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    Leslie M Shaw PhD

    TitleAssociate Professor
    InstitutionUniversity of Massachusetts Medical School
    DepartmentCancer Biology
    AddressUniversity of Massachusetts Medical School
    364 Plantation Street, LRB
    Worcester MA 01605
    Phone508-856-8675
      Other Positions
      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentCancer Biology

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentInterdisciplinary Graduate Program

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentMD/PhD Program

      InstitutionUMMS - Programs, Centers and Institutes
      DepartmentCancer Center

        Overview 
        Narrative

        Leslie Shaw, Ph.D.

        BREAST CANCER METASTASIS     

         

        Theoverall research interest of the Shaw lab is breast cancer progression andmetastasis.  We utilize both in vitro and in vivo approaches to investigate the mechanisms by which breast carcinoma cellsacquire the ability to metastasize to secondary organs and howthey survive and grow in these foreign microenvironments.  We are interested in identifying molecules or signaling pathwaysthat play an essential role in the acquisition of a metastatic phenotype and tounderstand their mechanism of action.  Froma translational perspective, the goal of our work is to develop novel targetsto predict or to treat metastatic breast cancer.   

         

        Insulin Receptor Substrate Proteins

        A majorfocus of the research in the lab for the past several years has been theInsulin Receptor Substrate (IRS) proteins, which are major downstream signalingintermediates of the insulin and insulin-like growth factor-1 (IGF-1)receptors.  We have established that IRS-1 andIRS-2 play divergent roles in murine mammary tumor progression and are notfunctionally redundant.  Specifically, wedemonstrated that metastasis is significantly impaired in the absence of IRS-2,but it is enhanced in tumor cells that lack IRS-1, but have increased IRS-2expression and activation.  These studieswere performed using both transgenic and orthotopic models of mammary tumorprogression.  Although functionaldifferences between IRS-1 and IRS-2 have been identified, the mechanism(s) bywhich these highly homologous proteins regulate distinct cellular outcomes incancer in response to common stimuli remains unknown and is the focus of ourongoing studies.  Specifically, we areinterested in understanding how IRS-2 contributes to the adaptation of tumorcells to their metabolic microenvironment to promote tumor progression, therole of feedback regulation in controlling the balance of IRS expression and activityand the importance ofintracellular IRS localization for tumor cell function.  With regard to the latter topic, wemade the novel observation that IRS-1 and IRS-2 have unique intracellularlocalization patterns in human breast tumors. Specifically, IRS-1 is expressed predominantly in the nucleus and IRS-2is localized either in the cytoplasm or at the cell membrane.   Analysis of our dataset for associations ofIRS-2 staining patterns with core clinical parameters and clinical outcomesrevealed a significant trend toward decreased overall survival (OS) with IRS-2membrane staining. We are interested in determining the functional significanceof IRS-2 localization at the membrane and how this localization is regulated. We  hypothesize that the trafficking of IRS-1 andIRS-2 to distinct intracellular compartments determines their access todownstream effectors and substrates, and as a consequence, divergent cellularresponses are elicited.   From a translational perspective, signalingpathways that are activated through IRS-2 or regulate IRS expression and/orlocalization could be exploited for therapeutic intervention of metastasis.

         

        Beclin 1

        We are interested in autophagy-independent functions of Beclin 1 inbreast cancer.  Beclin 1 is the mammalianhomolog of the yeast Atg6 gene, which plays an essential role in vesiclenucleation during the initiation of autophagy.  Beclin 1 is of interest for breast cancerbecause 70% of human breast tumors exhibit decreased expression of Beclin 1when compared with normal mammary epithelial tissue.  This decreased expression arises both fromthe monoallelic loss of the Beclin 1 gene in ~50% of breast tumors and aberrantDNA methylation that suppresses gene expression.  Moststudies that have investigated Beclin 1 function in cancer have focused on itsrole in regulating autophagy, a normal cellular process by which cells targetcytoplasmic components, including proteins, lipids and organelles, to the lysosome for degradation.   Alternative functions of Beclin 1 that couldcontribute to its role in cancer have received relatively little attention.  This is significant because Beclin 1 is anessential component of the core complex that regulates endocytic trafficking,which controls the spatial and temporal dynamics of growth factor receptorsignaling. In this regard, our studies have revealed that loss of Beclin 1 enhances and sustains IGF-1R activation and downstreamsignaling to AKT in breast carcinoma cells and that these changes in signalingare associated with increased growth and invasion. We are currently studying how Beclin 1 regulates trafficking ofthe IGF-1R and how this regulation influences downstream signaling through theIRS proteins to impact tumor cell function.

         




        Rotation Projects

        Rotation projects in the lab include: 1) Investigating howIRS-1 and IRS-2 regulate distinct downstream signaling pathways; 2)Investigating how stimuli in the tumor microenvironment and oncogenic signalsinfluence feedback regulation of IRS function; 3) Investigating how IRSintracellular localization is regulated and the importance for breast carcinomacell function; 4) Investigating how the IRS proteins influence IGF-1Rtrafficking; 5) Investigating the role of Beclin 1 in the regulation IGF-1R endocytictrafficking and downstream Akt activation; 6) Investigating the mechanism bywhich Beclin 1 regulates tumor cell invasion.  Basic cell biology, biochemistry and molecularbiology techniques will be used.  Inaddition, we have both transgenic and orthotopic mouse models of breast cancerestablished in the lab for studying metastasis.




        Post Docs
        ? ? ?A postdoctoralposition is available in the Shaw lab.  Candidatesmust have a PhD or MD/PhD degree in the biological sciences and be well versedin basic cell and molecular biology. Experience with mouse cancer models,preferably mammary tumor models, is a prerequisite. Interested individualsshould send their CV, a summary of research experience and the names of threereferences to Leslie.Shaw@umassmed.edu.  The University of Massachusetts MedicalSchool is an affirmative action, equal opportunity employer.




        Bibliographic 
        selected publications
        List All   |   Timeline
        1. Rahman M, Nirala NK, Singh A, Zhu LJ, Taguchi K, Bamba T, Fukusaki E, Shaw LM, Lambright DG, Acharya JK, Acharya UR. Drosophila Sirt2/mammalian SIRT3 deacetylates ATP synthase ß and regulates complex V activity. J Cell Biol. 2014 Jul 21; 206(2):289-305.
          View in: PubMed
        2. Goel HL, Gritsko T, Pursell B, Chang C, Shultz LD, Greiner DL, Norum JH, Toftgard R, Shaw LM, Mercurio AM. Regulated Splicing of the a6 Integrin Cytoplasmic Domain Determines the Fate of Breast Cancer Stem Cells. Cell Rep. 2014 May 8; 7(3):747-61.
          View in: PubMed
        3. Swaminathan S, Risacher SL, Yoder KK, West JD, Shen L, Kim S, Inlow M, Foroud T, Jagust WJ, Koeppe RA, Mathis CA, Shaw LM, Trojanowski JQ, Soares H, Aisen PS, Petersen RC, Weiner MW, Saykin AJ. Association of plasma and cortical amyloid beta is modulated by APOE e4 status. Alzheimers Dement. 2014 Jan; 10(1):e9-e18.
          View in: PubMed
        4. Goel HL, Pursell B, Chang C, Shaw LM, Mao J, Simin K, Kumar P, Vander Kooi CW, Shultz LD, Greiner DL, Norum JH, Toftgard R, Kuperwasser C, Mercurio AM. GLI1 regulates a novel neuropilin-2/a6ß1 integrin based autocrine pathway that contributes to breast cancer initiation. EMBO Mol Med. 2013 Apr; 5(4):488-508.
          View in: PubMed
        5. Shaw LM. The insulin receptor substrate (IRS) proteins: at the intersection of metabolism and cancer. Cell Cycle. 2011 Jun 1; 10(11):1750-6.
          View in: PubMed
        6. Clark JL, Dresser K, Hsieh CC, Sabel M, Kleer CG, Khan A, Shaw LM. Membrane localization of insulin receptor substrate-2 (IRS-2) is associated with decreased overall survival in breast cancer. Breast Cancer Res Treat. 2011 Dec; 130(3):759-72.
          View in: PubMed
        7. Yang X, Dutta U, Shaw LM. SHP2 mediates the localized activation of Fyn downstream of the a6ß4 integrin to promote carcinoma invasion. Mol Cell Biol. 2010 Nov; 30(22):5306-17.
          View in: PubMed
        8. Mardilovich K, Shaw LM. Hypoxia regulates insulin receptor substrate-2 expression to promote breast carcinoma cell survival and invasion. Cancer Res. 2009 Dec 1; 69(23):8894-901.
          View in: PubMed
        9. Kim TH, Kim HI, Soung YH, Shaw LA, Chung J. Integrin (alpha6beta4) signals through Src to increase expression of S100A4, a metastasis-promoting factor: implications for cancer cell invasion. Mol Cancer Res. 2009 Oct; 7(10):1605-12.
          View in: PubMed
        10. Shaw LM. IRS-1 and microRNAs: partners in growth regulation. Cell Cycle. 2009 Aug 15; 8(16):2485-6.
          View in: PubMed
        11. Mardilovich K, Pankratz SL, Shaw LM. Expression and function of the insulin receptor substrate proteins in cancer. Cell Commun Signal. 2009; 7:14.
          View in: PubMed
        12. Pankratz SL, Tan EY, Fine Y, Mercurio AM, Shaw LM. Insulin receptor substrate-2 regulates aerobic glycolysis in mouse mammary tumor cells via glucose transporter 1. J Biol Chem. 2009 Jan 23; 284(4):2031-7.
          View in: PubMed
        13. Dutta U, Shaw LM. A key tyrosine (Y1494) in the beta4 integrin regulates multiple signaling pathways important for tumor development and progression. Cancer Res. 2008 Nov 1; 68(21):8779-87.
          View in: PubMed
        14. Merdek KD, Yang X, Taglienti CA, Shaw LM, Mercurio AM. Intrinsic signaling functions of the beta4 integrin intracellular domain. J Biol Chem. 2007 Oct 12; 282(41):30322-30.
          View in: PubMed
        15. Gibson SL, Ma Z, Shaw LM. Divergent roles for IRS-1 and IRS-2 in breast cancer metastasis. Cell Cycle. 2007 Mar 15; 6(6):631-7.
          View in: PubMed
        16. Ma Z, Gibson SL, Byrne MA, Zhang J, White MF, Shaw LM. Suppression of insulin receptor substrate 1 (IRS-1) promotes mammary tumor metastasis. Mol Cell Biol. 2006 Dec; 26(24):9338-51.
          View in: PubMed
        17. Shaw LM. Tumor cell invasion assays. Methods Mol Biol. 2005; 294:97-105.
          View in: PubMed
        18. Nagle JA, Ma Z, Byrne MA, White MF, Shaw LM. Involvement of insulin receptor substrate 2 in mammary tumor metastasis. Mol Cell Biol. 2004 Nov; 24(22):9726-35.
          View in: PubMed
        19. Powelka AM, Sun J, Li J, Gao M, Shaw LM, Sonnenberg A, Hsu VW. Stimulation-dependent recycling of integrin beta1 regulated by ARF6 and Rab11. Traffic. 2004 Jan; 5(1):20-36.
          View in: PubMed
        20. Neid M, Datta K, Stephan S, Khanna I, Pal S, Shaw L, White M, Mukhopadhyay D. Role of insulin receptor substrates and protein kinase C-zeta in vascular permeability factor/vascular endothelial growth factor expression in pancreatic cancer cells. J Biol Chem. 2004 Feb 6; 279(6):3941-8.
          View in: PubMed
        21. Chung J, Bachelder RE, Lipscomb EA, Shaw LM, Mercurio AM. Integrin (alpha 6 beta 4) regulation of eIF-4E activity and VEGF translation: a survival mechanism for carcinoma cells. J Cell Biol. 2002 Jul 8; 158(1):165-74.
          View in: PubMed
        22. Jauliac S, López-Rodriguez C, Shaw LM, Brown LF, Rao A, Toker A. The role of NFAT transcription factors in integrin-mediated carcinoma invasion. Nat Cell Biol. 2002 Jul; 4(7):540-4.
          View in: PubMed
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