Explore This Lab

Overview

The focus of research in the Laboratory of Bin Zheng, PhD, at Massachusetts General Hospital is metabolic signaling in melanoma. We are interested in understanding how rewired metabolism in cancer cells is coordinated with other hallmarks of cancer to influence caner initiation, promotion and progression.

Approximately half of all melanomas harbor an activating mutation in BRAF (BRAFV600E) that drives cancer growth due to the constitutive activation of the downstream MEK/ERK pathway. The “addiction” of melanomas harboring this BRAF mutation has stimulated the development of BRAF inhibitors (BRAFi) such as vemurafenib and dabrafenib. These BRAFi have shown great clinical benefits in malignant melanoma with BRAFV600E mutations in the initial phase of treatment. However, the vast majority of the responsive melanoma patients treated with BRAF inhibitors develop resistance during the course of treatment and relapsed.

In addition to the BRAF-targeted therapy, another recent major groundbreaking approach in melanoma treatment is to target the immune checkpoints that exploit melanoma’s intrinsically high immunogenicity. Biological drugs that target CTLA-4, PD-1 or PD-L1 have shown significant clinical benefits in melanoma patients with a high degree of durable responses, but only in a subset of patients. Therefore, improving the response rates of immunotherapies and overcoming BRAFi resistance represent two of the greatest challenges facing this field.

The overarching goal of our research is to address this by gaining a better understanding of metabolic programming in melanoma and to translate these basic research findings into better strategies for melanoma prevention, diagnosis and treatment. Preclinical work from our laboratory on AMPK and phenformin have led to a phase I clinical trial evaluating phenformin with the dabrafenib BRAF inhibitor and trametinib MEK inhibitor combination in patients with BRAF mutant melanoma.

We currently focus on the following areas of research:

1) BRAF-dependent metabolic wiring and rewiring
2) Metabolic heterogeneity in cancer
3) Metabolic regulation of tumor immunity
4) Roles of AMPK at the interface of metabolism and cancer
5) Reviving phenformin for cancer therapy


Publications

Selected Publications

Swanson KD, Zheng B. Supplementing Cancer? Mol Cell. 2018 Mar 15;69(6):917-918. doi: 10.1016/j.molcel.2018.02.036. PubMed PMID: 29547718.

Kim SH, Li M, Trousil S, Zhang Y, Pasca di Magliano M, Swanson KD, Zheng B. Phenformin Inhibits Myeloid-Derived Suppressor Cells and Enhances the Anti-Tumor Activity of PD-1 Blockade in Melanoma. J Invest Dermatol. 2017 Aug;137(8):1740-1748. doi: 10.1016/j.jid.2017.03.033. Epub 2017 Apr 19. PubMed PMID: 28433543.

Trousil S, Chen S, Mu C, Shaw FM, Yao Z, Ran Y, Shakuntala T, Merghoub T,Manstein D, Rosen N, Cantley LC, Zippin JH, Zheng B. Phenformin Enhances the Efficacy of ERK Inhibition in NF1-Mutant Melanoma. J Invest Dermatol. 2017 May;137(5):1135-1143. doi: 10.1016/j.jid.2017.01.013. Epub 2017 Jan 28. PubMed PMID: 28143781

Wu L, Zhou B, Oshiro-Rapley N, Li M, Paulo JA, Webster CM, Mou F, Kacergis MC, Talkowski ME, Carr CE, Gygi SP, Zheng B, Soukas AA. An Ancient, Unified Mechanism for Metformin Growth Inhibition in C. elegans and Cancer. Cell. 2016 Dec 15;167(7):1705-1718.e13. doi: 10.1016/j.cell.2016.11.055. PubMed PMID: 27984722

Shen CH, Kim SH, Trousil S, Frederick DT, Piris A, Yuan P, Cai L, Gu L, Li M, Lee JH, Mitra D, Fisher DE, Sullivan RJ, Flaherty KT, Zheng B. Loss of cohesion complex components STAG2 or STAG3 confers resistance to BRAF inhibition in melanoma. Nat Med. 2016 Sep;22(9):1056-61. doi: 10.1038/nm.4155. Epub 2016 Aug 8. PubMed PMID: 27500726

Trousil S, Zheng B. Addicted to AA (Acetoacetate): A Point of Convergence between Metabolism and BRAF Signaling. Mol Cell. 2015 Aug 6;59(3):333-4. doi: 10.1016/j.molcel.2015.07.024. PubMed PMID: 26253025

Zheng B, Fisher DE. Metabolic vulnerability in melanoma: a ME2 (me too) story. J Invest Dermatol. 2015 Mar;135(3):657-659. doi: 10.1038/jid.2014.449. PubMed PMID: 25666673

Shen CH, Yuan P, Perez-Lorenzo R, Zhang Y, Lee SX, Ou Y, Asara JM, Cantley LC, Zheng B. Phosphorylation of BRAF by AMPK impairs BRAF-KSR1 association and cell proliferation. Mol Cell. 2013 Oct 24;52(2):161-72. doi:10.1016/j.molcel.2013.08.044. Epub 2013 Oct 3. PubMed PMID: 24095280

Yuan P, Ito K, Perez-Lorenzo R, Del Guzzo C, Lee JH, Shen CH, Bosenberg MW, McMahon M, Cantley LC, Zheng B. Phenformin enhances the therapeutic benefit of BRAF(V600E) inhibition in melanoma. Proc Natl Acad Sci U S A. 2013 Nov 5;110(45):18226-31. doi: 10.1073/pnas.1317577110. Epub 2013 Oct 21. PubMed PMID: 24145418

Wu N, Zheng B, Shaywitz A, Dagon Y, Tower C, Bellinger G, Shen CH, Wen J, Asara J, McGraw TE, Kahn BB, Cantley LC. AMPK-dependent degradation of TXNIP upon energy stress leads to enhanced glucose uptake via GLUT1. Mol Cell. 2013 Mar 28;49(6):1167-75. doi: 10.1016/j.molcel.2013.01.035. Epub 2013 Feb 28. PubMed PMID: 23453806

Dagon Y, Hur E, Zheng B, Wellenstein K, Cantley LC, Kahn BB. p70S6 kinase phosphorylates AMPK on serine 491 to mediate leptin's effect on food intake. Cell Metab. 2012 Jul 3;16(1):104-12. doi: 10.1016/j.cmet.2012.05.010. Epub 2012 Jun 21. PubMed PMID: 22727014

Tsou P, Zheng B, Hsu CH, Sasaki AT, Cantley LC. A fluorescent reporter of AMPK activity and cellular energy stress. Cell Metab. 2011 Apr 6;13(4):476-486. doi: 10.1016/j.cmet.2011.03.006. PubMed PMID: 21459332

Amato S, Liu X, Zheng B, Cantley L, Rakic P, Man HY. AMP-activated protein kinase regulates neuronal polarization by interfering with PI 3-kinase localization. Science. 2011 Apr 8;332(6026):247-51. doi: 10.1126/science.1201678. Epub 2011 Mar 24. PubMed PMID: 21436401

Li Y, Xu S, Mihaylova MM, Zheng B, Hou X, Jiang B, Park O, Luo Z, Lefai E, Shyy JY, Gao B, Wierzbicki M, Verbeuren TJ, Shaw RJ, Cohen RA, Zang M. AMPK phosphorylates and inhibits SREBP activity to attenuate hepatic steatosis and atherosclerosis in diet-induced insulin-resistant mice. Cell Metab. 2011 Apr 6;13(4):376-388. doi: 10.1016/j.cmet.2011.03.009. PubMed PMID: 21459323

Zheng B, Jeong JH, Asara JM, Yuan YY, Granter SR, Chin L, Cantley LC. Oncogenic B-RAF negatively regulates the tumor suppressor LKB1 to promote melanoma cell proliferation. Mol Cell. 2009 Jan 30;33(2):237-47. doi: 10.1016/j.molcel.2008.12.026. PubMed PMID: 19187764

Tang T, Zheng B, Chen SH, Murphy AN, Kudlicka K, Zhou H, Farquhar MG. hNOA1 interacts with complex I and DAP3 and regulates mitochondrial respiration and apoptosis. J Biol Chem. 2009 Feb 20;284(8):5414-24. doi: 10.1074/jbc.M807797200. Epub 2008 Dec 22. PubMed PMID: 19103604

Zheng B, Cantley LC. Regulation of epithelial tight junction assembly and disassembly by AMP-activated protein kinase. Proc Natl Acad Sci U S A. 2007 Jan 16;104(3):819-22. Epub 2007 Jan 4. PubMed PMID: 17204563

Asara JM, Zhang X, Zheng B, Maroney LA, Christofk HR, Wu N, Cantley LC. In-gel stable isotope labeling for relative quantification using mass spectrometry. Nat Protoc. 2006;1(1):46-51. PubMed PMID: 17406210.

Zheng B, Tang T, Tang N, Kudlicka K, Ohtsubo K, Ma P, Marth JD, Farquhar MG, Lehtonen E. Essential role of RGS-PX1/sorting nexin 13 in mouse development and regulation of endocytosis dynamics. Proc Natl Acad Sci U S A. 2006 Nov 7;103(45):16776-81. Epub 2006 Oct 31. PubMed PMID: 17077144

Zheng B, Lavoie C, Tang TD, Ma P, Meerloo T, Beas A, Farquhar MG. Regulation of epidermal growth factor receptor degradation by heterotrimeric Galphas protein. Mol Biol Cell. 2004 Dec;15(12):5538-50. Epub 2004 Oct 6. PubMed PMID: 15469987

Zheng B, Berrie CP, Corda D, Farquhar MG. GDE1/MIR16 is a glycerophosphoinositol phosphodiesterase regulated by stimulation of G protein-coupled receptors. Proc Natl Acad Sci U S A. 2003 Feb 18;100(4):1745-50. Epub 2003 Feb 7. PubMed PMID: 12576545

Zheng B, Ma YC, Ostrom RS, Lavoie C, Gill GN, Insel PA, Huang XY, Farquhar MG. RGS-PX1, a GAP for GalphaS and sorting nexin in vesicular trafficking. Science. 2001 Nov 30;294(5548):1939-42. PubMed PMID: 11729322.

Zheng B, Chen D, Farquhar MG. MIR16, a putative membrane glycerophosphodiester phosphodiesterase, interacts with RGS16. Proc Natl Acad Sci U S A. 2000 Apr 11;97(8):3999-4004. PubMed PMID: 10760272

De Vries L, Zheng B, Fischer T, Elenko E, Farquhar MG. The regulator of G protein signaling family. Annu Rev Pharmacol Toxicol. 2000;40:235-71. Review. PubMed PMID: 10836135.

Zheng B, De Vries L, Gist Farquhar M. Divergence of RGS proteins: evidence for the existence of six mammalian RGS subfamilies. Trends Biochem Sci. 1999 Nov;24(11):411-4. Review. PubMed PMID: 10542401.

Full list of publications