Levi Beverly, Ph.D.

Levi Beverly, Ph.D.

Education:

B.S., University of Cincinnati, Cincinnati OH, 2000
Ph.D., Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati, Cincinnati OH, 2007
Postdoctoral Fellowship, Memorial Sloan-Kettering Cancer Center, New York City NY 2010
Postdoctoral Fellowship, National Cancer Institute, National Institutes of Health, Bestheda MD, 2011

Curriculum Vitae

Current Positions:

Associate Professor, Department of Medicine, University of Louisville School of Medicine
Co-Director, Experimental Therapeutics & Diagnostics Program, James Graham Brown Cancer Center
Member, Institute for Molecular Diversity and Drug Design, University of Louisville
Member, Department of Pharmacology and Toxicology, University of Louisville School of Medicine
Member, Department of Bioengineering, University of Louisville

Contact Information:

Clinical Translational Research Building, Room 2204
University of Louisville
505 Hancock St.
Louisville, KY 40202, USA
Phone 502-852-8968
Fax 502-852-7979
Email: Levi.Beverly@louisville.edu

Research Description

The Beverly lab is interested in using models of human cancer to elucidate the mechanisms of tumor initiation, progression and regression following therapeutic intervention.  To this end, we have adopted a philosophy of combining pre-clinical models with biochemistry, molecular biology and cultured human cells to dissect signaling pathways and cellular processes involved in all aspects of cancer biology.  Using information gathered from these experiments, we proceed back into our model systems to determine how our understanding of the disease initiation, progression or regression has advanced. To this end the research in the lab can be broken down into multiple specific areas of interest.

1. Characterizing the basic biological processes regulated by Ubiquilin proteins in human lung cancer.

The Ubiquilin family of proteins (UBQLN) consists of five related proteins (UBQLN1-4 and UBQLNL) that all contain ubiquitin-like (UBL) and ubiquitin-associated (UBA) domains. Our laboratory recently discovered a link between Ubiquilin (UBQLN) protein function and processes involved in tumorigenesis. Furthermore, we found multiple somatic non-synonymous recurrent mutations in UBQLN family members and loss of either UBQLN1 or UBQLN2 in over 50% of human lung adenocarcinoma (hLAC). This data predicts that over 700,000 people die world-wide every year from lung cancer that has altered UBQLN function.  Importantly, most patients who succumb to lung cancer, die from the metastatic disease and not from the primary tumor burden.  Metastatic cancer progression requires the cells to acquire new aggressive properties, such as increased migration, invasion, survival and growth at the metastatic site.  The identification of regulators of these properties will be crucial for our future success in decreasing cancer mortality rates. Thus, the goal of our work is to understand the detailed mechanisms by which disruption of the UBQLN-family of proteins contributes to the metastatic progression of hLAC.

2. Understanding how interactions between lung cancer cells and the microenvironment increase metastasis.

The environment surrounding and within a tumor, the tumor microenvironment, is comprised of a variety of extracellular components and multiple cell types. The interactions between different cell types and their associated extracellular matrices are thought to play a role in cancer progression and metastasis as well as therapeutic responses to cytotoxic and immune checkpoint therapies. The precise molecular details for how interactions between the individual components of the tumor microenvironment impact cancer progression and metastasis are not well understood. Elucidating the complex interactions within the tumor microenvironment is essential for identifying novel therapeutic targets, but has proven challenging because isolating and studying cancer associated stromal cells from primary lung tumors has remained difficult.  To begin to fill this knowledge gap, we identified a rapid, reliable and reproducible culture system that allows for the isolation and expansion of large quantities of primary cancer-associated mesenchymal (CaM) cells. Using these CaM cells we are studying how the ECM they deposit can alter metastatic phenotypes of lung cancer cells.

3.  Identification of novel drug combinations to increase pediatric AML cure rates and decrease long-term detrimental side effects.

Acute myeloid leukemia (AML), defined as a malignant clonal expansion of immature myeloid progenitors, is the second most common childhood leukemia. Pediatric acute myeloid leukemia has the worst overall patient survival of all pediatric cancers (<70%) and patients that survive are more likely to develop secondary long-term chronic diseases. Our research is attempting to uncover novel vulnerabilities of pediatric AML that can be targeted to increase the overall survival rate, whilst decreasing the immediate and long-term organ toxicities.

Literature Cited:

  1. Sharp CN, Doll M, Dupre TV, Beverly LJ, Siskind LJ.  Moderate aging does not exacerbate cisplatin-induced kidney injury or fibrosis despite altered inflammatory cytokine expression and immune cell infiltration.  American Journal of Physiology-Renal Physiology 2019 Jan 1;316(1):F162-72. doi: 10.1152/ajprenal.00463.2018. PMID: 30484347; PMCID: PMC6383196.
  2. Barve A, Casson L, Krem M, Wunderlich M, Mulloy JC, Beverly LJ.  Comparative utility of NRG and NRGS mice for the study of normal hematopoiesis, leukemogenesis, and therapeutic response.  Experimental Hematology 2018 Nov;67:18-31. doi: 10.1016/j.exphem.2018.08.004. PMID: 30125602; PMCID: PMC6200600.
  3. Ketchem CJ, Kucera C, Barve A, Beverly LJ.  The antiarrhythmic drug, Amiodarone, decreases AKT activity and sensitizes human acute myeloid leukemia cells to apoptosis by ABT-263.  American Journal of Medical Science 2018 May;355(5):488-96. doi: 10.1016/j.amjms.2018.01.011. PMID: 29753379.
  4. Beverly LJ, Krem MM.  Teaching old drugs new tricks: Repositioning pharmaceuticals for bench to bedside success.  American Journal of Medical Science 2018 Mar;355(3):205-6. doi: 10.1016/j.amjms.2017.12.007. PMID: 29549920.
  5. Sharp CN, Doll MA, Megyesi J, Oropilla GB, Beverly LJ, Siskind LJ.  Subclinical kidney injury induced by repeated cisplatin administration results in progressive chronic kidney disease.  American Journal of Physiology-Renal Physiology 2018 Jul 1;315(1):F161-72.  doi: 10.1152/ajprenal.00636.2017. PMID: 29384415; PMCID: PMC6087791.
  6. Kurlawala Z, Dunaway R, Shah PP, Gosney JA, Siskind LJ, Ceresa BP, Beverly LJ.  Regulation of insulin-like growth factor receptors by Ubiquilin1.  Biochemical Journal 2017 Dec 6;474(24):4105-18. doi: 10.1042/BCJ20170620. PMID: 29054976; PMCID: PMC5842694.
  7. Dupre TV, Doll MA, Shah PP, Sharp CN, Siow D, Megyesi J, Shayman J, Bielawska A, Bielawski J, Beverly LJ, Hernandez-Corbacho M, Clarke CJ, Snider AJ, Schnellmann RG, Obeid LM, Hannun YA, Siskind LJ.  Inhibiting glucosylceramide synthase exacerbates cisplatin-induced acute kidney injury.  Journal of Lipid Research 2017 Jul;58(7):1439-52. doi: 10.1194/jlr.M076745. PMID: 28490444; PMCID: PMC5496040.
  8. Yadav S, Singh N, Shah PP, Rowbotham DA, Malik D, Srivastav A, Shankar J, Lam WL, Lockwood WW, Beverly LJ.  MIR155 regulation of Ubiquilin1 and Ubiquilin2: Implications in cellular protection and tumorigenesis.  Neoplasia 2017 Apr;19(4):321-32. doi: 10.1016/j.neo.2017.02.001. PMID: 28315615; PMCID: PMC5361868.
  9. Shah PP, Dupre TV, Siskind LJ, Beverly LJ.  Common cytotoxic chemotherapeutics induce epithelial-mesenchymal transition (EMT) downstream of ER stress.  Oncotarget 2017 Apr 4;8(14):22625-39. doi: 10.18632/oncotarget.15150. PMID: 28186986; PMCID: PMC5410250.
  10. Kurlawala Z, Shah PP, Shah C, Beverly LJ.  The STI and UBA domains of UBQLN1 are critical determinants of substrate interaction and proteostasis.  Journal of Cellular Biochemistry 2017 Aug;118(8):2261-70. doi: 10.1002/jcb.25880. Epub 2017 Apr 25. PMID: 28075048; PMCID: PMC5462870.
  11. Kabeer F, Beverly LJ, Darrasse-Jèze G, Podsypanina K.  Methods to study metastasis in genetically modified mice.  Cold Spring Harbor Protocols 2016 Feb 1;2016(2):pdb.top069948. doi: 10.1101/pdb.top069948. PubMed PMID: 26832689.
  12. Beverly LJ, Podsypanina K.  Murine stem cell-based retrovirus production for marking primary mouse mammary cells for metastasis studies.  Cold Spring Harbor Protocols 2016 Feb 1;2016(2):pdb.prot078337. doi: 10.1101/pdb.prot078337. PubMed PMID: 26832680.
  13. Sundaram K, Mather AR, Marimuthu S, Shah PP, Snider AJ, Obeid LM, Hannun YA, Beverly LJ, Siskind LJ.  Loss of neutral ceramidase protects cells from nutrient- and energy -deprivation-induced cell death.  Biochemical Journal 2016 Mar 15;473(6):743-55. doi: 10.1042/BJ20150586. PMID: 26747710; PMCID: PMC5513154.
  14. Sharp CN, Doll MA, Dupre TV, Shah PP, Subathra M, Siow D, Arteel GE, Megyesi J, Beverly LJ, Siskind LJ.  Repeated administration of low-dose cisplatin in mice induces fibrosis.  American Journal of Physiology-Renal Physiology 2016 Mar 15;310(6):F560-8. doi: 10.1152/ajprenal.00512.2015. PMID: 26739893; PMCID: PMC4796272.
  15. Dupre TV, Doll MA, Shah PP, Sharp CN, Kiefer A, Scherzer MT, Saurabh K, Saforo D, Siow D, Casson L, Arteel GE, Jenson AB, Megyesi J, Schnellmann RG, Beverly LJ, Siskind LJ.  Suramin protects from cisplatin-induced acute kidney injury.  American Journal of Physiology-Renal Physiology 2016 Feb 1;310(3):F248-58. doi: 10.1152/ajprenal.00433.2015. PMID: 26661653; PMCID: PMC4877945.
  16. Chang KT, Anishkin A, Patwardhan GA, Beverly LJ, Siskind LJ, Colombini M.  Ceramide channels: destabilization by Bcl-xL and role in apoptosis.  Biochimica et Biophysica Acta 2015 Oct;1848(10 Pt A):2374-84. doi: 10.1016/j.bbamem.2015.07.013.  PMID: 26215742; PMCID: PMC4554889.
  17. Shah PP, Beverly LJ.  Regulation of VCP/p97 demonstrates the critical balance between cell death and epithelial-mesenchymal transition (EMT) downstream of ER stress. Oncotarget 2015 Jul 10;6(19):17725-37. PMID: 25970786; PMCID: PMC4627341.
  18. Patwardhan GA, Beverly LJ, Siskind LJ.  Sphingolipids and mitochondrial apoptosis.  Journal of Bioenergetics & Biomembranes 2016 Apr;48(2):153-68. doi: 10.1007/s10863-015-9602-3. Review. PMID: 25620271; PMCID: PMC5434644.
  19. Saurabh K, Scherzer MT, Shah PP, Mims AS, Lockwood WW, Kraft AS, Beverly LJ.  The PIM family of oncoproteins: small kinases with huge implications in myeloid leukemogenesis and as therapeutic targets.  Oncotarget 2014 Sep 30;5(18):8503-14. PMID: 25238262; PMCID: PMC4226700.
  20. Stathem M, Marimuthu S, O'Neal J, Rathmell JC, Chesney JA, Beverly LJ, Siskind LJ.  Glucose availability and glycolytic metabolism dictate glycosphingolipid levels.  Journal of Cellular Biochemistry 2015 Jan;116(1):67-80. doi: 10.1002/jcb.24943. PMID: 25145677; PMCID: PMC4229434.
  21. Shah PP, Lockwood WW, Saurabh K, Kurlawala Z, Shannon SP, Waigel S, Zacharias W, Beverly LJ.  Ubiquilin1 represses migration and epithelial-to-mesenchymal transition of human non-small cell lung cancer cells.  Oncogene2015 Mar 26;34(13):1709-17. doi: 10.1038/onc.2014.97. Epub 2014 Apr 21. PMID: 24747970; PMCID: PMC4205225.
  22. Saurabh K, Scherzer MT, Song A, Yip KW, Reed JC, Li C, Beverly LJ.  Dissecting the in vivo leukemogenic potency of BCLxl.  Journal of Leukemia (Los Angel) 2014;2(5):158. PMID: 26636115; PMCID: PMC4666309.
  23. Rhyasen GW, Bolanos L, Fang J, Rasch C, Jerez A, Varney M, Wunderlich M, Rigolino C, Mathews L, Ferrer M, Southall N, Guha R, Keller J, Thomas C, Beverly LJ, Cortelezzi A, Oliva EN, Cuzzola M, Maciejewski JP, Mulloy JC, Starczynowski DT.  Targeting IRAK1 as a novel therapeutic approach for Myelodysplastic Syndrome.  Cancer Cell 2013 July 8;24(1):90-104. PMID: 23845443; PMCID: PMC3711103.
  24. Lockwood WW, Chandel SK, Stewart GL, Erdjument-Bromage H, Beverly LJ.  The novel ubiquitin ligase complex, SCFFbxw4, interacts with the COP9 signalosome in an f-box dependent manner, is mutated, lost and under-expressed in human cancers.  PLoS One 2013 May 2;8(5):e63610.  PMID:23658844; PMCID: PMC3642104.
  25. Beverly LJ, Howell LA, Hernandez-Corbacho M, Casson L, Chipuk JE, Siskind LJ.  BAK activation is necessary and sufficient to drive ceramide synthase-dependent ceramide accumulation following inhibition of BCL2-like proteins.  Biochemical Journal 2013 May 15;452(1):111-9. doi: 10.1042/BJ20130147. PMID: 23480852; PMCID: PMC3642864.
  26. Casson L, Howell L, Mathews LA, Ferrer M, Southall N, Guha R, Keller JM, Thomas C, Siskind LJ, Beverly LJ.  Inhibition of ceramide metabolism sensitizes human leukemia cells to inhibition of BCL2-like proteins.  PLoS One 2013;8(1):e54525. PMID:23342165; PMCID: PMC3546986.
  27. Beverly LJ.  Oncogenic driver supersedes bone marrow preparation as the critical determinant of leukemic outcome: A one day protocol for bone marrow harvest, infection and transplantationBone Marrow Transplant 2013 Jul;48(7):1002-5.  PMID: 23318537.
  28. Beverly LJ, Lockwood WW, Erdjument-Bromage H, Varmus HE. Ubiquitination, localization and stability of an anti-apoptotic BCL2-like protein, BCL2L10/BCLb, are regulated by Ubiquilin1.  Proceedings of the National Academy of Sciences USA 2012 Jan 17; 109(3):E119-26. PMID: 22233804; PMCID: PMC3271887.
  29. Beverly LJ, Varmus HE.  MYC-induced leukemogenesis is accelerated by all six members of the anti-apoptotic BCL family.  Oncogene 2009 Mar 5;28(9):1274-9. PMID: 19137012; PMCID: PMC2743088.
  30. Podsypanina K, Du YC, Jechlinger M, Beverly LJ, Hambartzumyan D, Varmus HE.  Seeding and propagation of untransformed mouse mammary cells in the lung.  Science 2008 Sep 26;321(5897):1841-4. PMID: 18755941; PMC2694414.
  31. Beverly LJ, Ascano JM, Capobianco AJ.  Expression of JAGGED1 in T-lymphocytes results in thymic involution by inducing apoptosis of thymic stromal epithelial cells.  Genes & Immunity 2006 Sep;7(6):476-86.  PMID: 16791277.
  32. Beverly LJ, Capobianco AJ.  Perturbation of Ikaros isoform selection by MLV integration is a cooperative event in Notch(IC)-induced T cell leukemogenesis.  Cancer Cell 2003 Jun;3(6):551-64. PMID: 12842084.  [ https://www.sciencedirect.com/science/article/pii/S1535610803001375?via%3Dihub ]

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