Photo of Brendan D. Manning,  PhD

Brendan D. Manning, PhD

Harvard T.H. Chan School Of Public Health

Harvard T.H. Chan School Of Public Health
Phone: (617) 432-5614
Fax: (617) 432-5236


bmanning@hsph.harvard.edu

Brendan D. Manning, PhD

Harvard T.H. Chan School Of Public Health

EDUCATIONAL TITLES

  • Professor, Genetics and Complex Diseases, Harvard T.H. Chan School Of Public Health
  • Director, Program in the Biological Sciences of Public Health, Genetics and Complex Diseases, Harvard T.H. Chan School Of Public Health

DF/HCC PROGRAM AFFILIATION

Research Abstract

Research in the Manning laboratory is aimed at characterizing biochemical links between cell signaling networks and metabolic networks in both normal and cancer cells. The goal of this research is to reveal how signaling events propagated by growth factors, the availability of energy and nutrients, and exposure to environmental stresses are perceived and integrated to properly control cell growth and survival. Importantly, these integrated signaling networks are comprised of the oncogenes and tumor suppressors that underlie the majority of human cancers, and their altered functions in cancer cells disconnect these pathways from normal control mechanisms, leading to uncontrolled cell growth and survival. To elucidate the mechanistic basis of these regulatory networks, the laboratory uses a multi-tiered approach involving biochemistry, cell biology, genomics, proteomics, metabolomics, and animal models. We are particularly interested in pathways controlling and controlled by the products of the tumor suppressor genes, TSC1 and TSC2, mutated in the diseases tuberous sclerosis complex (TSC) and lymphangioleiomyomatosis (LAM). Our work in this field has defined the molecular link between these tumor suppressors and control of the nutrient-sensing protein kinase mammalian target of rapamycin (mTOR) by the PI3K-Akt pathway, one of the most frequently activated oncogenic signaling pathways. Using cell and mouse models, we are delineating the contributions and therapeutic opportunities arising from the aberrant activation of this pathway across diverse cancer lineages, with a focus on its impact on tumor cell metabolism.

Publications

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  • Zhang Y, Manning BD. mTORC1 signaling activates NRF1 to increase cellular proteasome levels. Cell Cycle 2015; 14:2011-7. PubMed
  • Priolo C, Ricoult SJ, Khabibullin D, Filippakis H, Yu J, Manning BD, Clish C, Henske EP. TSC2 Loss Increases Lysophosphatidylcholine Synthesis in Lymphangioleiomyomatosis. Am J Respir Cell Mol Biol 2015. PubMed
  • Dowdle WE, Nyfeler B, Nagel J, Elling RA, Liu S, Triantafellow E, Menon S, Wang Z, Honda A, Pardee G, Cantwell J, Luu C, Cornella-Taracido I, Harrington E, Fekkes P, Lei H, Fang Q, Digan ME, Burdick D, Powers AF, Helliwell SB, D'Aquin S, Bastien J, Wang H, Wiederschain D, Kuerth J, Bergman P, Schwalb D, Thomas J, Ugwonali S, Harbinski F, Tallarico J, Wilson CJ, Myer VE, Porter JA, Bussiere DE, Finan PM, Labow MA, Mao X, Hamann LG, Manning BD, Valdez RA, Nicholson T, Schirle M, Knapp MS, Keaney EP, Murphy LO. Selective VPS34 inhibitor blocks autophagy and uncovers a role for NCOA4 in ferritin degradation and iron homeostasis in vivo. Nat Cell Biol 2014. PubMed
  • Liu XS, Haines JE, Mehanna EK, Genet MD, Ben-Sahra I, Asara JM, Manning BD, Yuan ZM. ZBTB7A acts as a tumor suppressor through the transcriptional repression of glycolysis. Genes Dev 2014; 28:1917-28. PubMed
  • Kwiatkowski DJ, Manning BD. Molecular basis of giant cells in tuberous sclerosis complex. N Engl J Med 2014; 371:778-80. PubMed
  • Harputlugil E, Hine C, Vargas D, Robertson L, Manning BD, Mitchell JR. The TSC complex is required for the benefits of dietary protein restriction on stress resistance in vivo. Cell Rep 2014; 8:1160-70. PubMed
  • Zhang Y, Nicholatos J, Dreier JR, Ricoult SJ, Widenmaier SB, Hotamisligil GS, Kwiatkowski DJ, Manning BD. Coordinated regulation of protein synthesis and degradation by mTORC1. Nature 2014. PubMed
  • Lall R, Ganapathy S, Yang M, Xiao S, Xu T, Su H, Shadfan M, Asara JM, Ha CS, Ben-Sahra I, Manning BD, Little JB, Yuan ZM. Low-dose radiation exposure induces a HIF-1-mediated adaptive and protective metabolic response. Cell Death Differ 2014; 21:836-44. PubMed
  • Menon S, Dibble CC, Talbott G, Hoxhaj G, Valvezan AJ, Takahashi H, Cantley LC, Manning BD. Spatial control of the TSC complex integrates insulin and nutrient regulation of mTORC1 at the lysosome. Cell 2014; 156:771-85. PubMed
  • Liu P, Gan W, Inuzuka H, Lazorchak AS, Gao D, Arojo O, Liu D, Wan L, Zhai B, Yu Y, Yuan M, Kim BM, Shaik S, Menon S, Gygi SP, Lee TH, Asara JM, Manning BD, Blenis J, Su B, Wei W. Sin1 phosphorylation impairs mTORC2 complex integrity and inhibits downstream Akt signalling to suppress tumorigenesis. Nat Cell Biol 2013; 15:1340-50. PubMed
  • Kelsey I, Manning BD. mTORC1 status dictates tumor response to targeted therapeutics. Sci Signal 2013; 6:pe31. PubMed
  • Howell JJ, Ricoult SJ, Ben-Sahra I, Manning BD. A growing role for mTOR in promoting anabolic metabolism. Biochem Soc Trans 2013; 41:906-12. PubMed
  • Liu Y, Marks K, Cowley GS, Carretero J, Liu Q, Nieland TJ, Xu C, Cohoon TJ, Gao P, Zhang Y, Chen Z, Altabef AB, Tchaicha JH, Wang X, Choe S, Driggers EM, Zhang J, Bailey ST, Sharpless NE, Hayes DN, Patel NM, Janne PA, Bardeesy N, Engelman JA, Manning BD, Shaw RJ, Asara JM, Scully R, Kimmelman A, Byers LA, Gibbons DL, Wistuba II, Heymach JV, Kwiatkowski DJ, Kim WY, Kung AL, Gray NS, Root DE, Cantley LC, Wong KK. Metabolic and functional genomic studies identify deoxythymidylate kinase as a target in LKB1-mutant lung cancer. 2013; 3:870-9. PubMed
  • Ersoy BA, Tarun A, D'Aquino K, Hancer NJ, Ukomadu C, White MF, Michel T, Manning BD, Cohen DE. Phosphatidylcholine transfer protein interacts with thioesterase superfamily member 2 to attenuate insulin signaling. Sci Signal 2013; 6:ra64. PubMed
  • Menon S, Manning BD. Cell signalling: nutrient sensing lost in cancer. Nature 2013; 498:444-5. PubMed
  • Manning BD. Adaptation to starvation: translating a matter of life or death. Cancer Cell 2013; 23:713-5. PubMed
  • Dibble CC, Manning BD. Signal integration by mTORC1 coordinates nutrient input with biosynthetic output. Nat Cell Biol 2013; 15:555-64. PubMed
  • Ben-Sahra I, Howell JJ, Asara JM, Manning BD. Stimulation of de novo pyrimidine synthesis by growth signaling through mTOR and S6K1. Science 2013; 339:1323-8. PubMed
  • Ricoult SJ, Manning BD. The multifaceted role of mTORC1 in the control of lipid metabolism. EMBO Rep. 2013; 14:242-51. PubMed
  • Byles V, Covarrubias AJ, Ben-Sahra I, Lamming DW, Sabatini DM, Manning BD, Horng T. The TSC-mTOR pathway regulates macrophage polarization. Nat Commun 2013; 4:2834. PubMed
  • Dibble CC, Elis W, Menon S, Qin W, Klekota J, Asara JM, Finan PM, Kwiatkowski DJ, Murphy LO, Manning BD. TBC1D7 Is a Third Subunit of the TSC1-TSC2 Complex Upstream of mTORC1. Mol Cell 2012; 47:535-46. PubMed
  • Menon S, Yecies JL, Zhang HH, Howell JJ, Nicholatos J, Harputlugil E, Bronson RT, Kwiatkowski DJ, Manning BD. Chronic Activation of mTOR Complex 1 Is Sufficient to Cause Hepatocellular Carcinoma in Mice. Sci Signal 2012; 5:ra24. PubMed
  • Auricchio N, Malinowska I, Shaw R, Manning BD, Kwiatkowski DJ. Therapeutic Trial of Metformin and Bortezomib in a Mouse Model of Tuberous Sclerosis Complex (TSC). PLoS ONE 2012; 7:e31900. PubMed
  • Manning BD. Comment on "A dynamic network model of mTOR signaling reveals TSC-independent mTORC2 regulation": building a model of the mTOR signaling network with a potentially faulty tool. Sci Signal 2012; 5:lc3; author reply lc4. PubMed
  • Tanaka K, Babic I, Nathanson D, Akhavan D, Guo D, Gini B, Dang J, Zhu S, Yang H, de Jesus J, Amzajerdi AN, Zhang Y, Dibble CC, Dan H, Rinkenbaugh A, Yong WH, Vinters HV, Gera JF, Cavenee WK, Cloughesy TF, Manning BD, Baldwin AS, Mischel PS. Oncogenic EGFR signaling activates an mTORC2-NF-虜B pathway that promotes chemotherapy resistance. 2011; 1:524-538. PubMed
  • De Raedt T, Walton Z, Yecies JL, Li D, Chen Y, Malone CF, Maertens O, Jeong SM, Bronson RT, Lebleu V, Kalluri R, Normant E, Haigis MC, Manning BD, Wong KK, Macleod KF, Cichowski K. Exploiting cancer cell vulnerabilities to develop a combination therapy for ras-driven tumors. Cancer Cell 2011; 20:400-13. PubMed
  • Yecies JL, Zhang HH, Menon S, Liu S, Yecies D, Lipovsky AI, Gorgun C, Kwiatkowski DJ, Hotamisligil GS, Lee CH, Manning BD. Akt stimulates hepatic SREBP1c and lipogenesis through parallel mTORC1-dependent and independent pathways. Cell Metab 2011; 14:21-32. PubMed
  • Yecies JL, Manning BD. Transcriptional control of cellular metabolism by mTOR signaling. Cancer Res 2011; 71:2815-20. PubMed
  • Howell JJ, Manning BD. mTOR couples cellular nutrient sensing to organismal metabolic homeostasis. Trends Endocrinol Metab 2011; 22:94-102. PubMed
  • Yecies JL, Manning BD. mTOR links oncogenic signaling to tumor cell metabolism. J Mol Med 2011; 89:221-8. PubMed
  • Manning BD. Insulin signaling: inositol phosphates get into the Akt. Cell 2010; 143:861-3. PubMed
  • Düvel K, Yecies JL, Menon S, Raman P, Lipovsky AI, Souza AL, Triantafellow E, Ma Q, Gorski R, Cleaver S, Vander Heiden MG, MacKeigan JP, Finan PM, Clish CB, Murphy LO, Manning BD. Activation of a metabolic gene regulatory network downstream of mTOR complex 1. Mol Cell 2010; 39:171-83. PubMed
  • Yecies JL, Manning BD. Chewing the fat on tumor cell metabolism. Cell 2010; 140:28-30. PubMed
  • Dibble CC, Asara JM, Manning BD. Characterization of Rictor phosphorylation sites reveals direct regulation of mTOR complex 2 by S6K1. Mol Cell Biol 2009; 29:5657-70. PubMed
  • Dibble CC, Manning BD. A molecular link between AKT regulation and chemotherapeutic response. Cancer Cell 2009; 16:178-80. PubMed
  • James MF,Han S,Polizzano C,Plotkin SR,Manning BD,Stemmer-Rachamimov AO,Gusella JF,Ramesh V. NF2/Merlin is a Novel Negative Regulator of mTOR Complex 1 and Activation of mTORC1 is Associated with Meningioma and Schwannoma Growth. Mol Cell Biol 2009; 29:4250-61. PubMed
  • Huang J, Wu S, Wu CL, Manning BD. Signaling events downstream of mammalian target of rapamycin complex 2 are attenuated in cells and tumors deficient for the tuberous sclerosis complex tumor suppressors. Cancer Res 2009; 69:6107-14. PubMed
  • Huang J, Manning BD. A complex interplay between Akt, TSC2 and the two mTOR complexes. Biochem Soc Trans 2009; 37:217-22. PubMed
  • Zhang HH, Huang J, Düvel K, Boback B, Wu S, Squillace RM, Wu CL, Manning BD. Insulin stimulates adipogenesis through the Akt-TSC2-mTORC1 pathway. PLoS ONE 2009; 4:e6189. PubMed
  • Manning BD. Challenges and opportunities in defining the essential cancer kinome. Sci Signal 2009; 2:pe15. PubMed
  • Chakrabarti P, Anno T, Manning BD, Luo Z, Kandror KV. The mammalian target of rapamycin complex 1 regulates leptin biosynthesis in adipocytes at the level of translation: the role of the 5'-untranslated region in the expression of leptin messenger ribonucleic acid. Mol Endocrinol 2008; 22:2260-7. PubMed
  • Huang J, Manning BD. The TSC1-TSC2 complex: a molecular switchboard controlling cell growth. Biochem J 2008; 412:179-90. PubMed
  • Huang J, Dibble CC, Matsuzaki M, Manning BD. The TSC1-TSC2 complex is required for proper activation of mTOR complex 2. Mol Cell Biol 2008; 28:4104-15. PubMed
  • Ozcan U, Ozcan L, Yilmaz E, Duvel K, Sahin M, Manning BD, Hotamisligil GS. Loss of the tuberous sclerosis complex tumor suppressors triggers the unfolded protein response to regulate insulin signaling and apoptosis. Mol Cell 2008; 29:541-51. PubMed
  • Manning BD, Cantley LC. AKT/PKB signaling: navigating downstream. Cell 2007; 129:1261-74. PubMed
  • Zhang HH, Lipovsky AI, Dibble CC, Sahin M, Manning BD. S6K1 regulates GSK3 under conditions of mTOR-dependent feedback inhibition of Akt. Mol Cell 2006; 24:185-97. PubMed
  • Sodhi A, Chaisuparat R, Hu J, Ramsdell AK, Manning BD, Sausville EA, Sawai ET, Molinolo A, Gutkind JS, Montaner S. The TSC2/mTOR pathway drives endothelial cell transformation induced by the Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor. Cancer Cell 2006; 10:133-43. PubMed
  • Kwiatkowski DJ, Manning BD. Tuberous sclerosis: a GAP at the crossroads of multiple signaling pathways. Hum Mol Genet 2005; 14 Spec No. 2:R251-8. PubMed
  • Manning BD,Logsdon MN,Lipovsky AI,Abbott D,Kwiatkowski DJ,Cantley LC. Feedback inhibition of Akt signaling limits the growth of tumors lacking Tsc2. Genes Dev 2005; 19:1773-8. PubMed
  • Brugarolas J, Lei K, Hurley RL, Manning BD, Reiling JH, Hafen E, Witters LA, Ellisen LW, Kaelin WG. Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex. Genes Dev 2004; 18:2893-904. PubMed
  • Manning BD. Balancing Akt with S6K: implications for both metabolic diseases and tumorigenesis. J Cell Biol 2004; 167:399-403. PubMed
  • Shaw RJ, Bardeesy N, Manning BD, Lopez L, Kosmatka M, DePinho RA, Cantley LC. The LKB1 tumor suppressor negatively regulates mTOR signaling. Cancer Cell 2004; 6:91-9. PubMed
  • Manning BD, Cantley LC. Rheb fills a GAP between TSC and TOR. Trends Biochem Sci 2003; 28:573-6. PubMed
  • Luo J, Manning BD, Cantley LC. Targeting the PI3K-Akt pathway in human cancer: rationale and promise. Cancer Cell 2003; 4:257-62. PubMed
  • Tee AR, Manning BD, Roux PP, Cantley LC, Blenis J. Tuberous sclerosis complex gene products, Tuberin and Hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb. Curr Biol 2003; 13:1259-68. PubMed
  • Manning BD, Cantley LC. United at last: the tuberous sclerosis complex gene products connect the phosphoinositide 3-kinase/Akt pathway to mammalian target of rapamycin (mTOR) signalling. Biochem Soc Trans 2003; 31:573-8. PubMed
  • Manning BD, Cantley LC. Hitting the target: emerging technologies in the search for kinase substrates. Sci STKE 2002; 2002:PE49. PubMed
  • Tee AR, Fingar DC, Manning BD, Kwiatkowski DJ, Cantley LC, Blenis J. Tuberous sclerosis complex-1 and -2 gene products function together to inhibit mammalian target of rapamycin (mTOR)-mediated downstream signaling. Proc Natl Acad Sci U S A 2002; 99:13571-6. PubMed
  • Manning BD, Tee AR, Logsdon MN, Blenis J, Cantley LC. Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway. Mol Cell 2002; 10:151-62. PubMed
  • Barrett JG, Manning BD, Snyder M. The Kar3p kinesin-related protein forms a novel heterodimeric structure with its associated protein Cik1p. Mol Biol Cell 2000; 11:2373-85. PubMed
  • Manning BD, Snyder M. Drivers and passengers wanted! the role of kinesin-associated proteins. Trends Cell Biol 2000; 10:281-9. PubMed
  • Manning BD, Barrett JG, Wallace JA, Granok H, Snyder M. Differential regulation of the Kar3p kinesin-related protein by two associated proteins, Cik1p and Vik1p. J Cell Biol 1999; 144:1219-33. PubMed
  • Manning BD, Padmanabha R, Snyder M. The Rho-GEF Rom2p localizes to sites of polarized cell growth and participates in cytoskeletal functions in Saccharomyces cerevisiae. Mol Biol Cell 1997; 8:1829-44. PubMed
  • Lessie TG, Hendrickson W, Manning BD, Devereux R. Genomic complexity and plasticity of Burkholderia cepacia. FEMS Microbiol Lett 1996; 144:117-28. PubMed
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