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Alonzo H Ross PhD

TitleProfessor Emeritus
InstitutionUMass Chan Medical School
DepartmentBiochemistry and Molecular Biotechnology
AddressUMass Chan Medical School
364 Plantation Street LRB-819
Worcester MA 01605
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    Other Positions
    InstitutionT.H. Chan School of Medicine
    DepartmentBiochemistry and Molecular Biotechnology

    InstitutionT.H. Chan School of Medicine
    DepartmentMolecular, Cell and Cancer Biology

    Collapse Biography 
    Collapse education and training
    Cornell University, Ithaca, NY, United StatesBAArts
    Stanford University, Palo Alto, CA, United StatesPH DPhilosophy

    Collapse Overview 
    Collapse overview

    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

    Collapse 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.

    Collapse Bibliographic 
    Collapse selected publications
    Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Faculty can login to make corrections and additions.
    Newest   |   Oldest   |   Most Cited   |   Most Discussed   |   Timeline   |   Field Summary   |   Plain Text
    PMC Citations indicate the number of times the publication was cited by articles in PubMed Central, and the Altmetric score represents citations in news articles and social media. (Note that publications are often cited in additional ways that are not shown here.) Fields are based on how the National Library of Medicine (NLM) classifies the publication's journal and might not represent the specific topic of the publication. Translation tags are based on the publication type and the MeSH terms NLM assigns to the publication. Some publications (especially newer ones and publications not in PubMed) might not yet be assigned Field or Translation tags.) Click a Field or Translation tag to filter the publications.
    1. Yerramilli VS, Ross AH, Scarlata S, Gericke A. IQGAP1 scaffolding links phosphoinositide kinases to cytoskeletal reorganization. Biophys J. 2022 03 01; 121(5):793-807. PMID: 35077666.
      Citations: 2     Fields:    
    2. Weatherbee JL, Kraus JL, Ross AH. ER stress in temozolomide-treated glioblastomas interferes with DNA repair and induces apoptosis. Oncotarget. 2016 Jul 12; 7(28):43820-43834. PMID: 27286262.
      Citations: 13     Fields:    Translation:HumansAnimalsCells
    3. Heinrich F, Chakravarthy S, Nanda H, Papa A, Pandolfi PP, Ross AH, Harishchandra RK, Gericke A, L?sche M. The PTEN Tumor Suppressor Forms Homodimers in Solution. Structure. 2015 Oct 06; 23(10):1952-1957. PMID: 26299948.
      Citations: 25     Fields:    Translation:HumansCells
    4. Karpel-Massler G, Shu C, Chau L, Banu M, Halatsch ME, Westhoff MA, Ramirez Y, Ross AH, Bruce JN, Canoll P, Siegelin MD. Combined inhibition of Bcl-2/Bcl-xL and Usp9X/Bag3 overcomes apoptotic resistance in glioblastoma in vitro and in vivo. Oncotarget. 2015 Jun 10; 6(16):14507-21. PMID: 26008975.
      Citations: 32     Fields:    Translation:HumansAnimalsCells
    5. Harishchandra RK, Neumann BM, Gericke A, Ross AH. Biophysical methods for the characterization of PTEN/lipid bilayer interactions. Methods. 2015 May; 77-78:125-35. PMID: 25697761.
      Citations: 5     Fields:    Translation:HumansAnimalsCells
    6. Ramirez YP, Mladek AC, Phillips RM, Gynther M, Rautio J, Ross AH, Wheelhouse RT, Sakaria JN. Evaluation of novel imidazotetrazine analogues designed to overcome temozolomide resistance and glioblastoma regrowth. Mol Cancer Ther. 2015 Jan; 14(1):111-9. PMID: 25351918.
      Citations: 10     Fields:    Translation:HumansAnimalsCells
    7. Pulido R, Baker SJ, Barata JT, Carracedo A, Cid VJ, Chin-Sang ID, Dav? V, den Hertog J, Devreotes P, Eickholt BJ, Eng C, Furnari FB, Georgescu MM, Gericke A, Hopkins B, Jiang X, Lee SR, L?sche M, Malaney P, Matias-Guiu X, Molina M, Pandolfi PP, Parsons R, Pinton P, Rivas C, Rocha RM, Rodr?guez 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 01; 7(332):pe15. PMID: 24985344.
      Citations: 30     Fields:    Translation:HumansCells
    8. 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. PMID: 24757258.
      Citations: 44     Fields:    Translation:HumansCells
    9. Jiang Z, Redfern RE, Isler Y, Ross AH, Gericke A. Cholesterol stabilizes fluid phosphoinositide domains. Chem Phys Lipids. 2014 Sep; 182:52-61. PMID: 24556334.
      Citations: 28     Fields:    Translation:Humans
    10. Ramirez YP, Weatherbee JL, Wheelhouse RT, Ross AH. Glioblastoma multiforme therapy and mechanisms of resistance. Pharmaceuticals (Basel). 2013 Nov 25; 6(12):1475-506. PMID: 24287492.
    11. Gericke A, Leslie NR, L?sche 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. PMID: 23775692.
      Citations: 25     Fields:    Translation:HumansAnimalsCells
    12. Shenoy S, Shekhar P, Heinrich F, Daou MC, Gericke A, Ross AH, L?sche 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. PMID: 22505997.
      Citations: 43     Fields:    Translation:HumansCells
    13. 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. PMID: 21732409.
      Citations: 28     Fields:    Translation:HumansAnimalsCells
    14. 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. PMID: 21364280.
      Citations: 88     Fields:    Translation:HumansAnimalsCells
    15. 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. PMID: 20435409.
      Citations: 16     Fields:    Translation:HumansAnimalsCells
    16. 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. PMID: 20718038.
      Citations: 22     Fields:    Translation:HumansCells
    17. 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 01; 70(17):6870-9. PMID: 20736377.
      Citations: 62     Fields:    Translation:HumansAnimalsCells
    18. 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. PMID: 20501802.
      Citations: 18     Fields:    Translation:HumansAnimalsCells
    19. 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. PMID: 20495567.
      Citations: 93     Fields:    Translation:HumansAnimalsCells
    20. 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. PMID: 20470863.
      Citations: 44     Fields:    Translation:AnimalsCells
    21. Gilbert CA, Ross AH. Cancer stem cells: cell culture, markers, and targets for new therapies. J Cell Biochem. 2009 Dec 01; 108(5):1031-8. PMID: 19760641.
      Citations: 81     Fields:    Translation:HumansCells
    22. Ross AH, Gericke A. Phosphorylation keeps PTEN phosphatase closed for business. Proc Natl Acad Sci U S A. 2009 Feb 03; 106(5):1297-8. PMID: 19174524.
      Citations: 40     Fields:    Translation:Cells
    23. 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. PMID: 18812521.
      Citations: 49     Fields:    Translation:HumansAnimalsCells
    24. 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. PMID: 18220422.
      Citations: 51     Fields:    Translation:HumansCells
    25. Li L, Ross AH. Why is PTEN an important tumor suppressor? J Cell Biochem. 2007 Dec 15; 102(6):1368-74. PMID: 17972252.
      Citations: 47     Fields:    Translation:Humans
    26. 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. PMID: 16651633.
      Citations: 23     Fields:    Translation:AnimalsCells
    27. Gericke A, Munson M, Ross AH. Regulation of the PTEN phosphatase. Gene. 2006 Jun 07; 374:1-9. PMID: 16675164.
      Citations: 87     Fields:    Translation:HumansAnimalsCells
    28. Liu F, Wagner S, Campbell RB, Nickerson JA, Schiffer CA, Ross AH. PTEN enters the nucleus by diffusion. J Cell Biochem. 2005 Oct 01; 96(2):221-34. PMID: 16088943.
      Citations: 52     Fields:    Translation:HumansCells
    29. 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. PMID: 16195916.
      Citations: 19     Fields:    Translation:HumansAnimalsCells
    30. 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. PMID: 15658102.
      Citations: 10     Fields:    Translation:AnimalsCells
    31. 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. PMID: 15249580.
      Citations: 33     Fields:    Translation:Animals
    32. 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. PMID: 15056462.
      Citations: 12     Fields:    Translation:Animals
    33. Gr?co 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. PMID: 15277705.
      Citations: 3     Fields:    Translation:AnimalsCells
    34. 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. PMID: 14697668.
      Citations: 6     Fields:    Translation:AnimalsCells
    35. Campbell RB, Liu F, Ross AH. Allosteric activation of PTEN phosphatase by phosphatidylinositol 4,5-bisphosphate. J Biol Chem. 2003 Sep 05; 278(36):33617-20. PMID: 12857747.
      Citations: 102     Fields:    Translation:HumansCells
    36. 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. PMID: 12503079.
      Citations: 5     Fields:    Translation:HumansAnimalsCells
    37. 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. PMID: 12100976.
      Citations: 6     Fields:    Translation:AnimalsCells
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