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    Alonzo H Ross PhD

    TitleProfessor
    InstitutionUniversity of Massachusetts Medical School
    DepartmentBiochemistry and Molecular Pharmacology
    AddressUniversity of Massachusetts Medical School
    364 Plantation Street, LRB-819
    Worcester MA 01605
    Phone508-856-8016
      Other Positions
      InstitutionUMMS - School of Medicine
      DepartmentCancer Biology

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentBiochemistry and Molecular Pharmacology

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentCancer Biology

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentInterdisciplinary Graduate Program

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentNeuroscience

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentTranslational Science

        Overview 
        Narrative

        Academic Background

        B.A., Cornell University, 1972
        Ph.D. 1977, Stanford University
        Damon Runyon Postdoctoral fellow, 1977-1981, M.I.T.
        The Wistar Institute, 1981-88
        The Worcester Foundation for Experimental Biology, 1988-97
        University of Massachusetts Medical School, 1997-


        PTEN phosphatase and tumor suppressor,CNS Stem Cells and neural tumors.

        Photo: Alonzo H. Ross Even though phosphorylation of phosphatidylinositols by phosphoinositide 3-kinase has an important and pervasive role in the nervous system, little is known about the phosphatases that reverse this reaction. Recently, such a phosphatase, PTEN, was cloned as a tumor suppressor for gliomas. We now know that PTEN is a tumor suppressor for many tumor types and is a phosphatidylinositol phosphatase specific for the 3-position of the inositol ring. PTEN is expressed in most, if not all, neurons and is localized in the nucleus and cytoplasm.

        Balance between phosphatidylinositol 4,5 bisphosphate and phosphatidylinositol 3,4,5 trisphtrisphosphate is determined by relative  activities of phosphatidylinositol 3-kinase and PTEN phosphatase

        Figure 1. Balance between phosphatidylinositol 4,5 bisphosphate and phosphatidylinositol 3,4,5 trisphosphate is determined by relative activities of phosphatidylinositol 3-kinase and PTEN phosphatase.

        Micrograph showing that exogenously expressed green

        Figure 2. Micrograph showing that exogenously expressed green fluorescent protein PTEN is present in both the nucleus and cytoplasm of HeLa cells.

        Fit of kinetic data for activation of PTEN by

        Figure 3. Fit of kinetic data for activation of PTEN by phosphatidylinositol 4,5 bisphosphate.

        Magnetic resonance image of patient's brain bearing a large

        Figure 4. Magnetic resonance image of patient's brain bearing a large glioma brain tumor.

        We are examining the regulation of PTEN activity at the protein level. In recent experiments, we measured reaction rates for varying concentrations of monodisperse (i.e., not in a vesicle or micelle) PI(3,4,5)P3. The kinetic curves did not follow the typical Michaelis-Menten form, especially at higher PI(3,4,5)P3levels. The kinetic curves were sigmoidal, indicating that the enzymatic activity increases as the reaction progresses. One possible explanation is that the PTEN product, PI(4,5)P2, is a positive regulator of PTEN activity. We measured PTEN activity as a function of PI(4,5)P2concentration and found that PI(4,5)P2activated PTEN with a Kact = 20 micromolar. This regulation is specific. For example, PI(3,4)P2 and PI(3,5)P2 do not activate PTEN. Based on these data, we propose that PI(4,5)P2 binds to a site distinct from the phosphatase active site, induces an allosteric conformational change, and, thereby, activates PTEN, leading to a positive feedback loop for PTEN activity. This model predicts that PTEN would be preferentially activated at the PI(4,5)P2-bearing plasma membrane or at PI(4,5)P2 -rich membrane domains.

        We also are carrying out two projects to improve therapies for brain tumors. Glioblastoma multiformi is the most aggressive brain tumor, and despite treatment with surgery, radiotherapy and chemotherapy, the prognosis is poor. Some cells are resistant to these therapies, and eventually the tumor recurs. Recent models suggest that the resistant cells are cancer stem cells. These cells express stem cell markers, self-renew and can differentiate along developmental lineages. Cancer therapies directed against the cancer stem cells might yield real cures.

        A problem in this field is that cancer cells change in culture. As a result, it is important to use freshly excised tumors or low passage cell cultures. We are collaborating with Dr. Rick Moser of the Neurosurgery Department. We have put a series of these tumors into culture with defined medium. Under these conditions, the cells grow as aggregates of cells, known as neurospheres. Cells grown under these conditions more closely resemble the original tumor cells.

        We are testing a new approach to enhance the efficacy of temozolomide (TMZ), which is the chemotherapy drug of choice for brain tumors. In particular, we are modulating signaling pathways to enhance TMZ-induced cell death and senescence of cancer stem cells. We have observed enhanced efficacy both in culture and in mice with ex vivo treated cells.

        We also are studying meningiomas, which are common brain tumors and usually benign. Resection of meningiomas can be difficult for the surgeon and the patient. Drugs to reduce tumor growth and prevent tumor recurrence would be a helpful alternative, but unfortunately, chemotherapy has not been useful for these tumors. As a result, we wish to develop therapies directed to specific signaling pathways that drive proliferation of meningioma cells. Using protein arrays, we have found that 15/15 meningioma cultures have strongly activated epidermal growth factor receptor, and 14/15 cultures have activated platelet-derived growth factor receptor. Drugs that inhibit these receptors slow meningioma cell proliferation and induce cell death.

        We hope to carry both the glioblastoma and meningioma projects to clinical trials



        Rotation Projects

        Rotation Projects

        Potential Rotation Projects

        • Allostericregulation of PTEN using biophysical techniques.
        • Analysis of PTEN structure by NMR.
        • Therapies directed against cancer stem cells for human glioblastomas.
        • Signaling directed therapies for meningioma brain tumors.



        Bibliographic 
        selected publications
        List All   |   Timeline
        1. Pulido R, Baker SJ, Barata JT, Carracedo A, Cid VJ, Chin-Sang ID, Davé V, den Hertog J, Devreotes P, Eickholt BJ, Eng C, Furnari FB, Georgescu MM, Gericke A, Hopkins B, Jiang X, Lee SR, Lösche M, Malaney P, Matias-Guiu X, Molina M, Pandolfi PP, Parsons R, Pinton P, Rivas C, Rocha RM, Rodríguez MS, Ross AH, Serrano M, Stambolic V, Stiles B, Suzuki A, Tan SS, Tonks NK, Trotman LC, Wolff N, Woscholski R, Wu H, Leslie NR. A unified nomenclature and amino acid numbering for human PTEN. Sci Signal. 2014 Jul 1; 7(332):pe15.
          View in: PubMed
        2. Pareja F, Macleod D, Shu C, Crary JF, Canoll PD, Ross AH, Siegelin MD. PI3K and Bcl-2 Inhibition Primes Glioblastoma Cells to Apoptosis through Downregulation of Mcl-1 and Phospho-BAD. Mol Cancer Res. 2014 Jul; 12(7):987-1001.
          View in: PubMed
        3. Jiang Z, Redfern RE, Isler Y, Ross AH, Gericke A. Cholesterol stabilizes fluid phosphoinositide domains. Chem Phys Lipids. 2014 Sep; 182:52-61.
          View in: PubMed
        4. Ramirez YP, Weatherbee JL, Wheelhouse RT, Ross AH. Glioblastoma multiforme therapy and mechanisms of resistance. Pharmaceuticals (Basel). 2013; 6(12):1475-506.
          View in: PubMed
        5. Gericke A, Leslie NR, Lösche M, Ross AH. PtdIns(4,5)P2-mediated cell signaling: emerging principles and PTEN as a paradigm for regulatory mechanism. Adv Exp Med Biol. 2013; 991:85-104.
          View in: PubMed
        6. Shenoy S, Shekhar P, Heinrich F, Daou MC, Gericke A, Ross AH, Lösche M. Membrane association of the PTEN tumor suppressor: molecular details of the protein-membrane complex from SPR binding studies and neutron reflection. PLoS One. 2012; 7(4):e32591.
          View in: PubMed
        7. Burstein SH, McQuain CA, Ross AH, Salmonsen RA, Zurier RE. Resolution of inflammation by N-arachidonoylglycine. J Cell Biochem. 2011 Nov; 112(11):3227-33.
          View in: PubMed
        8. Siegelin MD, Dohi T, Raskett CM, Orlowski GM, Powers CM, Gilbert CA, Ross AH, Plescia J, Altieri DC. Exploiting the mitochondrial unfolded protein response for cancer therapy in mice and human cells. J Clin Invest. 2011 Apr; 121(4):1349-60.
          View in: PubMed
        9. Mihaliak AM, Gilbert CA, Li L, Daou MC, Moser RP, Reeves A, Cochran BH, Ross AH. Clinically relevant doses of chemotherapy agents reversibly block formation of glioblastoma neurospheres. Cancer Lett. 2010 Oct 28; 296(2):168-77.
          View in: PubMed
        10. Redfern RE, Daou MC, Li L, Munson M, Gericke A, Ross AH. A mutant form of PTEN linked to autism. Protein Sci. 2010 Oct; 19(10):1948-56.
          View in: PubMed
        11. Gilbert CA, Daou MC, Moser RP, Ross AH. Gamma-secretase inhibitors enhance temozolomide treatment of human gliomas by inhibiting neurosphere repopulation and xenograft recurrence. Cancer Res. 2010 Sep 1; 70(17):6870-9.
          View in: PubMed
        12. Siegelin MD, Plescia J, Raskett CM, Gilbert CA, Ross AH, Altieri DC. Global targeting of subcellular heat shock protein-90 networks for therapy of glioblastoma. Mol Cancer Ther. 2010 Jun; 9(6):1638-46.
          View in: PubMed
        13. Sheng Z, Li L, Zhu LJ, Smith TW, Demers A, Ross AH, Moser RP, Green MR. A genome-wide RNA interference screen reveals an essential CREB3L2-ATF5-MCL1 survival pathway in malignant glioma with therapeutic implications. Nat Med. 2010 Jun; 16(6):671-7.
          View in: PubMed
        14. Siegelin MD, Raskett CM, Gilbert CA, Ross AH, Altieri DC. Sorafenib exerts anti-glioma activity in vitro and in vivo. Neurosci Lett. 2010 Jul 12; 478(3):165-70.
          View in: PubMed
        15. Gilbert CA, Ross AH. Cancer stem cells: cell culture, markers, and targets for new therapies. J Cell Biochem. 2009 Dec 1; 108(5):1031-8.
          View in: PubMed
        16. Ross AH, Gericke A. Phosphorylation keeps PTEN phosphatase closed for business. Proc Natl Acad Sci U S A. 2009 Feb 3; 106(5):1297-8.
          View in: PubMed
        17. Li L, Dutra A, Pak E, Labrie JE, Gerstein RM, Pandolfi PP, Recht LD, Ross AH. EGFRvIII expression and PTEN loss synergistically induce chromosomal instability and glial tumors. Neuro Oncol. 2009 Feb; 11(1):9-21.
          View in: PubMed
        18. Redfern RE, Redfern D, Furgason ML, Munson M, Ross AH, Gericke A. PTEN phosphatase selectively binds phosphoinositides and undergoes structural changes. Biochemistry. 2008 Feb 19; 47(7):2162-71.
          View in: PubMed
        19. Li L, Ross AH. Why is PTEN an important tumor suppressor? J Cell Biochem. 2007 Dec 15; 102(6):1368-74.
          View in: PubMed
        20. Jang T, Savarese T, Low HP, Kim S, Vogel H, Lapointe D, Duong T, Litofsky NS, Weimann JM, Ross AH, Recht L. Osteopontin expression in intratumoral astrocytes marks tumor progression in gliomas induced by prenatal exposure to N-ethyl-N-nitrosourea. Am J Pathol. 2006 May; 168(5):1676-85.
          View in: PubMed
        21. Gericke A, Munson M, Ross AH. Regulation of the PTEN phosphatase. Gene. 2006 Jun 7; 374:1-9.
          View in: PubMed
        22. Liu F, Wagner S, Campbell RB, Nickerson JA, Schiffer CA, Ross AH. PTEN enters the nucleus by diffusion. J Cell Biochem. 2005 Oct 1; 96(2):221-34.
          View in: PubMed
        23. Daou MC, Smith TW, Litofsky NS, Hsieh CC, Ross AH. Doublecortin is preferentially expressed in invasive human brain tumors. Acta Neuropathol. 2005 Nov; 110(5):472-80.
          View in: PubMed
        24. Savarese TM, Jang T, Low HP, Salmonsen R, Litofsky NS, Matuasevic Z, Ross AH, Recht LD. Isolation of immortalized, INK4a/ARF-deficient cells from the subventricular zone after in utero N-ethyl-N-nitrosourea exposure. J Neurosurg. 2005 Jan; 102(1):98-108.
          View in: PubMed
        25. Mitra P, Zhang Y, Rameh LE, Ivshina MP, McCollum D, Nunnari JJ, Hendricks GM, Kerr ML, Field SJ, Cantley LC, Ross AH. A novel phosphatidylinositol(3,4,5)P3 pathway in fission yeast. J Cell Biol. 2004 Jul 19; 166(2):205-11.
          View in: PubMed
        26. Jang T, Litofsky NS, Smith TW, Ross AH, Recht LD. Aberrant nestin expression during ethylnitrosourea-(ENU)-induced neurocarcinogenesis. Neurobiol Dis. 2004 Apr; 15(3):544-52.
          View in: PubMed
        27. Gréco B, Low HP, Johnson EC, Salmonsen RA, Gallant J, Jones SN, Ross AH, Recht LD. Differentiation prevents assessment of neural stem cell pluripotency after blastocyst injection. Stem Cells. 2004; 22(4):600-8.
          View in: PubMed
        28. Li L, He F, Litofsky NS, Recht LD, Ross AH. Profiling of genes expressed by PTEN haploinsufficient neural precursor cells. Mol Cell Neurosci. 2003 Dec; 24(4):1051-61.
          View in: PubMed
        29. Campbell RB, Liu F, Ross AH. Allosteric activation of PTEN phosphatase by phosphatidylinositol 4,5-bisphosphate. J Biol Chem. 2003 Sep 5; 278(36):33617-20.
          View in: PubMed
        30. Lachyankar MB, Condon PJ, Daou MC, De AK, Levine JB, Obermeier A, Ross AH. Novel functional interactions between Trk kinase and p75 neurotrophin receptor in neuroblastoma cells. J Neurosci Res. 2003 Jan 15; 71(2):157-72.
          View in: PubMed
        31. Li L, Liu F, Ross AH. PTEN regulation of neural development and CNS stem cells. J Cell Biochem. 2003 Jan 1; 88(1):24-8.
          View in: PubMed
        32. Schonhoff CM, Daou MC, Jones SN, Schiffer CA, Ross AH. Nitric oxide-mediated inhibition of Hdm2-p53 binding. Biochemistry. 2002 Nov 19; 41(46):13570-4.
          View in: PubMed
        33. Engstrom CM, Demers D, Dooner M, McAuliffe C, Benoit BO, Stencel K, Joly M, Hulspas R, Reilly JL, Savarese T, Recht LD, Ross AH, Quesenberry PJ. A method for clonal analysis of epidermal growth factor-responsive neural progenitors. J Neurosci Methods. 2002 Jun 30; 117(2):111-21.
          View in: PubMed
        34. Li L, Liu F, Salmonsen RA, Turner TK, Litofsky NS, Di Cristofano A, Pandolfi PP, Jones SN, Recht LD, Ross AH. PTEN in neural precursor cells: regulation of migration, apoptosis, and proliferation. Mol Cell Neurosci. 2002 May; 20(1):21-9.
          View in: PubMed
        35. Ross AH, Lachyankar MB, Recht LD. PTEN: a newly identified regulator of neuronal differentiation. Neuroscientist. 2001 Aug; 7(4):278-81.
          View in: PubMed
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