DOCSLIB.ORG

TAM Receptor Tyrosine Kinases in Cancer Drug Resistance Mikaella Vouri and Sassan Hafizi

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
TAM Receptor Tyrosine Kinases in Cancer Drug Resistance Mikaella Vouri and Sassan Hafizi Published OnlineFirst May 19, 2017; DOI: 10.1158/0008-5472.CAN-16-2675 Cancer Review Research TAM Receptor Tyrosine Kinases in Cancer Drug Resistance Mikaella Vouri and Sassan Hafizi Abstract Receptor tyrosine kinases (RTK) are major regulators of key spread, progression, and mortality, there is an increasing need for biological processes, including cell growth, survival, and differ- understanding the mechanisms by which cancer cells can evade entiation, and were established early on as proto-oncogenes, therapy-induced cell death. The TAM (Tyro3, Axl, Mer) subfamily with aberrant expression linked to tumor progression in many of RTKs in particular feature in a variety of cancer types that have cancers. Therefore, RTKs have emerged as major targets for selec- developed resistance to a broad range of therapeutic agents, tive therapy with small-molecule inhibitors. However, despite including both targeted as well as conventional chemotherapeu- improvements in survival rates, it is now apparent that the tics. This article reviews the roles of TAMs as tumor drivers and as targeting of RTKs with selective inhibitors is only transiently mediators of chemoresistance, and the potential effectiveness of effective, as the majority of patients eventually become resistant targeting them as part of therapeutic strategies to delay or combat to therapy. As chemoresistance is the leading cause of cancer resistance. Cancer Res; 77(11); 2775–8. Ó2017 AACR. Introduction and regulation of proinflammatory cytokine production (2, 3). MerTK is most distinctly recognized for its role in negative The TAM (Tyro3, Axl, MerTK) family of receptor tyrosine regulation of the immune system through its ability to mediate kinases (RTK) is defined by each member possessing an extracel- phagocytosis of apoptotic cells (4). Tyro3 has a more restricted lular combination of two immunoglobulin-like domains and two tissue expression profile and has been implicated in various roles, fibronectin type III repeats, a transmembrane portion, and an including myelination in the brain (5). intracellular region with intrinsic tyrosine kinase activity. The human TAM genes share similar genomic structures, and their resulting proteins share significant structural similarities, with The TAMs as Mediators of Chemoresistance greatest homology in the tyrosine kinase domain. The apparent Although the TAMs are not strong oncogenes, it is increas- molecular weights range from 100 to 140 kDa for Axl and Tyro3 ingly clear that their overexpression contributes to acquiring and 165 to 205 kDa for MerTK due to posttranslational modifica- resistance to both conventional as well as targeted chemother- tions, including glycosylation, phosphorylation, and ubiquitina- apeutics in both solid and blood cancers. Early observations tion. The established natural ligands for the TAMs are two homol- included increased Axl expression with resistance to the small ogous vitamin K–dependent proteins, Gas6 (all three TAMs), and molecule inhibitor imatinib (targets BCR-Abl, c-Kit, and protein S (Tyro3 and MerTK; ref. 1). PDGFR) in chronic myelogenous leukemia (CML; ref. 6) and to the chemotherapy drugs doxorubicin, VP16, and cisplatin TAM Functions in acute myeloid leukemia (7). Increased resistance to imatinib due to Axl and MerTK overexpression has also been reported in All three TAMs have transforming potential; however, Axl gastrointestinal stromal tumors (8) and non–smallcelllung overexpression has most frequently been detected in multiple carcinoma (NSCLC; ref. 9). cancers, and its role in supporting tumorigenesis is well recog- MerTK overexpression has been detected in high-grade glio- nized. Axl supports tumor growth and dissemination through blastomas and its knockdown to result in increased sensitivity to positive effects on cell survival, proliferation, migration, and etoposide while, conversely, control cells showed elevated MerTK invasion. Alongside these, Axl signaling is also involved in other activation upon DNA damage with increase resistance to etopo- processes ranging from the differentiation of cells in the erythroid side (10). Inhibition of Axl and MerTK also led to increased lineage, protecting blood vessels from injury, clearance of apo- chemosensitivity to temozolomide, carboplatin, and vincristine ptotic cells, angiogenesis, hematopoiesis, platelet aggregation, in astrocytoma (11), and to cisplatin and vincristine in neuro- blastoma (12). Axl was also shown to promote resistance to ALK inhibitors in neuroblastoma through induction of epithelial– Institute of Biomedical and Biomolecular Science, School of Pharmacy and mesenchymal transition (EMT; ref. 13). MerTK inhibition by an Biomedical Sciences, University of Portsmouth, Portsmouth, United Kingdom. mAb was able to increase sensitivity to carboplatin in NSCLC due Corresponding Author: Sassan Hafizi, University of Portsmouth, St. Michael's to receptor internalization and subsequent degradation, which Building, White Swan Road, Portsmouth PO1 2DT, United Kingdom. Phone: led to STAT6, Akt, and ERK1/2 signaling inhibition (14). MerTK 4423-9284-2665; Fax: 4423-9284-3565; E-mail: sassan.hafi[email protected] was also shown in NSCLC to be essential for increased resistance doi: 10.1158/0008-5472.CAN-16-2675 to erlotinib through the regulation of MAPK and FAK signaling Ó2017 American Association for Cancer Research. pathways (15). www.aacrjournals.org 2775 Downloaded from cancerres.aacrjournals.org on September 28, 2021. © 2017 American Association for Cancer Research. Published OnlineFirst May 19, 2017; DOI: 10.1158/0008-5472.CAN-16-2675 Vouri and Hafizi Knockdown of Axl by short hairpin (sh)RNA has revealed Axl to identified as a marker for poor overall survival in ovarian cancer promote the survival of cutaneous squamous carcinoma cells (30). Also, galectin-3, a sugar-binding protein that has been through Akt activation and inhibition of the proapoptotic Bcl-2 implicated in cancer cell behaviors (31), was indicated to be a family proteins (16). Recently in melanoma, Tyro3 was shown novel ligand for MerTK (4). Axl expression has also been corre- to regulate the expression of microphthalmia-associated tran- lated with markers of DNA repair in different solid cancers; Axl scription factor, a master regulator of melanocyte development, inhibition induced reversal of EMT and decreased expression of and to promote tumorigenesis in spite of B-Raf–induced senes- DNA repair genes, rendering cancer cells sensitive to PARP inhi- cence (17). Tyro3 was also shown to promote cell proliferation bition in a synergistic manner (32). and chemoresistance in breast cancer (18). In addition, down- regulation of both Axl and Tyro3 was able to reverse taxol TAM Inhibition to Treat Tumor Drug resistance in ovarian cancer (19). Increased Axl expression has also been associated with acquired Resistance resistance to selective EGFR small-molecule inhibition. In lung In addition to their roles in primary tumorigenesis, the prev- cancers, this includes resistance to erlotinib through the induction alence of TAM receptors in patients displaying acquired drug- of an EMT-like state (20), as well as to gefitinib (21). In triple- resistant tumors renders the TAMs a viable target for therapies negative breast cancer cells, expression of Axl was identified as a against such evolved tumors. Importantly, TAM signaling inhibi- predictor for lack of response to lapatinib and erlotinib (22). tion sensitizes cells to chemotherapy, indicating that its effects are Targeting EGFR antibodies such as cetuximab has also led to multifaceted, and the aim of "shutting down" multiple key resistance in NSCLC and head and neck carcinomas through Axl biological processes in cancer cells can be achieved through a overexpression, via MAPK signaling (23). Such an association single target. A plethora of new, more specific, and higher affinity between EGFR and Axl molecular pathways also manifests itself targeting agents are currently under development (Table 1) that through hetero-interaction between EGFR and Axl molecules, may prove to be effective for preventing, delaying, or combating which can diversify downstream signaling pathways beyond tumor drug resistance. those triggered by EGFR alone (24). A recent example is from a study that showed Axl to be The prominent expression and functions of TAM receptors upregulated in CML patients that had developed resistance to across the immune system also suggests a potential role in BCR-Abl small-molecule inhibition, including through a T315I mediating resistance to immune checkpoint inhibitors in can- mutation in BCR-Abl. The selective Axl small-molecule inhibitor cer therapy. TAM receptors are notably expressed in many BGB324 inhibited the resistant CML cells independent of BCR- myeloid immune cells, including macrophages and dendritic Abl mutational status (33). This example indicates an efficacious cells (DC), and they may cooperate to create an immunosup- employment of Axl inhibition at the earliest signs of resistance pressive tumor microenvironment permissive to tumorigenesis development to first-line or targeted therapies. (25). MerTK is implicated in the suppression of the M1 mac- rophage proinflammatory cytokine response, and Axl is required for the termination of Toll-like receptor–dependent inflammatory response in DCs (25). Also, the TAMs have been Table 1. TAM-selective inhibitors currently in development shown to negatively regulate natural killer (NK) cell functional Name Target(s) Development stage maturation and normal expression of inhibitory
Load more

Recommended publications
  • LY2801653 Is an Orally Bioavailable Multi-Kinase Inhibitor with Potent
    Invest New Drugs (2013) 31:833–844 DOI 10.1007/s10637-012-9912-9 PRECLINICAL STUDIES LY2801653 is an orally bioavailable multi-kinase inhibitor with potent activity against MET, MST1R, and other oncoproteins, and displays anti-tumor activities in mouse xenograft models S. Betty Yan & Victoria L. Peek & Rose Ajamie & Sean G. Buchanan & Jeremy R. Graff & Steven A. Heidler & Yu-Hua Hui & Karen L. Huss & Bruce W. Konicek & Jason R. Manro & Chuan Shih & Julie A. Stewart & Trent R. Stewart & Stephanie L. Stout & Mark T. Uhlik & Suzane L. Um & Yong Wang & Wenjuan Wu & Lei Yan & Wei J. Yang & Boyu Zhong & Richard A. Walgren Received: 19 October 2012 /Accepted: 3 December 2012 /Published online: 29 December 2012 # The Author(s) 2012. This article is published with open access at Springerlink.com Summary The HGF/MET signaling pathway regulates a of a potent, orally bioavailable, small-molecule inhibitor wide variety of normal cellular functions that can be subverted LY2801653 targeting MET kinase. LY2801653 is a type-II to support neoplasia, including cell proliferation, survival, ATP competitive, slow-off inhibitor of MET tyrosine kinase apoptosis, scattering and motility, invasion, and angiogenesis. with a dissociation constant (Ki) of 2 nM, a pharmacodynamic −1 MET over-expression (with or without gene amplification), residence time (Koff) of 0.00132 min and t1/2 of 525 min. aberrant autocrine or paracrine ligand production, and mis- LY2801653 demonstrated in vitro effects on MET pathway- sense MET mutations are mechanisms that lead to activation dependent cell scattering and cell proliferation; in vivo anti- of the MET pathway in tumors and are associated with poor tumor effects in MET amplified (MKN45), MET autocrine prognostic outcome.
    [Show full text]
  • Crystal Structure of the Kinase Domain of Mertk in Complex with AZD7762 Provides Clues for Structure-Based Drug Development
    International Journal of Molecular Sciences Article Crystal Structure of the Kinase Domain of MerTK in Complex with AZD7762 Provides Clues for Structure-Based Drug Development Tae Hyun Park 1,2 , Seung-Hyun Bae 1,3 , Seoung Min Bong 1, Seong Eon Ryu 2, Hyonchol Jang 1,3 and Byung Il Lee 1,3,* 1 Research Institute, National Cancer Center, Goyang, 10408 Gyeonggi, Korea; [email protected] (T.H.P.); [email protected] (S.-H.B.); [email protected] (S.M.B.); [email protected] (H.J.) 2 Department of Bioengineering, Hanyang University, 04763 Seoul, Korea; [email protected] 3 Department of Cancer Biomedical Science, National Cancer Center Graduate School of Cancer Science and Policy, Goyang, 10408 Gyeonggi, Korea * Correspondence: [email protected]; Tel.: +82-31-920-2223; Fax: +82-31-920-2006 Received: 29 August 2020; Accepted: 21 October 2020; Published: 23 October 2020 Abstract: Aberrant tyrosine-protein kinase Mer (MerTK) expression triggers prosurvival signaling and contributes to cell survival, invasive motility, and chemoresistance in many kinds of cancers. In addition, recent reports suggested that MerTK could be a primary target for abnormal platelet aggregation. Consequently, MerTK inhibitors may promote cancer cell death, sensitize cells to chemotherapy, and act as new antiplatelet agents. We screened an inhouse chemical library to discover novel small-molecule MerTK inhibitors, and identified AZD7762, which is known as a checkpoint-kinase (Chk) inhibitor. The inhibition of MerTK by AZD7762 was validated using an in vitro homogeneous time-resolved fluorescence (HTRF) assay and through monitoring the decrease in phosphorylated MerTK in two lung cancer cell lines.
    [Show full text]
  • MERTK Antibody Catalog Number: MKT-101AP Lot Number: General Information
    FabGennix International, Inc. 9191 Kyser Way Bldg. 4 Suite 402 Frisco, TX 75033 Tel: (214)-387-8105, 1-800-786-1236 Fax: (214)-387-8105 Email: [email protected] Web: www.FabGennix.com Rabbit Polyclonal Anti-MERTK antibody Catalog Number: MKT-101AP Lot Number: General Information Product MERTK Antibody Description Affinity Purified Human cellular proto-oncogene (c- mer) mRNA Antibody C-epitope Accession # Uniprot: Q12866 GenBank: U08023.1 Verified Applications CM, ELISA, ICC, IF, IHC, IP, WB Species Cross Reactivity Human, Mouse, Rat Host Rabbit Immunogen Synthetic peptide taken within amino acid region 900-994 on MerTK protein. Alternative Nomenclature c mer proto oncogene tyrosine kinase antibody, cMER antibody, Eyk antibody, MER antibody, MER receptor tyrosine kinase antibody, MERK antibody, MERPEN antibody, Mertk antibody, MERTK c-mer proto-oncogene tyrosine kinase antibody, MGC133349 antibody, nmf12 antibody, Nyk antibody, Proto oncogene tyrosine protein kinase MER antibody, Receptor tyrosine kinase MerTK antibody, RP38 antibody, STK kinase antibody, Tyrosine-protein kinase Mer antibody Physical Properties Quantity 100 µg Volume 200 µl Form Affinity Purified Immunoglobulins Determinant C-epitope Immunoglobulin & Concentration 0.75 mg/ml IgG in antibody stabilization buffer Storage Store at -20⁰C for long term storage. Related Products Catalog # BIOTIN-Conjugated MKT100-BIOTIN FITC-Conjugated MKT100-FITC Antigenic Blocking Peptide P-MKT100 Western Blot Positive Control PC-MKT Tel: (214)-387-8105, 1-800-786-1236 Fax: (214)-387-8105 Email: [email protected] Web: www.FabGennix.com Recommended Dilutions DOT Blot 1:10,000 ELISA 1:10,000 Immunocytochemistry 1:200 Immunofluorescence 1:200 Immunohistochemistry 1:200 Immunoprecipitation 1:200 Western Blot 1:750 Application Verification: WB using MKT-101AP and human RPE cells.
    [Show full text]
  • Diverse, Biologically Relevant, and Targetable Gene Rearrangements in Triple-Negative Breast Cancer and Other Malignancies Timothy M
    Published OnlineFirst May 26, 2016; DOI: 10.1158/0008-5472.CAN-16-0058 Cancer Therapeutics, Targets, and Chemical Biology Research Diverse, Biologically Relevant, and Targetable Gene Rearrangements in Triple-Negative Breast Cancer and Other Malignancies Timothy M. Shaver1,2, Brian D. Lehmann1,2, J. Scott Beeler1,2, Chung-I Li3, Zhu Li1,2, Hailing Jin1,2, Thomas P. Stricker4, Yu Shyr5,6, and Jennifer A. Pietenpol1,2 Abstract Triple-negative breast cancer (TNBC) and other molecularly discovered a clinical occurrence and cell line model of the target- heterogeneous malignancies present a significant clinical chal- able FGFR3–TACC3 fusion in TNBC. Expanding our analysis to lenge due to a lack of high-frequency "driver" alterations amena- other malignancies, we identified a diverse array of novel and ble to therapeutic intervention. These cancers often exhibit geno- known hybrid transcripts, including rearrangements between mic instability, resulting in chromosomal rearrangements that noncoding regions and clinically relevant genes such as ALK, affect the structure and expression of protein-coding genes. How- CSF1R, and CD274/PD-L1. The over 1,000 genetic alterations ever, identification of these rearrangements remains technically we identified highlight the importance of considering noncod- challenging. Using a newly developed approach that quantita- ing gene rearrangement partners, and the targetable gene tively predicts gene rearrangements in tumor-derived genetic fusions identified in TNBC demonstrate the need to advance material, we identified
    [Show full text]
  • Mertk Regulates Thymic Selection of Autoreactive T Cells
    MerTK regulates thymic selection of autoreactive T cells Mark A. Walleta, Rafael R. Floresa, Yaming Wanga, Zuoan Yia, Charles J. Krogera, Clayton E. Mathewsb, H. Shelton Earpc,d, Glenn Matsushimaa,c,e, Bo Wanga, and Roland Tischa,c,1 aDepartment of Microbiology and Immunology, cUNC Lineberger Comprehensive Cancer Center, dDepartment of Medicine and Pharmacology, eUNC Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599-7020; and bDepartment of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL 32610 Communicated by Hugh O. McDevitt, Stanford University, Stanford, CA, January 23, 2009 (received for review September 30, 2008) T cell-mediated autoimmune diseases such as type 1 diabetes (T1D) Our group and others demonstrated that the Mer tyrosine are believed to be the result in part of inefficient negative selection kinase (MerTK) negatively regulates antigen presenting cells of self-specific thymocytes. However, the events regulating thymic (APC) such as DC and macrophages (M␾) (18–21). MerTK negative selection are not fully understood. In the current study, belongs to a family of receptor tyrosine kinases (RTKs) con- we demonstrate that nonobese diabetic (NOD) mice lacking ex- sisting of Axl and Tyro3 (22, 23). Mice lacking expression of all pression of the Mer tyrosine kinase (MerTK) have reduced inflam- 3 RTKs have hyperactive APC in the periphery, resulting in mation of the pancreatic islets and fail to develop diabetes. systemic autoimmunity characterized by T cell infiltrates in Furthermore, NOD mice deficient in MerTK expression (Mer؊/؊) several tissues (24). In addition to DC and M␾, MerTK is exhibit a reduced frequency of ␤ cell-specific T cells independent of expressed by NK T cells, NK cells, epithelia and endothelia cell immunoregulatory effectors.
    [Show full text]
  • Mertk Inhibition Is a Novel Therapeutic Approach for Glioblastoma Multiforme
    www.impactjournals.com/oncotarget/ Oncotarget, Vol. 5, No. 5 MerTK inhibition is a novel therapeutic approach for glioblastoma multiforme Kristina H. Knubel1, Ben M. Pernu1, Alexandra Sufit1, Sarah Nelson1, Angela M. Pierce1, Amy K. Keating1 1 Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA Correspondence to: Amy K Keating, email: [email protected] Keywords: MerTK, Axl, glioma, Foretinib, intracranial model Received: January 16, 2014 Accepted: March 10, 2014 Published: March 12, 2014 This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT: Glioblastoma is an aggressive tumor that occurs in both adult and pediatric patients and is known for its invasive quality and high rate of recurrence. Current therapies for glioblastoma result in high morbidity and dismal outcomes. The TAM subfamily of receptor tyrosine kinases includes Tyro3, Axl, and MerTK. Axl and MerTK exhibit little to no expression in normal brain but are highly expressed in glioblastoma and contribute to the critical malignant phenotypes of survival, chemosensitivity and migration. We have found that Foretinib, a RTK inhibitor currently in clinical trial, inhibited phosphorylation of TAM receptors, with highest efficacy against MerTK, and blocked downstream activation of Akt and Erk in adult and pediatric glioblastoma cell lines, findings that are previously unreported. Survival, proliferation, migration, and collagen invasion were hindered in vitro. Foretinib treatment in vivo abolished MerTK phosphorylation and reduced tumor growth 3-4 fold in a subcutaneous mouse model.
    [Show full text]
  • A High-Throughput Integrated Microfluidics Method Enables
    ARTICLE https://doi.org/10.1038/s42003-019-0286-9 OPEN A high-throughput integrated microfluidics method enables tyrosine autophosphorylation discovery Hadas Nevenzal1, Meirav Noach-Hirsh1, Or Skornik-Bustan1, Lev Brio1, Efrat Barbiro-Michaely1, Yair Glick1, Dorit Avrahami1, Roxane Lahmi1, Amit Tzur1 & Doron Gerber1 1234567890():,; Autophosphorylation of receptor and non-receptor tyrosine kinases is a common molecular switch with broad implications for pathogeneses and therapy of cancer and other human diseases. Technologies for large-scale discovery and analysis of autophosphorylation are limited by the inherent difficulty to distinguish between phosphorylation and autopho- sphorylation in vivo and by the complexity associated with functional assays of receptors kinases in vitro. Here, we report a method for the direct detection and analysis of tyrosine autophosphorylation using integrated microfluidics and freshly synthesized protein arrays. We demonstrate the efficacy of our platform in detecting autophosphorylation activity of soluble and transmembrane tyrosine kinases, and the dependency of in vitro autopho- sphorylation assays on membranes. Our method, Integrated Microfluidics for Autopho- sphorylation Discovery (IMAD), is high-throughput, requires low reaction volumes and can be applied in basic and translational research settings. To our knowledge, it is the first demonstration of posttranslational modification analysis of membrane protein arrays. 1 The Mina and Everard Goodman Faculty of Life Sciences and the Institute of Nanotechnology and Advanced Materials, Bar-Ilan University, Building #206, Ramat-Gan 5290002, Israel. These authors contributed equally: Hadas Nevenzal, Meirav Noach-Hirsh. These authors jointly supervised this work: Amit Tzur, Doron Gerber. Correspondence and requests for materials should be addressed to A.T. (email: [email protected]) or to D.G.
    [Show full text]
  • The Receptor Tyrosine Kinase Mertk Activates Phospholipase C γ
    The receptor tyrosine kinase MerTK activates phospholipase C ␥2 during recognition of apoptotic thymocytes by murine macrophages Jill C. Todt,* Bin Hu,* and Jeffrey L. Curtis*,†,‡,§,1 *Division of Pulmonary & Critical Care Medicine, Department of Internal Medicine, †Comprehensive Cancer Center, and ‡Graduate Program in Immunology, University of Michigan Health Care System, Ann Arbor; and §Pulmonary & Critical Care Medicine Section, Medical Service, Department of Veterans Affairs Health Care System, Ann Arbor, Michigan Abstract: Apoptotic leukocytes must be cleared autoimmunity as a result of inappropriate presentation of self- efficiently by macrophages (Mø). Apoptotic cell antigens [2–4]. Ingestion of apoptotic cells by macrophages phagocytosis by Mø requires the receptor tyrosine (Mø) reduces inflammatory cytokine production by secretion of ␤ kinase (RTK) MerTK (also known as c-Mer and transforming growth factor- and prostaglandin E2 [5, 6], Tyro12), the phosphatidylserine receptor (PS-R), which hastens resolution of inflammation [1] but which may and the classical protein kinase C (PKC) isoform also impair host defenses [7, 8]. Understanding signaling path- ␤II, which translocates to Mø membrane and cy- ways in apoptotic cell clearance could improve therapies of toskeletal fractions in a PS-R-dependent manner. diseases that combine cell death and immunocompromise, How these molecules cooperate to induce phago- such as acute lung injury, in which secondary infection is a cytosis is unknown. As the phosphatidylinositol- major cause of mortality [9]. specific phospholipase (PI–PLC) ␥2 is downstream Specific recognition of apoptotic cells by Mø is initiated by of RTKs in some cell types and can activate classi- at least two pathways. First, using a 70-kDa glycosylated type cal PKCs, we hypothesized that MerTK signals via II transmembrane protein, the phosphatidylserine receptor PLC ␥2.
    [Show full text]
  • Pathogenicity Control That Serve As Mda5 Ligands, in Addition to Editing Other RNA Targets
    RESEARCH HIGHLIGHTS A gut vascular barrier Insulin resistance: old or obese? While macrophage-dependent inflammation is the driver of obesity- The blood-brain barrier is the best-characterized vascular ‘firewall’ associated insulin resistance, the mechanisms of age-associated insulin in the body. In Science, Rescigno and colleagues identify a resistance remain unclear. In Nature, Zheng and colleagues show that vascular barrier in the gut that is analogous to that in the brain fat resident T cells modulate age-associated insulin resistance in mice. and is present in both mice and humans. They identify a distinct reg gut vascular barrier (GVB) composed of closely interacting Although the macrophage subsets remain unchanged, the Treg cell popula- endothelial cells, glial cells and pericytes. This GVB prevents the tion expands substantially with age in the visceral adipose tissue (VAT). translocation of large molecules from the gut lumen. However, oral Selective depletion of Treg cells in the fat of aged mice leads to improved infection of mice with Salmonella typhimurium disrupts the GVB insulin sensitivity, remodeling of VAT, less hepatic steatosis, lower body and allows the translocation of much larger molecules, as well mass, greater oxygen consumption and higher core body temperature, as dissemination of the bacterium itself. The ability of without systemic inflammation. VAT Treg cells have higher expression of S. typhimurium to cross the GVB depends on its ability to impair Pparg, Gata3, Irf4, Ctla4, Il2ra and Il10 and of the IL-33 receptor ST2 than Wnt signaling in the endothelium. Therefore, in addition to the that of splenic Treg cells and maintain considerable suppressive ability in epithelium, the GVB presents a second, independent barrier that aged mice.
    [Show full text]
  • Mertk: a Novel Target in Non-Small Cell Lung Cancer
    MERTK: A NOVEL TARGET IN NON-SMALL CELL LUNG CANCER by CHRISTOPHER T. CUMMINGS B.S., University of Nebraska, Lincoln, 2009 A thesis submitted to the Faculty of the Graduate School of the University of Colorado in partial fulfillment of the requirements for the degree of Doctor of Philosophy Cancer Biology Program 2015 ii This thesis for the Doctor of Philosophy degree by Christopher T. Cummings has been approved for the Cancer Biology Program by Lynn E. Heasley, Chair Christopher D. Baker Mark L. Dell’Acqua Arthur Gutierrez-Hartmann Christopher C. Porter Mary E. Reyland Douglas K. Graham, Advisor Date: 04/30/2015 iii Cummings, Christopher T. (Ph.D., Cancer Biology) MERTK: A Novel Target in Non-Small Cell Lung Cancer Thesis directed by Professor Douglas K. Graham ABSTRACT The American Cancer Society projects 221,200 new diagnoses and 158,040 deaths to occur in 2015 as a result of lung cancer. With a five-year relative survival rate that has only marginally improved from the 1970’s (12%) to today (18%), new treatments are desperately needed for these large numbers of patients. Molecularly targeted therapies have begun to answer this call, with therapeutics against EGFR, ALK, and ROS1 now improving outcomes for patients with these specific genetic aberrations. However, the molecular events underlying lung cancer are complex, and many more therapeutic targets remain unidentified or untargeted. MERTK, a receptor tyrosine kinase of the TAM (TYRO3, AXL, and MERTK) family, is over-expressed or ectopically expressed in a wide variety of cancers, resulting in activation of several canonical oncogenic signaling pathways.
    [Show full text]
  • Enhanced Expression of Receptor Tyrosine Kinase Mer (MERTK) on SOCS3-Treated Polarized RAW 264.7 Anti-Inflammatory M2c Macrophages
    Wright State University CORE Scholar Browse all Theses and Dissertations Theses and Dissertations 2019 Enhanced expression of receptor tyrosine kinase Mer (MERTK) on SOCS3-treated polarized RAW 264.7 anti-inflammatory M2c macrophages Sankhadip Bhadra Wright State University Follow this and additional works at: https://corescholar.libraries.wright.edu/etd_all Part of the Immunology and Infectious Disease Commons, and the Microbiology Commons Repository Citation Bhadra, Sankhadip, "Enhanced expression of receptor tyrosine kinase Mer (MERTK) on SOCS3-treated polarized RAW 264.7 anti-inflammatory M2c macrophages" (2019). Browse all Theses and Dissertations. 2105. https://corescholar.libraries.wright.edu/etd_all/2105 This Thesis is brought to you for free and open access by the Theses and Dissertations at CORE Scholar. It has been accepted for inclusion in Browse all Theses and Dissertations by an authorized administrator of CORE Scholar. For more information, please contact [email protected]. Enhanced expression of receptor tyrosine kinase Mer (MERTK) on SOCS3-treated polarized RAW 264.7 anti-inflammatory M2c macrophages A thesis submitted in partial fulfillment of the requirements for the degree of Master of Science By SANKHADIP BHADRA M.Sc., Microbiology, GITAM University, INDIA, 2015 B.Sc., Microbiology, University of Calcutta, INDIA, 2013 2019 Wright State University WRIGHT STATE UNIVERSITY GRADUATE SCHOOL July 31, 2019 I HEREBY RECOMMEND THAT THE THESIS PREPARED UNDER MY SUPERVISION BY Sankhadip Bhadra ENTITLED Enhanced expression of receptor tyrosine kinase Mer (MERTK) on SOCS3-treated polarized RAW 264.7 anti-inflammatory M2c macrophages BE ACCEPTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF Master of Science. ----------------------------- Nancy J.
    [Show full text]
  • Kinome Expression Profiling to Target New Therapeutic Avenues in Multiple Myeloma
    Plasma Cell DIsorders SUPPLEMENTARY APPENDIX Kinome expression profiling to target new therapeutic avenues in multiple myeloma Hugues de Boussac, 1 Angélique Bruyer, 1 Michel Jourdan, 1 Anke Maes, 2 Nicolas Robert, 3 Claire Gourzones, 1 Laure Vincent, 4 Anja Seckinger, 5,6 Guillaume Cartron, 4,7,8 Dirk Hose, 5,6 Elke De Bruyne, 2 Alboukadel Kassambara, 1 Philippe Pasero 1 and Jérôme Moreaux 1,3,8 1IGH, CNRS, Université de Montpellier, Montpellier, France; 2Department of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, Brussels, Belgium; 3CHU Montpellier, Laboratory for Monitoring Innovative Therapies, Department of Biologi - cal Hematology, Montpellier, France; 4CHU Montpellier, Department of Clinical Hematology, Montpellier, France; 5Medizinische Klinik und Poliklinik V, Universitätsklinikum Heidelberg, Heidelberg, Germany; 6Nationales Centrum für Tumorerkrankungen, Heidelberg , Ger - many; 7Université de Montpellier, UMR CNRS 5235, Montpellier, France and 8 Université de Montpellier, UFR de Médecine, Montpel - lier, France ©2020 Ferrata Storti Foundation. This is an open-access paper. doi:10.3324/haematol. 2018.208306 Received: October 5, 2018. Accepted: July 5, 2019. Pre-published: July 9, 2019. Correspondence: JEROME MOREAUX - [email protected] Supplementary experiment procedures Kinome Index A list of 661 genes of kinases or kinases related have been extracted from literature9, and challenged in the HM cohort for OS prognostic values The prognostic value of each of the genes was computed using maximally selected rank test from R package MaxStat. After Benjamini Hochberg multiple testing correction a list of 104 significant prognostic genes has been extracted. This second list has then been challenged for similar prognosis value in the UAMS-TT2 validation cohort.
    [Show full text]