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    Leslie M Shaw PhD

    TitleAssociate Professor
    InstitutionUniversity of Massachusetts Medical School
    DepartmentMolecular, Cell and Cancer Biology
    AddressUniversity of Massachusetts Medical School
    364 Plantation Street, LRB
    Worcester MA 01605
    Phone508-856-8675
      Other Positions
      InstitutionUMMS - Programs, Centers and Institutes
      DepartmentCancer Center

        Overview 
        Narrative

        BREAST CANCER METASTASIS     

        The overall research interest of the Shaw lab is breast cancer progression and metastasis.  We utilize both in vitro and in vivo approaches to investigate the mechanisms by which breast carcinoma cells acquire the ability to metastasize to secondary organs and how they survive and grow in these foreign microenvironments.  We are interested in identifying molecules or signaling pathways that play an essential role in the acquisition of a metastatic phenotype and to understand their mechanism of action.  From a translational perspective, the goal of our work is to develop novel targets to predict or to treat metastatic breast cancer.   

        Insulin Receptor Substrate Proteins

        A major focus of the research in the lab for the past several years has been the Insulin Receptor Substrate (IRS) proteins, which are major downstream signaling intermediates of the insulin and insulin-like growth factor-1 (IGF-1) receptors.  We have established that IRS-1 and IRS-2 play divergent roles in murine mammary tumor progression and are not functionally redundant.  Specifically, we demonstrated 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-2 expression and activation.  These studies were performed using both transgenic and orthotopic models of mammary tumor progression.  Although functional differences between IRS-1 and IRS-2 have been identified, the mechanism(s) by which these highly homologous proteins regulate distinct cellular outcomes incancer in response to common stimuli remains unknown and is the focus of our ongoing studies.  Specifically, we are interested in understanding how IRS-2 contributes to the adaptation of tumor cells to their metabolic microenvironment to promote tumor progression, the role of feedback regulation in controlling the balance of IRS expression and activity and the importance of intracellular IRS localization for tumor cell function.  With regard to the latter topic, we made the novel observation that IRS-1 and IRS-2 have unique intracellular localization patterns in human breast tumors. Specifically, IRS-1 is expressed predominantly in the nucleus and IRS-2 is localized either in the cytoplasm or at the cell membrane.   Analysis of our dataset for associations of IRS-2 staining patterns with core clinical parameters and clinical outcomes revealed a significant trend toward decreased overall survival (OS) with IRS-2 membrane staining. We are interested in determining the functional significance of IRS-2 localization at the membrane and how this localization is regulated. We  hypothesize that the trafficking of IRS-1 and IRS-2 to distinct intracellular compartments determines their access to downstream effectors and substrates, and as a consequence, divergent cellular responses are elicited.   From a translational perspective, signaling pathways 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 in breast cancer.  Beclin 1 is the mammalian homolog of the yeast Atg6 gene, which plays an essential role in vesicle nucleation during the initiation of autophagy.  Beclin 1 is of interest for breast cancer because 70% of human breast tumors exhibit decreased expression of Beclin 1 when compared with normal mammary epithelial tissue.  This decreased expression arises both from the monoallelic loss of the Beclin 1 gene in ~50% of breast tumors and aberrant DNA methylation that suppresses gene expression.  Most studies that have investigated Beclin 1 function in cancer have focused on its role in regulating autophagy, a normal cellular process by which cells target cytoplasmic components, including proteins, lipids and organelles, to the lysosome for degradation.   Alternative functions of Beclin 1 that could contribute to its role in cancer have received relatively little attention.  This is significant because Beclin 1 is an essential component of the core complex that regulates endocytic trafficking, which controls the spatial and temporal dynamics of growth factor receptor signaling. In this regard, our studies have revealed that loss of Beclin 1 enhances and sustains IGF-1R and EGFR activation and downstream signaling in breast carcinoma cells and that these changes in signaling are associated with increased growth and invasion. We are currently studying how Beclin 1 regulates trafficking of the IGF-1R and how this regulation influences downstream signaling through the IRS 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.




        Rotation projects in the lab include: 1) Investigating how IRS-1 and IRS-2 regulate distinct downstream signaling pathways; 2) Investigating how stimuli in the tumor microenvironment and oncogenic signals influence feedback regulation of IRS function; 3) Investigating how IRS intracellular localization is regulated and the importance for breast carcinoma cell function; 4) Investigating how the IRS proteins influence IGF-1R trafficking; 5) Investigating the role of Beclin 1 in the regulation IGF-1R endocytic trafficking and downstream Akt activation; 6) Investigating the mechanism by which Beclin 1 regulates tumor cell invasion.  Basic cell biology, biochemistry and molecular biology techniques will be used.  In addition, we have both transgenic and orthotopic mouse models of breast cancer established in the lab for studying metastasis.

         



        Bibliographic 
        selected publications
        List All   |   Timeline
        1. Browne G, Taipaleenmäki H, Bishop NM, Madasu SC, Shaw LM, van Wijnen AJ, Stein JL, Stein GS, Lian JB. Runx1 is associated with breast cancer progression in MMTV-PyMT transgenic mice and its depletion in vitro inhibits migration and invasion. J Cell Physiol. 2015 Oct; 230(10):2522-32.
          View in: PubMed
        2. Rohatgi RA, Janusis J, Leonard D, Bellvé KD, Fogarty KE, Baehrecke EH, Corvera S, Shaw LM. Beclin 1 regulates growth factor receptor signaling in breast cancer. Oncogene. 2015 Oct 16; 34(42):5352-62.
          View in: PubMed
        3. 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
        4. Landis J, Shaw LM. Insulin receptor substrate 2-mediated phosphatidylinositol 3-kinase signaling selectively inhibits glycogen synthase kinase 3ß to regulate aerobic glycolysis. J Biol Chem. 2014 Jun 27; 289(26):18603-13.
          View in: PubMed
        5. 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
        6. 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
        7. 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
        8. 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
        9. 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
        10. 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
        11. 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
        12. Shaw LM. IRS-1 and microRNAs: partners in growth regulation. Cell Cycle. 2009 Aug 15; 8(16):2485-6.
          View in: PubMed
        13. 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
        14. 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
        15. 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
        16. 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
        17. 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
        18. 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
        19. Shaw LM. Tumor cell invasion assays. Methods Mol Biol. 2005; 294:97-105.
          View in: PubMed
        20. 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
        21. 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
        22. 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
        23. 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
        24. 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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