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Research Newsletter - February 2008

Spotlight Article

Identification of cells initiating human melanomas.

Markus Frank, MD, a researcher in the Transplantation Research Center of Children's Hospital Boston and Brigham and Women's Hospital and HSCI Affiliated Faculty, in collaboration with George Murphy, MD, chief of Dermatopathology at Brigham and Women's Hospital, Thomas Kupper, MD, of Brigham and Women's Hospital and HSCI Principal Faculty, and others, isolated melanoma stem cells and found that they have, on their surface, a special protein that helps shuttle toxic agents out of the cell. Previously, the Children's-BWH laboratory of Frank and Natasha Frank, MD discovered and cloned this protein, known as ABCB5, and showed that it renders melanoma cells resistant to chemotherapy drugs. In the new paper, they show that ABCB5 is unique to the subpopulation of melanoma stem cells.

But most strikingly, Frank and colleagues were able to leverage ABCB5 - normally a protector - to bring about the destruction of these highly virulent stem cells in mice bearing human melanomas. They injected the mice with monoclonal antibodies that bound only to cells with the ABCB5 protein - namely, melanoma stem cells. The antibodies stimulated an immune response against the stem cells that led to cell death and significantly inhibited melanoma growth as compared with untreated mice.

"This study lays the groundwork for a possible treatment, showing that targeting stem cells may be a viable strategy in cancer," says Frank. "Until this study, no evidence had been provided."

"The study also shows that melanomas are 'smart,' in that their virulence is hidden within small sub-populations that are difficult to identify and difficult to destroy as a result of expressing proteins like ABCB5," adds Murphy. "Now, the distinct possibility exists that such cells actually can be outsmarted. Hopefully, this will lead to new ways of treating metastatic disease, since our existing treatments don't work well."

Frank and colleagues, are pursuing further studies aimed at eventually bringing this finding to the clinic. They are studying various alternative ways of inhibiting ABCB5, such as human monoclonal antibodies or small inhibitory RNA molecules.

Schatton T, Murphy GF, Frank NY, Yamaura K, Waaga-Gasser AM, Gasser M, Zhan Q, Jordan S, Duncan LM, Weishaupt C, Fuhlbrigge RC, Kupper TS, Sayegh MH, Frank MH. Identification of cells initiating human melanomas. Nature. 2008 Jan 17;451(7176):345-9. Read Abstract.

Scientific Papers

Review and Commentary

  • Brunton SA, Stibbard JH, Rubin LL, Kruse LI, Guicherit OM, Boyd EA, Price S. Potent inhibitors of the hedgehog signaling pathway. J Med Chem. 2008 Mar 13;51(5):1108-10. Epub 2008 Feb 15. Read Abstract.
  • Daley GQ, Hyun I, Lindvall O. Mapping the Road to the Clinical Translation of Stem Cells. ISSCR: Committee Forum. Mapping the Road to the Clinical Translation of Stem Cells. Cell Stem Cell. 2008 Feb 7;2(2):139-140. Read Abstract.
  • Daley GQ, Scadden DT. Prospects for stem cell-based therapy. Cell. 2008 Feb 22;132(4):544-8. Read Abstract.
  • Daley GQ, Scadden DT. Prospects for stem cell-based therapy. Cell. 2008 Feb 22;132(4):544-8. Read Abstract.
  • Ikeda Y, Hoshijima M, Chien KR. Toward biologically targeted therapy of calcium cycling defects in heart failure. Physiology (Bethesda). 2008 Feb;23(1):6-16. Read Abstract.
  • Laird DJ, von Andrian UH, Wagers AJ. Stem cell trafficking in tissue development, growth, and disease. Cell. 2008 Feb 22;132(4):612-30. Review. Read Abstract.
  • McMahon AP, Aronow BJ, Davidson DR, Davies JA, Gaido KW, Grimmond S, Lessard JL, Little MH, Potter SS, Wilder EL, Zhang P; for the GUDMAP project. GUDMAP: The Genitourinary Developmental Molecular Anatomy Project. J Am Soc Nephrol. 2008 Feb 20. Read Abstract.
  • Orkin SH, Zon LI. Hematopoiesis: an evolving paradigm for stem cell biology. Cell. 2008 Feb 22;132(4):631-44. Read Abstract.
  • Orkin SH, Zon LI. SnapShot: hematopoiesis. Cell. 2008 Feb 22;132(4):712. Read Abstract.
  • Rossi DJ, Jamieson CH, Weissman IL. Stems cells and the pathways to aging and cancer. Cell. 2008 Feb 22;132(4):681-96. Review. Read Abstract.
  • Rubin LL. Stem cells and drug discovery: the beginning of a new era? Cell. 2008 Feb 22;132(4):549-52. Read Abstract.
  • White RM, Sessa A, Burke C, Bowman T, LeBlanc J, Ceol C, Bourque C, Dovey M, Goessling W, Burns CE, LI Zon. Transparent Adult Zebrafish as a Tool for In Vivo Transplantation Analysis. Cell Stem Cell. 2008 Feb 7;2(2):183-189. Read Abstract.
  • Wu SM, Chien KR, Mummery C. Origins and fates of cardiovascular progenitor cells. Cell. 2008 Feb 22;132(4):537-43. Read Abstract.

Blood

  • Bruns I, Steidl U, Fischer JC, Czibere A, Kobbe G, Raschke S, Singh R, Fenk R, Rosskopf M, Pechtel S, von Haeseler A, Wernet P, Tenen DG, Haas R, Kronenwett R. Pegylated granulocyte colony-stimulating factor mobilizes CD34+ cells with different stem and progenitor subsets and distinct functional properties in comparison with unconjugated granulocyte colony-stimulating factor. Haematologica. 2008 Mar;93(3):347-55. Epub 2008 Feb 11. Read Abstract.
  • Cantor AB, Iwasaki H, Arinobu Y, Moran TB, Shigematsu H, Sullivan MR, Akashi K, Orkin SH. Antagonism of FOG-1 and GATA factors in fate choice for the mast cell lineage. J Exp Med. 2008 Feb 25. Read Abstract.
  • Kim WJ, Okimoto RA, Purton LE, Goodwin M, Haserlat SM, Dayyani F, Sweetser DA, McClatchey AI, Bernard OA, Look AT, Bell DW, Scadden DT, Haber DA. Mutations in the neutral sphingomyelinase gene SMPD3 implicate the ceramide pathway in human leukemias. Blood. 2008 Feb 25. Read Abstract.
  • Loriaux MM, Levine RL, Tyner JW, Frohling S, Scholl C, Stoffregen EP, Wernig G, Erickson H, Eide CA, Berger R, Bernard OA, Griffin JD, Stone RM, Lee B, Meyerson M, Heinrich MC, Deininger MW, Gilliland DG, Druker BJ. High-throughput sequence analysis of the tyrosine kinome in acute myeloid leukemia. Blood. 2008 Feb 5. Read Abstract.
  • McKinney-Freeman SL, Lengerke C, Jang IH, Schmitt S, Wang Y, Philitas M, Daley GQ. Modulation of murine embryonic stem cell-derived CD41+c-kit+ hematopoietic progenitors by ectopic expression of Cdx genes. Blood. 2008 Feb 5. Read Abstract.
  • Meshinchi S, Stirewalt DL, Alonzo TA, Boggon TJ, Gerbing RB, Rocnik JL, Lange BJ, Gilliland DG, Radich JP. Structural and numerical variation of FLT3/ITD in pediatric AML. Blood. 2008 Feb 27. Read Abstract.

Cancer

  • Costoya JA, Hobbs RM, Pandolfi PP. Cyclin-dependent kinase antagonizes promyelocytic leukemia zinc-finger through phosphorylation. Oncogene. 2008 Feb 4. Read Abstract.
  • Cubells L, Vil√É de Muga S, Tebar F, Bonventre JV, Balsinde J, Pol A, Grewal T, Enrich C. Annexin A6-induced inhibition of cPLA2 is linked to CAV-1 export from the golgi. J Biol Chem. 2008 Feb 1. Read Abstract.
  • Hambardzumyan D, Becher OJ, Rosenblum MK, Pandolfi PP, Manova-Todorova K, Holland EC. PI3K pathway regulates survival of cancer stem cells residing in the perivascular niche following radiation in medulloblastoma in vivo. Genes Dev. 2008 Feb 15;22(4):436-48. Read Abstract.
  • Klimek VM, Fircanis S, Maslak P, Guernah I, Baum M, Wu N, Panageas K, Wright JJ, Pandolfi PP, Nimer SD. Tolerability, Pharmacodynamics, and Pharmacokinetics Studies of Depsipeptide (Romidepsin) in Patients with Acute Myelogenous Leukemia or Advanced Myelodysplastic Syndromes. Clin Cancer Res. 2008 Feb 1;14(3):826-832. Read Abstract.
  • Perera SA, Maser RS, Xia H, McNamara K, Protopopov A, Chen L, Hezel A, Kim CF, Bronson RT, Castrillon DH, Chin L, Bardeesy N, Depinho RA, Wong KK. Telomere dysfunction promotes genome instability and metastatic potential in a K-ras p53 mouse model of lung cancer. Carcinogenesis. 2008 Feb 17. Read Abstract.

Cardiovascular System

  • Arany Z, Foo SY, Ma Y, Ruas JL, Bommi-Reddy A, Girnun G, Cooper M, Laznik D, Chinsomboon J, Rangwala SM, Baek KH, Rosenzweig A, Spiegelman BM. HIF-independent regulation of VEGF and angiogenesis by the transcriptional coactivator PGC-1alpha. Nature. 2008 Feb 21;451(7181):1008-12. Read Abstract.

Developmental Biology

  • Levasseur DN, Wang J, Dorschner MO, Stamatoyannopoulos JA, Orkin SH. Oct4 dependence of chromatin structure within the extended Nanog locus in ES cells. Genes Dev. 2008 Mar 1;22(5):575-580. Epub 2008 Feb 18. Read Abstract.
  • Loscertales M, Mikels AJ, Hu JK, Donahoe PK, Roberts DJ. Chick pulmonary Wnt5a directs airway and vascular tubulogenesis. Development. 2008 Apr;135(7):1365-76. Epub 2008 Feb 27. Read Abstract.
  • Osafune K, Caron L, Borowiak M, Martinez RJ, Fitz-Gerald CS, Sato Y, Cowan CA, Chien KR, Melton DA. Marked differences in differentiation propensity among human embryonic stem cell lines. Nat Biotechnol. 2008 Mar;26(3):313-5. Epub 2008 Feb 17. Read Abstract.
  • Stadtfeld M, Maherali N, Breault DT, Hochedlinger K. Defining Molecular Cornerstones during Fibroblast to iPS Cell Reprogramming in Mouse. Cell Stem Cell 2008 Mar,2(3):230-240. Epub 2008 Feb 14. Read Abstract.
  • Trimarchi JM, Stadler MB, Cepko CL. Individual retinal progenitor cells display extensive heterogeneity of gene expression. PLoS ONE. 2008 Feb 13;3(2):e1588. Read Abstract.
  • Viswanathan SR, Daley GQ, Gregory RI. Selective Blockade of MicroRNA Processing by Lin-28. Science. 2008 Feb 21. Read Abstract.

Imaging

  • Guimaraes AR, Tabatabei S, Dahl D, McDougal WS, Weissleder R, Harisinghani MG. Pilot Study Evaluating Use of Lymphotrophic Nanoparticle-Enhanced Magnetic Resonance Imaging for Assessing Lymph Nodes in Renal Cell Cancer. Urology. 2008 Feb 21. Read Abstract.
  • Nahrendorf M, Aikawa E, Figueiredo JL, Stangenberg L, van den Borne SW, Blankesteijn WM, Sosnovik DE, Jaffer FA, Tung CH, Weissleder R. Transglutaminase activity in acute infarcts predicts healing outcome and left ventricular remodelling: implications for FXIII therapy and antithrombin use in myocardial infarction. Eur Heart J. 2008 Feb;29(4):445-54. Read Abstract.
  • Nahrendorf M, Sosnovik D, Chen JW, Panizzi P, Figueiredo JL, Aikawa E, Libby P, Swirski FK, Weissleder R. Activatable magnetic resonance imaging agent reports myeloperoxidase activity in healing infarcts and noninvasively detects the antiinflammatory effects of atorvastatin on ischemia-reperfusion injury. Circulation. 2008 Mar 4;117(9):1153-60. Epub 2008 Feb 11. Read Abstract.

Immunology

  • Figueiredo JL, Passerotti CC, Sponholtz T, Nguyen HT, Weissleder R. A Novel Method of Imaging Calcium Urolithiasis Using Fluorescence. J Urol. 2008 Feb 21. Read Abstract.
  • Gupta V, Alonso JL, Sugimori T, Issafi M, Xiong JP, Arnaout MA. Role of the beta-subunit arginine/lysine finger in integrin heterodimer formation and function. J Immunol. 2008 Feb 1;180(3):1713-8. Read Abstract.
  • Haxhinasto S, Mathis D, Benoist C. The AKT-mTOR axis regulates de novo differentiation of CD4+Foxp3+ cells. J Exp Med. 2008 Feb 18. Read Abstract.

Nervous System

  • Chamberlain CE, Jeong J, Guo C, Allen BL, McMahon AP. Notochord-derived Shh concentrates in close association with the apically positioned basal body in neural target cells and forms a dynamic gradient during neural patterning. Development. 2008 Mar;135(6):1097-106. Epub 2008 Feb 13. Read Abstract.
  • Koprich JB, Reske-Nielsen C, Mithal P, Isacson O. Neuroinflammation mediated by IL-1 beta increases susceptibility of dopamine neurons to degeneration in an animal model of Parkinson's disease. J Neuroinflammation. 2008 Feb 27;5(1):8. Read Abstract.

Renal System

  • Murray PT, Devarajan P, Levey AS, Eckardt KU, Bonventre JV, Lombardi R, Herget-Rosenthal S, Levin A. A Framework and Key Research Questions in AKI Diagnosis and Staging in Different Environments. Clin J Am Soc Nephrol. 2008 Feb 20. Read Abstract.