Lixin Wan, PhD

The Wan lab is focused on the regulation and role of Anaphase-Promoting Complexes (APC) in directing the destruction of key proteins that control transit through the cell cycle, and in shaping proteomic networks in normal versus cancer cells. The lab is now investigating how APC complexes are rewired in cancer cells, and during the acquisition of resistance to targeted and conventional therapeutics. The long term goal of the lab is to define vulnerabilities in these circuits to develop novel anti-cancer therapies.

Associations

• Molecular Oncology
• Cutaneous Oncology
• Molecular Medicine Program
• Melanoma & Skin Cancer Center of Excellence

Education & Training

Graduate:

• Chinese Academy of Sciences, PhD - Molecular Biology

Fellowship:

• Beth Israel Deaconess Medical Center Harvard Medical School - Pathology

• Liu X, Gillis N, Jiang C, McCofie A, Shaw TI, Tan AC, Zhao B, Wan L, Duckett DR, Teng M. An Epigenomic fingerprint of human cancers by landscape interrogation of super enhancers at the constituent level. PLoS Comput Biol. 2024 Feb.20(2):e1011873. Pubmedid: 38335222. Pmcid: PMC10883583.
• Yin T, Wang G, Wang L, Mudgal P, Wang E, Pan CC, Alexander PB, Wu H, Cao C, Liang Y, Tan L, Huang D, Chong M, Chen R, Lim BJW, Xiang K, Xue W, Wan L, Hu H, Loh YH, Wang XF, Li QJ. Breaking NGF-TrkA immunosuppression in melanoma sensitizes immunotherapy for durable memory T cell protection. Nat Immunol. 2024 Feb.25(2):268-281. Pubmedid: 38195702.
• Riley AK, Grant M, Snell A, Vichas A, Moorthi S, Urisman A, Castel P, Wan L, Berger AH. The deubiquitinase USP9X regulates RIT1 protein abundance and oncogenic phenotypes. bioRxiv. 2023 Dec. Pubmedid: 38077017. Pmcid: PMC10705424.
• Ullah R, Yin Q, Snell AH, Wan L. RAF-MEK-ERK pathway in cancer evolution and treatment. Semin Cancer Biol. 2022 Oct.85:123-154. Pubmedid: 33992782.
• Liu CH, Rao Y, Gao D, Wan L, Zhang L. Editorial: Ubiquitin Code: From Cell Biology to Translational Medicine. Front Cell Dev Biol. 2021 Oct.9:791967. Pubmedid: 34778279. Pmcid: PMC8581446.
• Dai X, Bu X, Gao Y, Guo J, Hu J, Jiang C, Zhang Z, Xu K, Duan J, He S, Zhang J, Wan L, Liu T, Zhou X, Hung MC, Freeman GJ, Wei W. Energy status dictates PD-L1 protein abundance and anti-tumor immunity to enable checkpoint blockade. Mol Cell. 2021 Jun.81(11):2317-2331.e6. Pubmedid: 33909988. Pmcid: PMC8178223.
• Liu J, Peng Y, Shi L, Wan L, Inuzuka H, Long J, Guo J, Zhang J, Yuan M, Zhang S, Wang X, Gao J, Dai X, Furumoto S, Jia L, Pandolfi PP, Asara JM, Kaelin WG, Liu J, Wei W. Skp2 dictates cell cycle-dependent metabolic oscillation between glycolysis and TCA cycle. Cell Res. 2021 Jan.31(1):80-93. Pubmedid: 32669607. Pmcid: PMC7852548.
• Liu J, Peng Y, Shi L, Wan L, Inuzuka H, Long J, Guo J, Zhang J, Yuan M, Zhang S, Wang X, Gao J, Dai X, Furumoto S, Jia L, Pandolfi PP, Asara JM, Kaelin WG, Liu J, Wei W. Author Correction: Skp2 dictates cell cycle-dependent metabolic oscillation between glycolysis and TCA cycle. Cell Res. 2021 Jan.31(1):104. Pubmedid: 32859994. Pmcid: PMC7852582.
• Mo Q, Wan L, Schell MJ, Jim H, Tworoger SS, Peng G. Integrative Analysis Identifies Multi-Omics Signatures That Drive Molecular Classification of Uveal Melanoma. Cancers (Basel). 2021 Dec.13(24). Pubmedid: 34944787. Pmcid: PMC8699355.
• Deng J, Hua L, Han T, Tian M, Wang D, Tang H, Sun S, Chen H, Cheng H, Zhang T, Xie Q, Wan L, Zhu H, Gong Y. The CREB-binding protein inhibitor ICG-001: a promising therapeutic strategy in sporadic meningioma with NF2 mutations. Neurooncol Adv. 2020 Feb.2(1):vdz055. Pubmedid: 32642722. Pmcid: PMC7212891.
• Yin Q, Wyatt CJ, Han T, Smalley KSM, Wan L. ITCH as a potential therapeutic target in human cancers. Semin Cancer Biol. 2020 Dec.67(Pt 2):117-130. Pubmedid: 32165318. Pmcid: PMC7724637.
• Lee YR, Chen M, Lee JD, Zhang J, Lin SY, Fu TM, Chen H, Ishikawa T, Chiang SY, Katon J, Zhang Y, Shulga YV, Bester AC, Fung J, Monteleone E, Wan L, Shen C, Hsu CH, Papa A, Clohessy JG, Teruya-Feldstein J, Jain S, Wu H, Matesic L, Chen RH, Wei W, Pandolfi PP. Reactivation of PTEN tumor suppressor for cancer treatment through inhibition of a MYC-WWP1 inhibitory pathway. Science. 2019 May.364(6441). Pubmedid: 31097636. Pmcid: PMC7081834.
• 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. Author Correction: Sin1 phosphorylation impairs mTORC2 complex integrity and inhibits downstream Akt signalling to suppress tumorigenesis. Nat Cell Biol. 2019 May.21(5):662-663. Pubmedid: 30783264.
• Emmons MF, Faião-Flores F, Sharma R, Thapa R, Messina JL, Becker JC, Schadendorf D, Seto E, Sondak VK, Koomen JM, Chen YA, Lau EK, Wan L, Licht JD, Smalley KSM. HDAC8 Regulates a Stress Response Pathway in Melanoma to Mediate Escape from BRAF Inhibitor Therapy. Cancer Res. 2019 Jun.79(11):2947-2961. Pubmedid: 30987999. Pmcid: PMC6548652.
• Hill KS, Roberts ER, Wang X, Marin E, Park TD, Son S, Ren Y, Fang B, Yoder S, Kim S, Wan L, Sarnaik AA, Koomen JM, Messina JL, Teer JK, Kim Y, Wu J, Chalfant CE, Kim M. PTPN11 Plays Oncogenic Roles and Is a Therapeutic Target for BRAF Wild-Type Melanomas. Mol Cancer Res. 2019 Feb.17(2):583-593. Pubmedid: 30355677. Pmcid: PMC6386183.
• Han T, Jiang S, Zheng H, Yin Q, Xie M, Little MR, Yin X, Chen M, Song SJ, Beg AA, Pandolfi PP, Wan L. Interplay between c-Src and the APC/C co-activator Cdh1 regulates mammary tumorigenesis. Nat Commun. 2019 Aug.10(1):3716. Pubmedid: 31420536. Pmcid: PMC6697746.
• Yin Q, Han T, Fang B, Zhang G, Zhang C, Roberts ER, Izumi V, Zheng M, Jiang S, Yin X, Kim M, Cai J, Haura EB, Koomen JM, Smalley KSM, Wan L. K27-linked ubiquitination of BRAF by ITCH engages cytokine response to maintain MEK-ERK signaling. Nat Commun. 2019 Apr.10(1):1870. Pubmedid: 31015455. Pmcid: PMC6478693.
• Han T, Yin Q, Wan L. Cycling for renewal: Cell cycle machinery maintains prostate cancer stem-like cells. EBioMedicine. 2019 Apr.42:24-25. Pubmedid: 30930046. Pmcid: PMC6491876.
• Huang LY, Zhao J, Chen H, Wan L, Inuzuka H, Guo J, Fu X, Zhai Y, Lu Z, Wang X, Han ZG, Sun Y, Wei W. SCF-mediated degradation of Brg1 suppresses gastric cancer metastasis. Nat Commun. 2018 Sep.9(1):3569. Pubmedid: 30177679. Pmcid: PMC6120942.
• Chen M, Wan L, Zhang J, Zhang J, Mendez L, Clohessy JG, Berry K, Victor J, Yin Q, Zhu Y, Wei W, Pandolfi PP. Deregulated PP1α phosphatase activity towards MAPK activation is antagonized by a tumor suppressive failsafe mechanism. Nat Commun. 2018 Jan.9(1):159. Pubmedid: 29335436. Pmcid: PMC5768788.
• Zhu B, Chen S, Wang H, Yin C, Han C, Peng C, Liu Z, Wan L, Zhang X, Zhang J, Lian CG, Ma P, Xu ZX, Prince S, Wang T, Gao X, Shi Y, Liu D, Liu M, Wei W, Wei Z, Pan J, Wang Y, Xuan Z, Hess J, Hayward NK, Goding CR, Chen X, Zhou J, Cui R. The protective role of DOT1L in UV-induced melanomagenesis. Nat Commun. 2018 Jan.9(1):259. Pubmedid: 29343685. Pmcid: PMC5772495.
• Wan L, Xu K, Wei Y, Zhang J, Han T, Fry C, Zhang Z, Wang YV, Huang L, Yuan M, Xia W, Chang WC, Huang WC, Liu CL, Chang YC, Liu J, Wu Y, Jin VX, Dai X, Guo J, Liu J, Jiang S, Li J, Asara JM, Brown M, Hung MC, Wei W. Phosphorylation of EZH2 by AMPK Suppresses PRC2 Methyltransferase Activity and Oncogenic Function. Mol Cell. 2018 Jan.69(2):279-291.e5. Pubmedid: 29351847. Pmcid: PMC5777296.
• Ren Y, Bi C, Zhao X, Lwin T, Wang C, Yuan J, Silva AS, Shah BD, Fang B, Li T, Koomen JM, Jiang H, Chavez JC, Pham L, Sudalagunta PR, Wan L, Wang X, Dalton WS, Moscinski LC, Shain KH, Vose J, Cleveland JL, Sotomayor EM, Fu K, Tao J. PLK1 stabilizes a MYC-dependent kinase network in aggressive B cell lymphomas. J Clin Invest. 2018 Dec.128(12):5517-5530. Pubmedid: 30260324. Pmcid: PMC6264635.
• Huang LY, Wang X, Cui XF, Li H, Zhao J, Wu CC, Min L, Zhou Z, Wan L, Wang YP, Zhang C, Gao WQ, Sun Y, Han ZG. IRTKS is correlated with progression and survival time of patients with gastric cancer. Gut. 2018 Aug.67(8):1400-1409. Pubmedid: 28647685.
• Han T, Yin Q, Wan L. AMPK lifts the PRC2-implemented gene repression. Mol Cell Oncol. 2018 Apr.5(3):e1441632. Pubmedid: 30250895. Pmcid: PMC6149850.
• Takada M, Zhang W, Suzuki A, Kuroda T, Yu Z, Inuzuka H, Gao D, Wan L, Zhuang M, Hu L, Zhai B, Fry C, Bloom K, Li G, Karpen G, Wei W, Zhang Q. FBW7 Loss Promotes Chromosomal Instability and Tumorigenesis via Cyclin E1/CDK2-Mediated Phosphorylation of CENP-A. Cancer Res. 2017 Sep.77(18):4881-4893. Pubmedid: 28760857. Pmcid: PMC5743019.
• Wu F, Dai X, Gan W, Wan L, Li M, Mitsiades N, Wei W, Ding Q, Zhang J. Prostate cancer-associated mutation in SPOP impairs its ability to target Cdc20 for poly-ubiquitination and degradation. Cancer Lett. 2017 Jan.385:207-214. Pubmedid: 27780719. Pmcid: PMC5148662.
• Lin S, Lu S, Mulaj M, Fang B, Keeley T, Wan L, Hao J, Muschol M, Sun J, Yang S. Monoubiquitination Inhibits the Actin Bundling Activity of Fascin. J Biol Chem. 2016 Dec.291(53):27323-27333. Pubmedid: 27879315. Pmcid: PMC5207158.
• Cao J, Dai X, Wan L, Wang H, Zhang J, Goff PS, Sviderskaya EV, Xuan Z, Xu Z, Xu X, Hinds P, Flaherty KT, Faller DV, Goding CR, Wang Y, Wei W, Cui R. The E3 ligase APC/C(Cdh1) promotes ubiquitylation-mediated proteolysis of PAX3 to suppress melanocyte proliferation and melanoma growth. Sci Signal. 2015 Sep.8(392):ra87. Pubmedid: 26329581.
• Wang L, Zhang J, Wan L, Zhou X, Wang Z, Wei W. Targeting Cdc20 as a novel cancer therapeutic strategy. Pharmacol Ther. 2015 Jul.151:141-151. Pubmedid: 25850036. Pmcid: PMC4457591.
• Wan L, Tan M, Yang J, Inuzuka H, Dai X, Wu T, Liu J, Shaik S, Chen G, Deng J, Malumbres M, Letai A, Kirschner MW, Sun Y, Wei W. APC(Cdc20) suppresses apoptosis through targeting Bim for ubiquitination and destruction. Dev Cell. 2014 May.29(4):377-391. Pubmedid: 24871945. Pmcid: PMC4081014.
• Liu J, Wan L, Liu P, Inuzuka H, Liu J, Wang Z, Wei W. SCF(β-TRCP)-mediated degradation of NEDD4 inhibits tumorigenesis through modulating the PTEN/Akt signaling pathway. Oncotarget. 2014 Feb.5(4):1026-1037. Pubmedid: 24657926. Pmcid: PMC4011580.
• Zhang J, Wan L, Dai X, Sun Y, Wei W. Functional characterization of Anaphase Promoting Complex/Cyclosome (APC/C) E3 ubiquitin ligases in tumorigenesis. Biochim Biophys Acta. 2014 Apr.1845(2):277-293. Pubmedid: 24569229. Pmcid: PMC3995847.
• Papa A, Wan L, Bonora M, Salmena L, Song MS, Hobbs RM, Lunardi A, Webster K, Ng C, Newton RH, Knoblauch N, Guarnerio J, Ito K, Turka LA, Beck AH, Pinton P, Bronson RT, Wei W, Pandolfi PP. Cancer-associated PTEN mutants act in a dominant-negative manner to suppress PTEN protein function. Cell. 2014 Apr.157(3):595-610. Pubmedid: 24766807. Pmcid: PMC4098792.
• Liu P, Begley M, Michowski W, Inuzuka H, Ginzberg M, Gao D, Tsou P, Gan W, Papa A, Kim BM, Wan L, Singh A, Zhai B, Yuan M, Wang Z, Gygi SP, Lee TH, Lu KP, Toker A, Pandolfi PP, Asara JM, Kirschner MW, Sicinski P, Cantley L, Wei W. Cell-cycle-regulated activation of Akt kinase by phosphorylation at its carboxyl terminus. Nature. 2014 Apr.508(7497):541-545. Pubmedid: 24670654. Pmcid: PMC4076493.
• 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 Nov.15(11):1340-1350. Pubmedid: 24161930. Pmcid: PMC3827117.
• Lau AW, Inuzuka H, Fukushima H, Wan L, Liu P, Gao D, Sun Y, Wei W. Regulation of APC(Cdh1) E3 ligase activity by the Fbw7/cyclin E signaling axis contributes to the tumor suppressor function of Fbw7. Cell Res. 2013 Jul.23(7):947-961. Pubmedid: 23670162. Pmcid: PMC3698637.
• Zhong J, Shaik S, Wan L, Tron AE, Wang Z, Sun L, Inuzuka H, Wei W. SCF β-TRCP targets MTSS1 for ubiquitination-mediated destruction to regulate cancer cell proliferation and migration. Oncotarget. 2013 Dec.4(12):2339-2353. Pubmedid: 24318128. Pmcid: PMC3926831.
• Cao J, Wan L, Hacker E, Dai X, Lenna S, Jimenez-Cervantes C, Wang Y, Leslie NR, Xu GX, Widlund HR, Ryu B, Alani RM, Dutton-Regester K, Goding CR, Hayward NK, Wei W, Cui R. MC1R is a potent regulator of PTEN after UV exposure in melanocytes. Mol Cell. 2013 Aug.51(4):409-422. Pubmedid: 23973372. Pmcid: PMC3792490.
• Fukushima H, Ogura K, Wan L, Lu Y, Li V, Gao D, Liu P, Lau AW, Wu T, Kirschner MW, Inuzuka H, Wei W. SCF-mediated Cdh1 degradation defines a negative feedback system that coordinates cell-cycle progression. Cell Rep. 2013 Aug.4(4):803-816. Pubmedid: 23972993. Pmcid: PMC3839583.
• Wang Z, Wan L, Zhong J, Inuzuka H, Liu P, Sarkar FH, Wei W. Cdc20: a potential novel therapeutic target for cancer treatment. Curr Pharm Des. 2013.19(18):3210-3214. Pubmedid: 23151139. Pmcid: PMC4014638.
• Wang Z, Inuzuka H, Zhong J, Fukushima H, Wan L, Liu P, Wei W. DNA damage-induced activation of ATM promotes β-TRCP-mediated Mdm2 ubiquitination and destruction. Oncotarget. 2012 Sep.3(9):1026-1035. Pubmedid: 22976441. Pmcid: PMC3660052.
• Wang Z, Inuzuka H, Zhong J, Wan L, Fukushima H, Sarkar FH, Wei W. Tumor suppressor functions of FBW7 in cancer development and progression. FEBS Lett. 2012 May.586(10):1409-1418. Pubmedid: 22673505. Pmcid: PMC3372850.
• Fukushima H, Matsumoto A, Inuzuka H, Zhai B, Lau AW, Wan L, Gao D, Shaik S, Yuan M, Gygi SP, Jimi E, Asara JM, Nakayama K, Nakayama KI, Wei W. SCF(Fbw7) modulates the NFkB signaling pathway by targeting NFkB2 for ubiquitination and destruction. Cell Rep. 2012 May.1(5):434-443. Pubmedid: 22708077. Pmcid: PMC3375724.
• Shaik S, Nucera C, Inuzuka H, Gao D, Garnaas M, Frechette G, Harris L, Wan L, Fukushima H, Husain A, Nose V, Fadda G, Sadow PM, Goessling W, North T, Lawler J, Wei W. SCF(β-TRCP) suppresses angiogenesis and thyroid cancer cell migration by promoting ubiquitination and destruction of VEGF receptor 2. J Exp Med. 2012 Jul.209(7):1289-1307. Pubmedid: 22711876. Pmcid: PMC3405505.
• Inuzuka H, Gao D, Finley LW, Yang W, Wan L, Fukushima H, Chin YR, Zhai B, Shaik S, Lau AW, Wang Z, Gygi SP, Nakayama K, Teruya-Feldstein J, Toker A, Haigis MC, Pandolfi PP, Wei W. Acetylation-dependent regulation of Skp2 function. Cell. 2012 Jul.150(1):179-193. Pubmedid: 22770219. Pmcid: PMC3595190.
• Wang Z, Gao D, Fukushima H, Inuzuka H, Liu P, Wan L, Sarkar FH, Wei W. Skp2: a novel potential therapeutic target for prostate cancer. Biochim Biophys Acta. 2012 Jan.1825(1):11-17. Pubmedid: 21963805. Pmcid: PMC3242930.
• Wang Z, Fukushima H, Inuzuka H, Wan L, Liu P, Gao D, Sarkar FH, Wei W. Skp2 is a promising therapeutic target in breast cancer. Front Oncol. 2012 Jan.1(57). Pubmedid: 22279619. Pmcid: PMC3263529.
• Gao D, Inuzuka H, Tan MK, Fukushima H, Locasale JW, Liu P, Wan L, Zhai B, Chin YR, Shaik S, Lyssiotis CA, Gygi SP, Toker A, Cantley LC, Asara JM, Harper JW, Wei W. mTOR drives its own activation via SCF(βTrCP)-dependent degradation of the mTOR inhibitor DEPTOR. Mol Cell. 2011 Oct.44(2):290-303. Pubmedid: 22017875. Pmcid: PMC3229299.
• Wang Z, Fukushima H, Gao D, Inuzuka H, Wan L, Lau AW, Liu P, Wei W. The two faces of FBW7 in cancer drug resistance. Bioessays. 2011 Nov.33(11):851-859. Pubmedid: 22006825. Pmcid: PMC3364519.
• Inuzuka H, Shaik S, Onoyama I, Gao D, Tseng A, Maser RS, Zhai B, Wan L, Gutierrez A, Lau AW, Xiao Y, Christie AL, Aster J, Settleman J, Gygi SP, Kung AL, Look T, Nakayama KI, DePinho RA, Wei W. SCF(FBW7) regulates cellular apoptosis by targeting MCL1 for ubiquitylation and destruction. Nature. 2011 Mar.471(7336):104-109. Pubmedid: 21368833. Pmcid: PMC3076007.
• Wan L, Zou W, Gao D, Inuzuka H, Fukushima H, Berg AH, Drapp R, Shaik S, Hu D, Lester C, Eguren M, Malumbres M, Glimcher LH, Wei W. Cdh1 regulates osteoblast function through an APC/C-independent modulation of Smurf1. Mol Cell. 2011 Dec.44(5):721-733. Pubmedid: 22152476. Pmcid: PMC3240853.
• Wang Z, Inuzuka H, Fukushima H, Wan L, Gao D, Shaik S, Sarkar FH, Wei W. Emerging roles of the FBW7 tumour suppressor in stem cell differentiation. EMBO Rep. 2011 Dec.13(1):36-43. Pubmedid: 22157894. Pmcid: PMC3246256.
• Gao D, Wan L, Wei W. Phosphorylation of Rictor at Thr1135 impairs the Rictor/Cullin-1 complex to ubiquitinate SGK1. Protein Cell. 2010 Oct.1(10):881-885. Pubmedid: 21204013. Pmcid: PMC3374330.
• Gao D, Inuzuka H, Korenjak M, Tseng A, Wu T, Wan L, Kirschner M, Dyson N, Wei W. Cdh1 regulates cell cycle through modulating the claspin/Chk1 and the Rb/E2F1 pathways. Mol Biol Cell. 2009 Jul.20(14):3305-3316. Pubmedid: 19477924. Pmcid: PMC2710831.

• Title: Restoring FZR1 Tumor Suppressor Function in Human Cancers
  Sponsor: Florida Biomedical Research Program (FBRP)
  PI: Wan, L.
• Title: Characterizing oncogenic function of ITCH in melanoma
  Sponsor: Nat Institutes of Health
  PI: Wan, L.
• Title: Ubiquitination-dependent Regulation of BRAF Function in Melanoma
  Sponsor: Amer Cancer Society
  PI: Wan, L.