA; [email protected] 4 Center for Blood Disorders, Augusta University, Augusta, GA 30912, USA; [email protected] 5 The Department of BioMedical Engineering, University of Wisconsin, Madison, WI 53706, USA; [email protected] (J.K.); [email protected] (Y.S.G.) * Correspondence: [email protected]; Tel.: +1-303-724-5614 Received: 25 August 2020; Accepted: 15 September 2020; Published: 18 September 2020 Abstract: Purinergic G-protein-coupled receptors are ancient and the most abundant group of G-protein-coupled receptors (GPCRs). The wide distribution of purinergic receptors in the cardiovascular system, together with the expression of multiple receptor subtypes in endothelial cells (ECs) and other vascular cells demonstrates the physiological importance of the purinergic signaling system in the regulation of the cardiovascular system.
    [Show full text]
  • Tumor Markers
    Tumor Markers Alan H.B. Wu, Ph.D. Professor, Laboratory Medicine, UCSF Section Chief, Clinical Chemistry, Toxicology, Pharmacogenomics Laboratory, SFGH Learning objectives • Know the ideal characteristics of a tumor marker • Understand the role of tumor markers for diagnosis and management of patients with cancer. • Know the emerging technologies for tumor markers • Understand the role of tumor markers for therapeutic selection How do we diagnose cancer today? Physical Examination Blood tests CT scans Biopsy Human Prostate Cancer Normal Blood Smear Chronic Myeloid Leukemia Death rates for cancer vs. heart disease New cancer cases per year Cancer Site or Type New Cases Prostate 218,000 Lung 222,500 Breast 207,500 Colorectal 149,000 Urinary system 131,500 Skin 68,770 Pancreas 43,100 Ovarian 22,000 Myeloma 20,200 Thyroid 44,700 Germ Cell 9,000 Types of Tumor Markers • Hormones (hCG; calcitonin; gastrin; prolactin;) • Enzymes (acid phosphatase; alkaline phosphatase; PSA) • Cancer antigen proteins & glycoproteins (CA125; CA 15.3; CA19.9) • Metabolites (norepinephrine, epinephrine) • Normal proteins (thyroglobulin) • Oncofetal antigens (CEA, AFP) • Receptors (ER, PR, EGFR) • Genetic changes (mutations/translocations, etc.) Characteristics of an ideal tumor marker • Specificity for a single type of cancer • High sensitivity and specificity for cancerous growth • Correlation of marker level with tumor size • Homogeneous (i.e., minimal post-translational modifications) • Short half-life in circulation Roles for tumor markers • Determine risk (PSA)
    [Show full text]
  • A Rhog-Mediated Signaling Pathway That Modulates Invadopodia Dynamics in Breast Cancer Cells Silvia M
    © 2017. Published by The Company of Biologists Ltd | Journal of Cell Science (2017) 130, 1064-1077 doi:10.1242/jcs.195552 RESEARCH ARTICLE A RhoG-mediated signaling pathway that modulates invadopodia dynamics in breast cancer cells Silvia M. Goicoechea, Ashtyn Zinn, Sahezeel S. Awadia, Kyle Snyder and Rafael Garcia-Mata* ABSTRACT micropinocytosis, bacterial uptake, phagocytosis and leukocyte One of the hallmarks of cancer is the ability of tumor cells to invade trans-endothelial migration (deBakker et al., 2004; Ellerbroek et al., surrounding tissues and metastasize. During metastasis, cancer cells 2004; Jackson et al., 2015; Katoh et al., 2006, 2000; van Buul et al., degrade the extracellular matrix, which acts as a physical barrier, by 2007). Recent studies have revealed that RhoG plays a role in tumor developing specialized actin-rich membrane protrusion structures cell invasion and may contribute to the formation of invadopodia called invadopodia. The formation of invadopodia is regulated by Rho (Hiramoto-Yamaki et al., 2010; Kwiatkowska et al., 2012). GTPases, a family of proteins that regulates the actin cytoskeleton. Invadopodia are actin-rich adhesive structures that form in the Here, we describe a novel role for RhoG in the regulation of ventral surface of cancer cells and allow them to degrade the invadopodia disassembly in human breast cancer cells. Our results extracellular matrix (ECM) (Gimona et al., 2008). Formation of show that RhoG and Rac1 have independent and opposite roles invadopodia involves a series of steps that include the disassembly in the regulation of invadopodia dynamics. We also show that SGEF of focal adhesions and stress fibers, and the relocalization of several (also known as ARHGEF26) is the exchange factor responsible of their components into the newly formed invadopodia (Hoshino for the activation of RhoG during invadopodia disassembly.
    [Show full text]
  • Screening for Tumor Suppressors: Loss of Ephrin PNAS PLUS Receptor A2 Cooperates with Oncogenic Kras in Promoting Lung Adenocarcinoma
    Screening for tumor suppressors: Loss of ephrin PNAS PLUS receptor A2 cooperates with oncogenic KRas in promoting lung adenocarcinoma Narayana Yeddulaa, Yifeng Xiaa, Eugene Kea, Joep Beumera,b, and Inder M. Vermaa,1 aLaboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA 92037; and bHubrecht Institute, Utrecht, The Netherlands Contributed by Inder M. Verma, October 12, 2015 (sent for review July 28, 2015; reviewed by Anton Berns, Tyler Jacks, and Frank McCormick) Lung adenocarcinoma, a major form of non-small cell lung cancer, injections in embryonic skin cells identified several potential tu- is the leading cause of cancer deaths. The Cancer Genome Atlas morigenic factors (14–16). None of the reported studies have analysis of lung adenocarcinoma has identified a large number of performed direct shRNA-mediated high-throughput approaches previously unknown copy number alterations and mutations, re- in adult mice recapitulating the mode of tumorigenesis in humans. quiring experimental validation before use in therapeutics. Here, we Activating mutations at positions 12, 13, and 61 amino acids in describe an shRNA-mediated high-throughput approach to test a set Kirsten rat sarcoma viral oncogene homolog (KRas) contributes of genes for their ability to function as tumor suppressors in the to tumorigenesis in 32% of lung adenocarcinoma patients (2) by background of mutant KRas and WT Tp53. We identified several activating downstream signaling cascades. Mice with the KRasG12D candidate genes from tumors originated from lentiviral delivery of allele develop benign adenomatous lesions with long latency to shRNAs along with Cre recombinase into lungs of Loxp-stop-Loxp- develop adenocarcinoma (17, 18).
    [Show full text]
  • High Throughput Strategies Aimed at Closing the GAP in Our Knowledge of Rho Gtpase Signaling
    cells Review High Throughput strategies Aimed at Closing the GAP in Our Knowledge of Rho GTPase Signaling Manel Dahmene 1, Laura Quirion 2 and Mélanie Laurin 1,3,* 1 Oncology Division, CHU de Québec–Université Laval Research Center, Québec, QC G1V 4G2, Canada; [email protected] 2 Montréal Clinical Research Institute (IRCM), Montréal, QC H2W 1R7, Canada; [email protected] 3 Université Laval Cancer Research Center, Québec, QC G1R 3S3, Canada * Correspondence: [email protected] Received: 21 May 2020; Accepted: 7 June 2020; Published: 9 June 2020 Abstract: Since their discovery, Rho GTPases have emerged as key regulators of cytoskeletal dynamics. In humans, there are 20 Rho GTPases and more than 150 regulators that belong to the RhoGEF, RhoGAP, and RhoGDI families. Throughout development, Rho GTPases choregraph a plethora of cellular processes essential for cellular migration, cell–cell junctions, and cell polarity assembly. Rho GTPases are also significant mediators of cancer cell invasion. Nevertheless, to date only a few molecules from these intricate signaling networks have been studied in depth, which has prevented appreciation for the full scope of Rho GTPases’ biological functions. Given the large complexity involved, system level studies are required to fully grasp the extent of their biological roles and regulation. Recently, several groups have tackled this challenge by using proteomic approaches to map the full repertoire of Rho GTPases and Rho regulators protein interactions. These studies have provided in-depth understanding of Rho regulators specificity and have contributed to expand Rho GTPases’ effector portfolio. Additionally, new roles for understudied family members were unraveled using high throughput screening strategies using cell culture models and mouse embryos.
    [Show full text]
  • Profiling Cytotoxic Micrornas in Pediatric and Adult Glioblastoma
    Oncogene https://doi.org/10.1038/s41388-020-1360-y ARTICLE Profiling cytotoxic microRNAs in pediatric and adult glioblastoma cells by high-content screening, identification, and validation of miR-1300 1 1 2 2 1 1 1 1,3 1 M. Boissinot ● H. King ● M. Adams ● J. Higgins ● G. Shaw ● T. A. Ward ● L. P. Steele ● D. Tams ● R. Morton ● 4 4 5 1,6 7 8 9 2,7 E. Polson ● B. da Silva ● A. Droop ● J. L. Hayes ● H. Martin ● P. Laslo ● E. Morrison ● D. C. Tomlinson ● 4 2,10 1,11 1,12 H. Wurdak ● J. Bond ● S. E. Lawler ● S. C. Short Received: 29 November 2019 / Revised: 20 May 2020 / Accepted: 5 June 2020 © The Author(s) 2020. This article is published with open access Abstract MicroRNAs play an important role in the regulation of mRNA translation and have therapeutic potential in cancer and other diseases. To profile the landscape of microRNAs with significant cytotoxicity in the context of glioblastoma (GBM), we performed a high-throughput screen in adult and pediatric GBM cells using a synthetic oligonucleotide library representing all known human microRNAs. Bioinformatics analysis was used to refine this list and the top seven microRNAs were validated in a 1234567890();,: 1234567890();,: larger panel of GBM cells using state-of-the-art in vitro assays. The cytotoxic effect of our most relevant candidate was assessed in a preclinical model. Our screen identified ~100 significantly cytotoxic microRNAs with 70% concordance between cell lines. MicroRNA-1300 (miR-1300) was the most potent and robust candidate. We observed a striking binucleated phenotype in miR- 1300 transfected cells due to cytokinesis failure followed by apoptosis.
    [Show full text]