Faculty

Keli Xu, PhD

Assistant Professor
Member of Cancer Institute, Tumor Cell Biology Program
Office: G757
(601) 815-3083
Lab: G754; (601) 815-6762
Email: kxu@umc.edu

Research Interests

  • Fringe-modulated Notch signaling in mammary gland, prostate, lung and pancreas
  • Cancer stem cell

Research program

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 levels. Different subtypes of breast cancer may have different cell-of-origin within mammary epithelial hierarchy. Notch signaling controls mammary 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) 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 discovered 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 context profoundly affecting tumor cell response to Notch activation. We are interested in identifying Notch pathway genes as biomarker and therapeutic target 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.

Selected publications

*In last four years. A complete publication list can be accessed through MyBibliography at NCBI.

Peer-reviewed papers

  • •Zhang S, Chung W-C, Xu K. (2015) Lunatic Fringe is a potent tumor suppressor in Kras-initiated pancreatic cancer. Oncogene (In press).
  • •Zhang S, Chung W-C, Wu G, Egan SE, Xu K. (2014) Tumor suppressive activity of Lunatic Fringe in prostate through differential modulation of Notch receptor activation. Neoplasia 16(2):158-167. PMID: 24709423
  • Zhang S, Chung W-C, Wu G, Egan SE, Miele L, Xu K. (2015) Manic Fringe promotes a claudin-low breast cancer phenotype through Notch-mediated PIK3CG induction. Cancer Res 75(10):1936-43. PMID: 25808869
  • Zhang S, Chung W-C, Miele L, Xu K. (2014) Targeting Met and Notch in the Lfng-deficient, Met-amplified triple negative breast cancer. Cancer Biol Ther 15(5):633-42. PMID: 24556651

Reviews, chapters and books

  • Xu K, Bägli DJ, Egan SE. (2014) NOTch just a bladder control problem. Cancer Cell 26(4):452-54. PMID: 25314075