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    Francis Ka Ming Chan PhD

    TitleAssociate Professor
    InstitutionUniversity of Massachusetts Medical School
    DepartmentPathology
    AddressUniversity of Massachusetts Medical School
    55 Lake Avenue North
    Worcester MA 01655
    Phone508-856-1664
      Other Positions
      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentImmunology and Virology

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentInterdisciplinary Graduate Program

      InstitutionUMMS - Programs, Centers and Institutes
      DepartmentCenter for AIDS Research

        Overview 
        Narrative

        Academic Background

        Education:

        1991B.A.University of California, San Diego (Summa Cum Laude)
        1996Ph.D.University of California, Berkeley
        Dr. Francis Chan

        The Role of Programmed Cell Death in Immune Functions and Diseases

        Cell death plays an essential role in metazoan homeostasis. Members of the tumor necrosis factor (TNF) and TNF receptor (TNFR) family are crucial regulators of cell death. Our lab is interested in how cell death contributes to the induction of immune responses. One of the ways by which cell death can modulate immune responses is through the induction of programmed necrosis. Necrotic cell death is distinguished from apoptosis by extensive cell and organelle swelling, the early rupture of plasma membrane, and the lack of caspase activation. The release of endogenous cellular adjuvants can cause inflammation and stimulate immune responses. Our long-term goal is to understand the biochemical regulation of programmed necrosis and the role programmed necrosis plays in inflammation, virus infections, autoimmune diseases and cancers.

        Current projects:

        1. Molecular regulation of programmed necrosis

        Using RNA interference, we have recently identified several kinases including RIP1 and RIP3 that critically regulate programmed necrosis. We show that a pro-necrotic signaling complex containing RIP1 and RIP3 are critically required for the induction of programmed necrosis. We are currently investigating how the assembly of this RIP1-RIP3 complex is regulated. Moreover, we are interested in identifying the downstream substrates for the RIP1-RIP3 kinase complex, and the effector mechanism that causes necrotic cell injury.

        2. Programmed necrosis in anti-viral immunity

        One of the physiological situations in which necrosis plays an important role is during viral infections. Using vaccinia virus infections in mice as models, we have demonstrated a critical role for RIP3-dependent programmed necrosis in virus-induced inflammation and innate immune responses. We are currently examining whether programmed necrosis and the subsequent inflammation it causes may also impact the induction of adaptive immune responses. In addition, we are evaluating the role of programmed necrosis in other virus infections.

        3. How do viruses inhibit host cell death?

        Inhibition of host cell death is widely touted as an immune evasion strategy employed by viruses. In support of this hypothesis, many viruses encode inhibitors against the host cell death machinery. We have recently identified several classes of viral inhibitors that potently inhibits programmed necrosis. One of the challenges in the future will be to identify the molecular mechanisms by which viral inhibitors modulate the pro-necrotic signaling pathway.

        4. Regulation of TRAIL signaling in immune cells

        TRAIL (TNF-related apoptosis inducing ligand) is a TNF-like cytokine with potent cytotoxicity against many tumor cells, but are generally non-toxic to normal cells. Of the five identified TRAIL receptors, two are termed “decoys” due to their ability to negatively regulate the apoptotic function of other TRAIL receptors. We have found that signaling by TRAIL is in part regulated at the level of assembly of “pre-ligand complexes” between death receptors and the decoy receptors. Current and future efforts will focus on understanding how the assembly of different TRAIL receptor complexes regulates death and non-death signaling in immune cells and cancer cells.

        Figure 1

        Figure 1: Electron micrograph of a vaccinia virus infected cell undergoing programmed necrosis. Note that the dying cell exhibits extensive intracellular vacuolation and mitochondrial swelling.

        Figure 2

        Figure 2: Electron micrograph of a necrotic cell exhibiting extensive loss of plasma membrane integrity.

        Figure 3

        Figure 3: A cartoon representation of how necrotic cell injury can trigger inflammation and stimulation immune responses during virus infections.



        Rotation Projects

        Potential Rotation Projects

        1. Examining TRAIL-induced apoptosis in cancer and normal cells.
          We have found that primary CD8+ T-cellsare resistant towhile most of the cancer cells are sensitive to TRAIL-induced apoptosis. However, werecently found that certain stimulation to the cells can reverse the cellular sensitivity to TRAIL. In this rotation project, the student will examine the molecular signals that controlcellular sensitivity to TRAIL-induced apoptosis.Specifically, the students will examine the role of lipid rafts and protein kinase C in regulating TRAIL response. The student will learn standard biochemical and molecular biology techniques in this project. In addition, the student willbe exposed to concepts relating to receptor signal transduction, cell death and TNF receptor biology.

        2. Molecular regulation of programmed necrosis.
          TNF stimulation through TNF receptors activates a myriad of biological responses ranging from cell death to inflammation. Interestingly, apoptosisis a dominant cell death pathway over programmed necrosis. Thus, inhibition of caspases, which is an essential step during apoptosis,is crucial for the induction of programmed necrosis. In this rotation project, the student will examine the signals that control the induction of apoptosis versus programmed necrosis. Specifically, the student will examine the role of several TNF receptor signaling molecules such as caspase-8, RIP and TRAF2 in this process.The students will learn about cell death and TNF receptor biology in this project.

        3. TNF-induced programmed necrosis in viral infections.
          We have identified several viral proteins termed vFLIPs that are potent inhibitors of TNF-indcued apoptosis and programmed necrosis. This finding strongly suggests that apoptosis and programmed necrosis play central role in host defense against viral infections.Inthis rotation project, the student will examinetransgenic mice that express a potent cell death inhibitor for their immune response to viral infections.The student will learn different immunological techniques and concepts in this rotation project.


        Post Docs

        A postdoctoral position is available
        to study in this laboratory.
        Contact Dr. Chan for additional details.

        Bibliographic 
        selected publications
        List All   |   Timeline
        1. Polykratis A, Hermance N, Zelic M, Roderick J, Kim C, Van TM, Lee TH, Chan FK, Pasparakis M, Kelliher MA. Cutting Edge: RIPK1 Kinase Inactive Mice Are Viable and Protected from TNF-Induced Necroptosis In Vivo. J Immunol. 2014 Aug 15; 193(4):1539-43.
          View in: PubMed
        2. Weng D, Marty-Roix R, Ganesan S, Proulx MK, Vladimer GI, Kaiser WJ, Mocarski ES, Pouliot K, Chan FK, Kelliher MA, Harris PA, Bertin J, Gough PJ, Shayakhmetov DM, Goguen JD, Fitzgerald KA, Silverman N, Lien E. Caspase-8 and RIP kinases regulate bacteria-induced innate immune responses and cell death. Proc Natl Acad Sci U S A. 2014 May 20; 111(20):7391-6.
          View in: PubMed
        3. Zhang J, Chan FK. Cell biology. RIPK3 takes another deadly turn. Science. 2014 Mar 21; 343(6177):1322-3.
          View in: PubMed
        4. Moriwaki K, Chan FK. Necrosis-dependent and independent signaling of the RIP kinases in inflammation. Cytokine Growth Factor Rev. 2014 Apr; 25(2):167-74.
          View in: PubMed
        5. McQuade T, Cho Y, Chan FK. Positive and negative phosphorylation regulates RIP1- and RIP3-induced programmed necrosis. Biochem J. 2013 Dec 15; 456(3):409-15.
          View in: PubMed
        6. Moquin DM, McQuade T, Chan FK. CYLD deubiquitinates RIP1 in the TNFa-induced necrosome to facilitate kinase activation and programmed necrosis. PLoS One. 2013; 8(10):e76841.
          View in: PubMed
        7. Moriwaki K, Chan FK. RIP3: a molecular switch for necrosis and inflammation. Genes Dev. 2013 Aug 1; 27(15):1640-9.
          View in: PubMed
        8. Sosna J, Voigt S, Mathieu S, Lange A, Thon L, Davarnia P, Herdegen T, Linkermann A, Rittger A, Chan FK, Kabelitz D, Sch├╝tze S, Adam D. TNF-induced necroptosis and PARP-1-mediated necrosis represent distinct routes to programmed necrotic cell death. Cell Mol Life Sci. 2014 Jan; 71(2):331-48.
          View in: PubMed
        9. Chan FK, Moriwaki K, De Rosa MJ. Detection of necrosis by release of lactate dehydrogenase activity. Methods Mol Biol. 2013; 979:65-70.
          View in: PubMed
        10. Kim CK, Toft JE, Papenfus M, Verutes G, Guerry AD, Ruckelshaus MH, Arkema KK, Guannel G, Wood SA, Bernhardt JR, Tallis H, Plummer ML, Halpern BS, Pinsky ML, Beck MW, Chan F, Chan KM, Levin PS, Polasky S. Catching the right wave: evaluating wave energy resources and potential compatibility with existing marine and coastal uses. PLoS One. 2012; 7(11):e47598.
          View in: PubMed
        11. Chan FK. Fueling the flames: Mammalian programmed necrosis in inflammatory diseases. Cold Spring Harb Perspect Biol. 2012 Nov; 4(11).
          View in: PubMed
        12. Ren SX, Cheng AS, To KF, Tong JH, Li MS, Shen J, Wong CC, Zhang L, Chan RL, Wang XJ, Ng SS, Chiu LC, Marquez VE, Gallo RL, Chan FK, Yu J, Sung JJ, Wu WK, Cho CH. Host immune defense peptide LL-37 activates caspase-independent apoptosis and suppresses colon cancer. Cancer Res. 2012 Dec 15; 72(24):6512-23.
          View in: PubMed
        13. Li J, McQuade T, Siemer AB, Napetschnig J, Moriwaki K, Hsiao YS, Damko E, Moquin D, Walz T, McDermott A, Chan FK, Wu H. The RIP1/RIP3 necrosome forms a functional amyloid signaling complex required for programmed necrosis. Cell. 2012 Jul 20; 150(2):339-50.
          View in: PubMed
        14. Chan FK, Baehrecke EH. RIP3 finds partners in crime. Cell. 2012 Jan 20; 148(1-2):17-8.
          View in: PubMed
        15. Fortes GB, Alves LS, de Oliveira R, Dutra FF, Rodrigues D, Fernandez PL, Souto-Padron T, De Rosa MJ, Kelliher M, Golenbock D, Chan FK, Bozza MT. Heme induces programmed necrosis on macrophages through autocrine TNF and ROS production. Blood. 2012 Mar 8; 119(10):2368-75.
          View in: PubMed
        16. Cho Y, McQuade T, Zhang H, Zhang J, Chan FK. RIP1-dependent and independent effects of necrostatin-1 in necrosis and T cell activation. PLoS One. 2011; 6(8):e23209.
          View in: PubMed
        17. Steindler L, Schwalbach MS, Smith DP, Chan F, Giovannoni SJ. Energy starved Candidatus Pelagibacter ubique substitutes light-mediated ATP production for endogenous carbon respiration. PLoS One. 2011; 6(5):e19725.
          View in: PubMed
        18. Zhang H, Zhou X, McQuade T, Li J, Chan FK, Zhang J. Functional complementation between FADD and RIP1 in embryos and lymphocytes. Nature. 2011 Mar 17; 471(7338):373-6.
          View in: PubMed
        19. Cho Y, Challa S, Chan FK. A RNA interference screen identifies RIP3 as an essential inducer of TNF-induced programmed necrosis. Adv Exp Med Biol. 2011; 691:589-93.
          View in: PubMed
        20. Challa S, Woelfel M, Guildford M, Moquin D, Chan FK. Viral cell death inhibitor MC159 enhances innate immunity against vaccinia virus infection. J Virol. 2010 Oct; 84(20):10467-76.
          View in: PubMed
        21. Challa S, Chan FK. Going up in flames: necrotic cell injury and inflammatory diseases. Cell Mol Life Sci. 2010 Oct; 67(19):3241-53.
          View in: PubMed
        22. Cho YS, Challa S, Clancy L, Chan FK. Lipopolysaccharide-induced expression of TRAIL promotes dendritic cell differentiation. Immunology. 2010 Aug; 130(4):504-15.
          View in: PubMed
        23. Cho YS, Park SY, Shin HS, Chan FK. Physiological consequences of programmed necrosis, an alternative form of cell demise. Mol Cells. 2010 Apr; 29(4):327-32.
          View in: PubMed
        24. Moquin D, Chan FK. The molecular regulation of programmed necrotic cell injury. Trends Biochem Sci. 2010 Aug; 35(8):434-41.
          View in: PubMed
        25. Cho YS, Challa S, Moquin D, Genga R, Ray TD, Guildford M, Chan FK. Phosphorylation-driven assembly of the RIP1-RIP3 complex regulates programmed necrosis and virus-induced inflammation. Cell. 2009 Jun 12; 137(6):1112-23.
          View in: PubMed
        26. Wang LJ, Jin HC, Wang X, Lam EK, Zhang JB, Liu X, Chan FK, Si JM, Sung JJ. ZIC1 is downregulated through promoter hypermethylation in gastric cancer. Biochem Biophys Res Commun. 2009 Feb 20; 379(4):959-63.
          View in: PubMed
        27. Chan FK. Three is better than one: pre-ligand receptor assembly in the regulation of TNF receptor signaling. Cytokine. 2007 Feb; 37(2):101-7.
          View in: PubMed
        28. Woelfel M, Bixby J, Brehm MA, Chan FK. Transgenic expression of the viral FLIP MC159 causes lpr/gld-like lymphoproliferation and autoimmunity. J Immunol. 2006 Sep 15; 177(6):3814-20.
          View in: PubMed
        29. Sedger LM, Osvath SR, Xu XM, Li G, Chan FK, Barrett JW, McFadden G. Poxvirus tumor necrosis factor receptor (TNFR)-like T2 proteins contain a conserved preligand assembly domain that inhibits cellular TNFR1-induced cell death. J Virol. 2006 Sep; 80(18):9300-9.
          View in: PubMed
        30. Zheng L, Bidere N, Staudt D, Cubre A, Orenstein J, Chan FK, Lenardo M. Competitive control of independent programs of tumor necrosis factor receptor-induced cell death by TRADD and RIP1. Mol Cell Biol. 2006 May; 26(9):3505-13.
          View in: PubMed
        31. Clancy L, Mruk K, Archer K, Woelfel M, Mongkolsapaya J, Screaton G, Lenardo MJ, Chan FK. Preligand assembly domain-mediated ligand-independent association between TRAIL receptor 4 (TR4) and TR2 regulates TRAIL-induced apoptosis. Proc Natl Acad Sci U S A. 2005 Dec 13; 102(50):18099-104.
          View in: PubMed
        32. Deng GM, Zheng L, Chan FK, Lenardo M. Amelioration of inflammatory arthritis by targeting the pre-ligand assembly domain of tumor necrosis factor receptors. Nat Med. 2005 Oct; 11(10):1066-72.
          View in: PubMed
        33. Chan FK. Monitoring molecular interactions in living cells using flow cytometric analysis of fluorescence resonance energy transfer. Methods Mol Biol. 2004; 261:371-82.
          View in: PubMed
        34. Chan FK, Holmes KL. Flow cytometric analysis of fluorescence resonance energy transfer: a tool for high-throughput screening of molecular interactions in living cells. Methods Mol Biol. 2004; 263:281-92.
          View in: PubMed
        35. Chan FK, Shisler J, Bixby JG, Felices M, Zheng L, Appel M, Orenstein J, Moss B, Lenardo MJ. A role for tumor necrosis factor receptor-2 and receptor-interacting protein in programmed necrosis and antiviral responses. J Biol Chem. 2003 Dec 19; 278(51):51613-21.
          View in: PubMed
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