Cancer Institute

  • Keli Xu

    xu_keli.jpgAssistant Professor, Department of Neurobiology & Anatomical Sciences
    Tumor Cell Biology Program
    PhD, Biochemistry, 2001, Rutgers University
    Postdoc, 2001-06, The Hospital for Sick Children, Toronto, Canada

    Contact information
    2500 N State St., Room G757
    Jackson, MS 39216
    E-mail: kxu@umc.edu

    Research interests

    • Fringe-modulated Notch signaling in the development and cancer of mammary gland, prostate,  lung and pancreas
    • Cancer stem cells

    Research synopsis

    Notch is a powerful regulator for the development and homeostasis of various tissues. Dysregulation of Notch signaling has been implicated in a number of pathological conditions including cancer. The Fringe glycosyltransferases modify Notch receptor and modulate Notch activation. Fine-tuning of Notch signaling by Fringe is critical in the regulation of stem cell function. We are interested in understanding roles of Fringe-modulated Notch signaling in tissue development and tumorigenesis in the following areas:

    • Breast cancers are heterogeneous at clinical and molecular level. Different subtypes of breast cancer may have different cell-of-origin within mammary epithelial hierarchy. Notch signaling controls mammary epithelial cell fate decision and differentiation. Thus genetic dissection of Notch pathways in the mammary gland may provide insights into intrinsic subtypes of breast cancer. We showed that Lunatic Fringe (Lfng), a glycosyltransferase that modifies Notch receptors thereby modulating Notch activation, regulates mammary stem/progenitor cell activity, and Lfng deficiency cooperates with the Met/Caveolin amplicon to induce basal-like breast cancer. Most recently we defined an oncogenic role for Manic Fringe (Mfng) through Notch-mediated Pik3cg induction in claudin-low breast cancer.
    • Elevated Notch ligand and receptor expression has been associated with aggressive forms of prostate cancer, suggesting a role for Notch signaling in prostate tumor initiation and progression. We have reported a critical role for Lfng in regulation of prostate epithelial differentiation and proliferation, as well as in prostate tumor suppression, through differential modulation of Notch receptor activation. We are currently determining roles of Lfng in the pathogenesis of basal- and luminal-originated prostate cancers.
    • Notch signaling coordinates a series of events during lung development, including proximodistal fate generation and branching, proximal airway cell fate specification, and alveologenesis. We have found that Jagged1 is the major regulator of Notch-dependent cell fate in proximal airways, and that Lfng-dependent Notch signaling is required for alveologenesis. Notch also plays complex roles in lung carcinogenesis, with the cellular (SCLC vs NSCLC) and microenvironmental (hypoxia) context profoundly affecting tumor cell response to Notch activation. We are interested in identifying Notch pathway genes as biomarker and therapeutic targets for lung cancer.
    • Notch controls pancreatic differentiation during development and is reactivated in pancreatic cancer. We recently discovered that Lfng is uniquely expressed in a subset of acinar cells in pancreas. Deletion of Lfng in the mouse pancreas caused increased Notch activation associated with accumulation of stem-like cells, and dramatically accelerated Kras-induced PDAC development. We hypothesize that Lfng-expressing acinar cells represent a cellular origin of Kras-induced PDAC, and Lfng-positive PDAC cells may be enriched for cancer stem cells. We are currently testing this hypothesis and identifying genes that are critical for PDAC initiation and progression.

     

    Current funding

    • NCI R21 Grant (CA175136) Functional analysis of Manic Fringe in the claudin-low breast cancer. PI, 2013-16
    • NCI P01 Grant (CA166009) Targeting multiple diseases through gamma secretase. Co-I, 2013-18
    • Intramural Research Support Program (IRSP) Award: Roles of Lunatic Fringe in putative cell of origin and cancer stem cells of pancreatic cancer. PI, 2016-17

    Selected publications

    A complete publication list can be accessed through MyBibliography at NCBI.

    Peer-reviewed papers

    • Lunatic Fringe is a potent tumor suppressor in Kras-initiated pancreatic cancer.  Zhang S, Chung W-C, Xu K. (2016) Oncogene. 35(19):2485-95. PMID: 26279302
    • Manic Fringe promotes a claudin-low breast cancer phenotype through Notch-mediated PIK3CG induction. Zhang S, Chung W-C, Wu G, Egan SE, Miele L, Xu K. (2015) Cancer Res. 75(10):1936-43. PMID: 25808869
    • Tumor suppressive activity of Lunatic Fringe in prostate through differential modulation of Notch receptor activation. Zhang S, Chung W-C, Wu G, Egan SE, Xu K. (2014) Neoplasia 16(2):158-167. PMID: 24709423
    • Targeting Met and Notch in the Lfng-deficient, Met-amplified triple negative breast cancer. Zhang S, Chung W-C, Miele L, Xu K. (2014) Cancer Biol Ther 15(5):633-42. PMID: 24556651
    • Jagged1 is the major regulator of Notch-dependent cell fate in proximal airways. Zhang S, Loch AJ, Radtke F, Egan SE, Xu K. (2013) Dev Dyn 242(6):678-86. PMID: 23526493
    • Lunatic fringe deficiency cooperates with the Met/Caveolin gene amplicon to induce basal-like breast cancer. Xu K, Usary J, Kousis P, Prat A, Wang D-Y, Adams JR, Wang W, Loch AJ, Deng T, Zhao W, Cardiff RD, Yoon K, Gaiano N, Ling V, Beyene J, Zacksenhaus E, Gridley T, Leong WL, Guidos CJ, Perou CM, Egan SE. (2012) Cancer Cell 21(5):626-41. PMCID: PMC3603366
    • Cooperation between PIK3Cα and p53 mutations in mouse mammary tumor formation.  Adams JR, Xu K, Liu JC, Agamez NR, Loch AJ, Wong RG, Wang W, Wright KL, Lane TF, Zacksenhaus E, Egan SE. (2011) Cancer Res 71(7):2706-2717. PMID:21324922
    • Lunatic Fringe prolongs Delta/Notch-induced self-renewal of committed αβ T-cell progenitors.  Yuan JS, Tan JB, Visan I, Matei IR, Urbanellis P, Xu K, Danska JS, Egan SE, Guidos CJ. (2011) Blood 117(4):1184-95. PMID:21097675
    • Lunatic Fringe-mediated Notch signaling is required for lung alveogenesis.  Xu K, Nieuwenhuis E, Cohen BL, Wang W, Canty AJ, Danska JS, Coultas L, Rossant J, Wu MY, Piscione TD, Nagy A, Gossler A, Hicks GG, Hui CC, Henkelman RM, Yu LX, Sled JG, Gridley T, Egan SE. 2010, Am J Physiol Lung Cell Mol Physiol. 298:L45-56. PMID: 19897741.
    • Lunatic and manic fringe cooperatively enhance marginal zone B cell precursor competition for delta-like 1 in splenic endothelial niches.  Tan JB, Xu K, Cretegny K, Visan I, Yuan JS, Egan SE, Guidos CJ. (2009) Immunity. 30:254-63. PMID:19217325