Explore This Lab

Overview

Our laboratory is working to decipher the molecular alterations in metabolic regulation and signal transduction that drives cancer, with a focus on melanoma. Our goal is to translate these findings into personalized targeted and immunotherapies, contributing to finding cures for melanoma. 

Approximately half of all cutaneous melanomas harbor a mutation in BRAF (BRAF V600E) that drives cancer growth by constitutively activating downstream MEK/ERK signaling. The “addiction” of melanomas harboring this mutation has stimulated the development of BRAF inhibitors (BRAFi), including Vemurafenib and Dabrafenib. These BRAFi show great clinical benefit in malignant melanoma with BRAF V600E mutations in the initial phase of treatment. However, the vast majority of the responsive patients treated with these inhibitors develop resistance and relapse during the course of treatment. In addition to BRAF-targeted therapy, another recent groundbreaking approach in melanoma treatment involves targeting the immune checkpoints that counter melanoma’s intrinsically high immunogenicity. Biological drugs that target PD-1 or PD-L1 have shown significant clinical benefit in melanoma patients and have produced a high degree of durable responses, However, these outcomes are only achieved in a subset of patients. Therefore, overcoming BRAFi resistance and improving the response rates of immune checkpoint blockade therapies and represent two of the greatest challenges facing this field. The central goal of our research is to address these outstanding problems by gaining a better understanding of metabolic programming and signal transduction in melanoma and translate these basic research findings into better strategies for melanoma prevention, diagnosis and treatment. Preclinical work from our laboratory on a central metabolic regulator, AMP activated protein kinase (AMPK) and repurposing of phenformin, a previously approved diabetes drug,  provided the basis for a Phase I clinical trial evaluating phenformin with the dabrafenib BRAF inhibitor and trametinib MEK inhibitor combination in patients with BRAF mutant melanoma (clinicaltrials.gov. NCT03026517).

We have been working on the following specific projects: 

  • Metabolic regulation of tumor immunity. We are pursuing the characterization of the metabolic vulnerabilities of myeloid-derived suppressor cells (MDSCs). MDSC is a major immune cell type that contributes to tumor-induced immune suppression and evasion of immune elimination. Importantly, MDSCs have been suggested to contribute to resistance to various cancer therapies in melanoma, including to anti-CTLA-4 and anti-PD-1 blockade. Hence, targeting MDSCs presents an attractive approach to modulate tumor immunity to improve current cancer immunotherapies.
  • Roles of AMPK at the interface of metabolism and cancer. We have an interest in understanding the role of AMPK in melanoma tumor development and progression. We are investigating downstream metabolic targets of AMPK in melanoma cells. In addition, we are characterizing the role of AMPK in modulating the function of MDSCs in the tumor microenvironment.  
  • Repurposing phenformin for cancer therapy. We continue to elucidate the mechanism of action for the anti-tumor activities of phenformin, and to facilitate the translational studies on repurposing phenformin for cancer prevention and treatment. 
  • Metabolic rewiring and BRAFi resistance. We are exploring metabolic changes that occur during the development of BRAFi resistance in melanoma and characterizing metabolic vulnerabilities that can be targeted to overcome BRAFi resistance in melanoma. These efforts may lead to better combinatory therapeutic strategies in melanoma. 
  • Metabolic heterogeneity in melanoma. Intratumor phenotypic heterogeneity has been shown to influence drug resistance and metastasis. In melanoma, a slow-cycling subpopulation of cells that is marked by expression of the H3K4 histone lysine demethylase KDM5B has previously been identified. We are therefore characterizing KDM5B-dependent metabolic heterogeneity in melanoma and explore its therapeutic implications.
  •  Alterations of 3D genome organization in melanoma. Mammalian genomes are folded in a highly organized fashion within the nucleus. The cohesin complex participates in the required 3D organization that regulates gene expression through generating and maintaining DNA loops. We recently discovered that loss of the tumor suppressor STAG2, which encodes a core subunit of the cohesin complex, as a novel mechanism of resistance to BRAF pathway inhibition in melanoma. We are currently characterizing direct targets of STAG2 in melanoma through various cutting edge epigenomic approaches, which will provide insights into how STAG2 contributes to malignant phenotypes in cancer.

 


Publications

Selected Publications

Zhou, Q., Kim, S. H., Pérez-Lorenzo, R., Liu, C., Huang, M., Dotto, G. P., Zheng, B*., & Wu, X*. 2020. Phenformin Promotes Keratinocyte Differentiation via the Calcineurin/NFAT Pathway. J. Inv. Derm.  S0022-202X(20)31732-2. Advance online publication. Published: June 30, 2020. (* equal contributions).

 

Zhao H, Zheng B. Dual Targeting of Autophagy and MEK in KRAS Mutant Cancer. Trends Cancer. 2019 Jun;5(6):327-329. doi: 10.1016/j.trecan.2019.04.003. Epub 2019 May 7. PubMed PMID: 31208693.

 

Strub T, Ghiraldini FG, Carcamo S, Li M, Wroblewska A, Singh R, Goldberg MS, Hasson D, Wang Z, Gallagher SJ, Hersey P, Ma'ayan A, Long GV, Scolyer RA, Brown B, Zheng B, Bernstein E. 2018. SIRT6 haploinsufficiency induces BRAF melanoma cell resistance to MAPK inhibitors via IGF signaling. Nat Commun. 2018; 9:3440.


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