Profile

BACKGROUND
The Wnt pathway is an evolutionarily conserved signaling pathway present in all metazoans. During development, Wnt signaling coordinate the formation of tissues, organs, and limbs, and its misregulation leads to a variety of human disease states such Alzheimeri's disease and cancer. My laboratory is interested in understanding the basic mechanism by which a Wnt signal is propagated and how this information can be used in regenerative medicine and in the treatment of cancer.

EXPERIMENTAL APPROACHES
A major experimental approach in my laboratory involves the use of Xenopus extracts and purified proteins to biochemically reconstitute Wnt signaling in vitro. Genome-scale screens, cultured mammalian cells, Xenopus embryos, Drosophila genetics (in collaboration with Dr. Laura Lee), and mouse studies are employed to compliment and extend our biochemical findings.

MECHANISM OF WNT SIGNAL TRANSDUCTION
One of the major mysteries of this pathway is how a Wnt signal is propagated from the cell surface. My laboratory has recently developed an in vitro system to study the mechanism of Wnt signal transduction from the plasma membrane. Towards this end, we have focused on understanding the mechanism of signaling from the coreceptor, LRP6, and the potential role of the membrane associated heterotrimeric G protein family members in Wnt signal transduction. Many components of the Wnt pathway are regulated by ubiquitin-mediated proteolysis. Recently, we have taken a genome-scale screen to identify deubiquitinating enzyme (DUBs) and ubiquitin ligases (E3s) that regulate the Wnt pathway. Several hits have been identified from these screens, and current efforts are directed towards validating their roles in Wnt signaling.

REGENERATIVE MEDICINE AND CANCER
In regenerative medicine, the healing process is manipulated to repair damaged tissues. Modern regenerative medicine is a field in which stem cells are manipulated to treat a variety of human diseases. Wnt signaling is one of a handful of molecular pathways critical to stem cells. Thus, agents that target Wnt signaling would be potentially useful for the treatment of cardiovascular disease, diabetes, neurodegeneration, and other disorders that may benefit from regenerative medicine.

Cancer stem cells (CSC) are fundamental to the initiation and maintenance of tumors. Failure to eradicate CSC (as is typical with conventional therapy) leaves behind a small reservoir of cells that drives relapse. Wnt inhibitors would be expected to specifically target this resistant CSC population. Using our Xenopus biochemical system, we have found several compounds that potently inhibit the Wnt pathway. One of these, VU-WS30, inhibits the viability of a variety of cancer cell lines that are highly dependent on Wnt signaling for growth and proliferation. Current efforts are directed towards identifying the molecular targets of VU-WS30 and other Wnt inhibitors identified in our screen.

Publications

The following timeline graph is generated from all co-authored publications.

Featured publications are shown below:

  1. Comparative genetic screens in human cells reveal new regulatory mechanisms in WNT signaling. Lebensohn AM, Dubey R, Neitzel LR, Tacchelly-Benites O, Yang E, Marceau CD, Davis EM, Patel BB, Bahrami-Nejad Z, Travaglini KJ, Ahmed Y, Lee E, Carette JE, Rohatgi R (2016) Elife
    › Primary publication · 27996937 (PubMed) · PMC5257257 (PubMed Central)
  2. The MAPK pathway regulates intrinsic resistance to BET inhibitors in colorectal cancer. Ma Y, Wang L, Neitzel LR, Loganathan S, Tang N, Qin L, Emily CE, Guo Y, Knapp S, Beauchamp RD, Lee E, Wang J (2016) Clin Cancer Res
    › Primary publication · 27678457 (PubMed)
  3. Reconstitution of the Cytoplasmic Regulation of the Wnt Signaling Pathway Using Xenopus Egg Extracts. Hyde AS, Hang BI, Lee E (2016) Methods Mol Biol : 101-9
    › Primary publication · 27590156 (PubMed)
  4. Identification of a Paralog-Specific Notch1 Intracellular Domain Degron. Broadus MR, Chen TW, Neitzel LR, Ng VH, Jodoin JN, Lee LA, Salic A, Robbins DJ, Capobianco AJ, Patton JG, Huppert SS, Lee E (2016) Cell Rep 15(9): 1920-9
    › Primary publication · 27210761 (PubMed) · PMC4889555 (PubMed Central)
  5. The Small Molecule IMR-1 Inhibits the Notch Transcriptional Activation Complex to Suppress Tumorigenesis. Astudillo L, Da Silva TG, Wang Z, Han X, Jin K, VanWye J, Zhu X, Weaver K, Oashi T, Lopes PE, Orton D, Neitzel LR, Lee E, Landgraf R, Robbins DJ, MacKerell AD, Capobianco AJ (2016) Cancer Res 76(12): 3593-603
    › Primary publication · 27197169 (PubMed) · PMC4911243 (PubMed Central)
  6. Wnt pathway activation by ADP-ribosylation. Yang E, Tacchelly-Benites O, Wang Z, Randall MP, Tian A, Benchabane H, Freemantle S, Pikielny C, Tolwinski NS, Lee E, Ahmed Y (2016) Nat Commun : 11430
    › Primary publication · 27138857 (PubMed) · PMC4857404 (PubMed Central)
  7. Wnt/Wingless Pathway Activation Is Promoted by a Critical Threshold of Axin Maintained by the Tumor Suppressor APC and the ADP-Ribose Polymerase Tankyrase. Wang Z, Tacchelly-Benites O, Yang E, Thorne CA, Nojima H, Lee E, Ahmed Y (2016) Genetics 203(1): 269-81
    › Primary publication · 26975665 (PubMed) · PMC4858779 (PubMed Central)
  8. GLI3 Links Environmental Arsenic Exposure and Human Fetal Growth. Winterbottom EF, Fei DL, Koestler DC, Giambelli C, Wika E, Capobianco AJ, Lee E, Marsit CJ, Karagas MR, Robbins DJ (2015) EBioMedicine 2(6): 536-43
    › Primary publication · 26288817 (PubMed) · PMC4535308 (PubMed Central)
  9. Inhibition of Wnt/β-catenin pathway promotes regenerative repair of cutaneous and cartilage injury. Bastakoty D, Saraswati S, Cates J, Lee E, Nanney LB, Young PP (2015) FASEB J 29(12): 4881-92
    › Primary publication · 26268926 (PubMed) · PMC4653050 (PubMed Central)
  10. Small-molecule high-throughput screening utilizing Xenopus egg extract. Broadus MR, Yew PR, Hann SR, Lee E (2015) Methods Mol Biol : 63-73
    › Primary publication · 25618336 (PubMed) · PMC4492114 (PubMed Central)
  11. Repurposing the FDA-approved pinworm drug pyrvinium as a novel chemotherapeutic agent for intestinal polyposis. Li B, Flaveny CA, Giambelli C, Fei DL, Han L, Hang BI, Bai F, Pei XH, Nose V, Burlingame O, Capobianco AJ, Orton D, Lee E, Robbins DJ (2014) PLoS One 9(7): e101969
    › Primary publication · 25003333 (PubMed) · PMC4086981 (PubMed Central)
  12. Pyrvinium attenuates Hedgehog signaling downstream of smoothened. Li B, Fei DL, Flaveny CA, Dahmane N, Baubet V, Wang Z, Bai F, Pei XH, Rodriguez-Blanco J, Hang B, Orton D, Han L, Wang B, Capobianco AJ, Lee E, Robbins DJ (2014) Cancer Res 74(17): 4811-21
    › Primary publication · 24994715 (PubMed) · PMC4321822 (PubMed Central)
  13. The Drosophila MCPH1-B isoform is a substrate of the APCCdh1 E3 ubiquitin ligase complex. Hainline SG, Rickmyre JL, Neitzel LR, Lee LA, Lee E (2014) Biol Open 3(7): 669-76
    › Primary publication · 24972868 (PubMed) · PMC4154303 (PubMed Central)
  14. Reconstitution Of β-catenin degradation in Xenopus egg extract. Chen TW, Broadus MR, Huppert SS, Lee E (2014) J Vis Exp (88)
    › Primary publication · 24962160 (PubMed) · PMC4133086 (PubMed Central)
  15. TRIP/NOPO E3 ubiquitin ligase promotes ubiquitylation of DNA polymerase η. Wallace HA, Merkle JA, Yu MC, Berg TG, Lee E, Bosco G, Lee LA (2014) Development 141(6): 1332-41
    › Primary publication · 24553286 (PubMed) · PMC3943184 (PubMed Central)