Darina Lazarova, PhD

Director of Master of Biomedical Sciences Program
Associate Professor of Molecular Biology
Department of Basic Sciences
Geisinger Commonwealth Research Department
North Campus

LOCATION(S)
Geisinger Commonwealth School of Medicine
Medical Sciences Building
525 Pine St.
Office 3042
Scranton, PA 18509
570-504-9645
Fax: 507-504-9639
dlazarova@som.geisinger.edu

Research interests

Darina Lazarova, PhD, is associate professor of molecular biology in the Department of Basic Sciences. She received her PhD in cell biology at Fordham University, New York, and did her postdoctoral work at Yale University School of Medicine. Her research interests include the molecular mechanisms by which histone deacetylase inhibitors exercise their effects on cancer cells, the networks established between major signaling pathways that allow malignant cells to resist therapeutic interventions and the modulation of these networks to overcome the robustness of the tumors.

Projects and research directions of the laboratory

  1. Compensatory proliferation and combination anti-cancer therapies. Synthetic histone deacetylase inhibitors (HDACis) exert a strong apoptotic effect on colon cancer cells with mutations in WNT/beta-catenin signaling. Since almost 80% of the sporadic colorectal cancer cases exhibit such mutations, the HDACis are promising class of therapeutic agents. However, cancer cell populations can evade programmed death by switching on cell survival pathways and re-adjusting the WNT/beta-catenin signaling levels. In order to counteract these immediate mechanisms of resistance, we are evaluating the anti-cancer potential of combinations of HDACis and inhibitors of compensatory cell survival pathways.
  2. Obesity shapes the mutation profile of colon cancer. Our analyses of sequencing and clinical data of patients with colon cancer (data from The Cancer Genome Atlas) have revealed that overweight and obese patients have lower number of driver gene mutations than patients with normal weight. Mutations in PTEN, JAK2 and KRAS are statistically lower in obese versus normal-weight colon cancer patients. These findings are critical in understanding the precise mechanism of how obesity increases the risk of colon cancer. Further confirmation of these preliminary data will impact prevention and treatment of colon cancer in individuals with high body-mass index.
  3. Diet-based prevention of colon cancer. The project examines the apoptotic effect of butyrate, a fermentation product of fiber, on colon cancer cells. To formulate a powerful dietary supplement aimed at decreasing the incidence of colonic neoplasms, we are evaluating the apoptotic potential of butyrate in combination with other diet-derived compounds. The most promising combinations are the ones that include diet-derived inhibitors of the apoptosis-induced cell proliferation pathways. One example is propolis, a product of honey bees. According to our analyses, propolis from New Zealand (Manuka Health, New Zealand) inhibits the activation of AKT and JAK/STAT in colon cancer cells undergoing apoptosis induced by butyrate. This suppression augments the apoptotic outcome in colon cancer cell populations. The immediate translation of these findings could be the formulation of dietary supplements that combine fiber (source of butyrate) with propolis. Such supplements could be offered to individuals at high risk of colon cancer (e.g., patients with IBD, colectomy, colonic polyps, etc.)
  4. Dietary and pharmaceutical interventions against obesity-associated colon cancer (CC). Approximately 70% of the adult U.S. population is overweight or obese. High body mass index (BMI) is associated with a higher risk of CC and 13 other types of cancer. Therefore, CC prevention approaches for at-risk high BMI cohorts is necessary. We have found that (a) the dietary supplement gamma-cyclodextrin decreases early stage intestinal tumor burden in obese mice, (b) in obesity, neoplastic development in human colon is characterized by a decreased number of PTEN and KRAS mutations (activating AKT and MAPK/ERK signaling). These findings suggest that gamma-cyclodextrin or small molecule inhibitors of AKT and MAPK/ERK signaling will decrease intestinal neoplastic development in individuals with high BMI. We will utilize mouse models of CC under the conditions of normal weight and obesity. Gamma-cyclodextrin and small molecule inhibitors of AKT and ERK will be evaluated for their ability to counteract the obesity-associated neoplastic burden. Future application of this approach could be the prevention of recurrence in overweight/obese CC patients. CC recurs in 40-60% of CC patients within three years after surgical resection, and interventions with gamma-cyclodextrin or AKT and ERK signaling inhibitors may change these statistics. Currently, gamma-cyclodextrin is generally recognized as safe (GRAS) by the U.S. Food and Drug Administration. Several small molecule inhibitors of the AKT and ERK signaling pathways are also currently applied in clinic, and therefore, available for our studies. 
  5. Inducible markers of colon cancer. We are currently developing a novel concept for induction of biomarkers that can facilitate the detection of neoplastic process in the human colon.

Student research opportunities

All projects described under “Research interests” are opportunities for student research involvement.

Recent publications

  • Bordonaro M, Lazarova D. Hypothesis: Obesity Is Associated with a Lower Mutation Threshold in Colon Cancer. J Cancer, 6(9): 825-831; 2015.
  • Lazarova D, Bordonaro M. Vimentin, colon cancer progression and resistance to butyrate and other HDACis. J Cell Mol Medicine, DOI: 10.1111/jcmm.12850; 2016.
  • Bordonaro M, Lazarova D. Determination of the role of CBP- and p300-mediated Wnt signaling on colonic cells. JMIR Res Protoc, 5(2): e66, DOI: 10.2196/resprot.5495, 2016.
  • Cho Y, Gutierrez L, Bordonaro M, Russo D, Anzelmi‎ F, Hooven JT, Cerra C, Lazarova DL. Effects of propolis and gamma-cyclodextrin on intestinal neoplasia in normal weight and obese mice. Cancer Med. 5(9):2448-58, 2016.
  • Bordonaro M., Shirasawa S, Lazarova DL. In hyperthermia increased ERK and WNT signaling suppress colorectal cancer cell growth. Cancers 8(5), pii: E49, 2016.
  • Lazarova D, Bordonaro, M.  ZEB1 Mediates Drug Resistance and EMT in p300-Deficient CRC. J Cancer 2017; 8(8): 1453-1459. Doi:10.7150/jca.18762.
  • Bordonaro M, Lazarova DL. CREB-binding protein, p300, butyrate, and Wnt signaling in colorectal cancer. World J Gastroenterol 21(27): 8238-8248; 2015.
  • Bordonaro M, Lazarova D. Hypothesis: Obesity Is Associated with a Lower Mutation Threshold in Colon Cancer. J Cancer, 6(9): 825-831; 2015.
  • Bordonaro, M., Drago, E., Atamna, W., and Lazarova, D.L. Comprehensive suppression of all apoptosis-induced proliferation pathways as a proposed approach to colorectal cancer prevention and therapy. PLoS One 9: e115068 (2014).
  • Bordonaro, M., and Lazarova, D.L. Hypothesis: cell signaling influences age-related risk of colorectal cancer. J. Cell. Mol. Med. 19: 74-81 (2014).
  • Lazarova, D.L., Chiaro, C., and Bordonaro, M. Butyrate induced changes in Wnt-signaling specific gene expression in colorectal cancer cells. BMC Research Notes 7: 226 (2014).
  • Bordonaro, M., and Lazarova, D.L. Butyrate, WNT signaling, and colorectal cancer. In: Butyrate: Food sources, functions and health benefits. Nova Science Publishers, Inc. (Hauppauge, NY) (2014).
  • Zeng, H., Lazarova, D.L., and Bordonaro, M. Mechanisms linking dietary fiber, gut microbiota and colon cancer prevention. World J. Gastrointestinal Oncol. 6 (2): 1-10 (2014).
  • Bordonaro, M., Venema, K., Putri, A.K., and Lazarova, D.L. Approaches that ascertain the role of dietary compounds in colonic cancer cells. World J. Gastrointestinal Oncol. 2014; 6 (1): 1-10 (2014). Full Text
  • Darina Lazarova1, Andrew Lee1, Terrence Wong1, Brigitte Marian2, Christopher Chiaro1, Christian Rainey3, Michael Bordonaro1. Modulation of Wnt Activity and Cell Physiology by Butyrate in LT97 Microadenoma Cells. J. Cancer. 2014; 5(3): 203-213. doi: 10.7150/jca.8569. Full Text
  • Huawei Zeng, Darina L Lazarova, Michael Bordonaro. Mechanisms linking dietary fiber, gut microbiota and colon cancer prevention. World J Gastrointest Oncol. Feb 2014; 15; 6(2): 41–51 . doi: 10.4251/wjgo.v6.i2.41
  • Bordonaro M, Lazarova DL. Chapter 8: Butyrate, WNT Signaling and Colorectal Cancer, Cong-Jun Li (Bovine Functional Genomics Laboratory, ARS, USDA, Maryland, USA) Butyrate: Food Sources, Functions and Health Benefits 2014. Biochemistry Research Trends . ISBN: 978-1-63117-657-9
  • Bordonaro M, Venema K, Putri AK, Lazarova, D.L. Approaches that ascertain the role of dietary compounds in colonic cancer cells. World J. Gastrointestinal Oncol. In Press (2013).
  • Drago E., Bordonaro M., Lee S., Atamna W., Lazarova DL. Propolis Augments Apoptosis Induced by Butyrate via Targeting Cell Survival Pathways. PLoS One. 8(9):e73151; 2013.
  • Lazarova DL, Wong T, Chiaro C, Drago E, Bordonaro M. p300 Influences Butyrate-Mediated WNT Hyperactivation In Colorectal Cancer Cells. J. Cancer 4:491-501, 2013.
  • Lazarova, DL, Chiaro C,, Wong T, Drago E, Rainey A, O’Malley S, Bordonaro M. CBP Activity Mediates Effects Of The Histone Deacetylase Inhibitor Butyrate On WNT Activity And Apoptosis In Colon Cancer Cells. J. Cancer 4(6): 481-490, 2013
  • Chiaro, C., D.L. Lazarova, and M. Bordonaro. Tcf3 and cell cycle factors contribute to butyrate resistance in colorectal cancer cells. Biochem Biophys Res Commun. Oct 11. pii: S0006-291X(12)01955-9. doi: 10.1016/j.bbrc.2012.10.018, 2012.
  • Lazarova DL, and M. Bordonaro. Extreme fluctuations in Wnt/beta-catenin signaling as an approach for colon cancer prevention and therapy. Adv Studies Biol. 4:351-362; 2012.
  • Lazarova DL, Bordonaro M. Extreme fluctuations in Wnt/beta-catenin signaling as an approach for colon cancer prevention and therapy. Advanced Studies in Biology, (2012), 4:351-362.
  • Zeng H., and D. L. Lazarova, Obesity-related colon cancer: dietary factors and their mechanisms of anticancer action, Clin. Exp. Pharmacol, Physiol. doi: 10.1111/j.1440-1681.2011.05518.x; 2011. Full Text
  • Bordonaro M, Tewari S, Cicco C, Atamna W, Lazarova DL. A switch from canonical to noncanonical Wnt signaling mediates drug resistance in colon cancer cells. PLoS One (2011), 6:e27308. Full Text
  • Bordonaro, M., Tewari, S., Atamna, W., and Lazarova, D.L., The notch ligand Delta-like 1 integrates inputs from TGFBeta/Activin and Wnt pathways, Exp. Cell Res. 317: 1368-1381, 2011. Full Text
  • Bordonaro M, Lazarova DL, Sartorelli AC. Role of Tcf-DNA binding and the chromatin remodeling factor Brg-1 in the modulation of Wnt activity by butyrate. Cell Cycle. 2008 Nov 5;7(21). PMID: 18948734. Full Text
  • Cai Y, Chin HF, Lazarova D, Menon S, Fu C, Cai H, Sclafani A, Rodgers DW, De La Cruz EM, Ferro-Novick S, Reinisch KM. The structural basis for activation of the Rab Ypt1p by the TRAPP membrane-tethering complexes. Cell. 2008 Jun 27;133(7):1202-13. PMID: 18585354. Full Text
  • Bordonaro M, Lazarova DL, Sartorelli AC. Hyperinduction of Wnt activity: a new paradigm for the treatment of colorectal cancer? Oncol Res. 2008;17(1):1-9. Review.PMID: 18488710. Full Text
  • Bordonaro M, Lazarova DL, Sartorelli AC. Butyrate and Wnt signaling: a possible solution to the puzzle of dietary fiber and colon cancer risk? Cell Cycle. 2008 May 1;7(9):1178-83Review. PMID: 18418037. Full Text
  • Bordonaro M, Lazarova DL, Sartorelli AC. The activation of beta-catenin by Wnt signaling mediates the effects of histone deacetylase inhibitors. Exp Cell Res. 2007 May 1;313(8):1652-66. PMID: 17359971. Full Text
  • Cai H, Yu S, Menon S, Cai Y, Lazarova D, Fu C, Reinisch K, Hay JC, Ferro-Novick S TRAPPI tethers COPII vesicles by binding the coat subunit Sec23. Nature. 2007 Feb 22;445(7130):941-4. PMID: 17287728. Full Text
  • Bordonaro M, Lazarova DL, Carbone R, Sartorelli AC. Modulation of Wnt-specific colon cancer cell kill by butyrate and lithium. Oncol Res. 2004;14(9):427-38.PMID: 15490974. Full Text
  • Bordonaro M, Lazarova DL, Sartorelli AC. Pharmacological and genetic modulation of Wnt-targeted Cre-Lox-mediated gene expression in colorectal cancer cells. Nucleic Acids Res. 2004 May 11;32(8):2660-74. PMID: 15141037. Full Text
  • Lazarova DL, Bordonaro M, Carbone R, Sartorelli AC.Linear relationship between Wnt activity levels and apoptosis in colorectal carcinoma cells exposed to butyrate. Int J Cancer. 2004 Jul 1;110(4):523-31. PMID: 15122584. Full Text
  • Bordonaro M, Lazarova DL, Augenlicht LH, Sartorelli AC. Cell type- and promoter-dependent modulation of the Wnt signaling pathway by sodium butyrate. Int J Cancer. 2002 Jan 1;97(1):42-51. PMID: 11774242. Full Text
  • Lazarova DL, Bordonaro M, Sartorelli AC. Transcriptional regulation of the vitamin D(3) receptor gene by ZEB. Cell Growth Differ. 2001 Jun;12(6):319-26. PMID: 11432806. Full Text
  • Lazarova DL, Spengler BA, Biedler JL, Ross RA. HuD, a neuronal-specific RNA-binding protein, is a putative regulator of N-myc pre-mRNA processing/stability in malignant human neuroblasts. Oncogene. 1999 Apr 29;18(17):2703-10. PMID: 10348344. Full Text
  • Ross RA, Lazarova DL, Manley GT, Smitt PS, Spengler BA, Posner JB, Biedler JL.HuD, a neuronal-specific RNA-binding protein, is a potential regulator of MYCN expression in human neuroblastoma cells. Eur J Cancer. 1997 Oct;33(12):2071-4. PMID: 9516855. Full Text
  • Spengler BA, Lazarova DL, Ross RA, Biedler JL.Cell lineage and differentiation state are primary determinants of MYCN gene expression and malignant potential in human neuroblastoma cells. Oncol Res. 1997;9(9):467-76. PMID: 9495452. Full Text
  • Zueva NN, Dalev PG, Lazarova DL. Properties, production, and practical uses of alkaline phosphatase] Biokhimiia. 1993 Jul;58(7):1009-23. Review. Russian. PMID: 8364120. Full Text

Book chapters

  • Bordonaro M, Lazarova DL. Butyrate, Wnt Signaling and Colorectal Cancer (Chapter 8) in book “Butyrate: Food Sources, Functions and Health Benefits.” Editor Congjun Li, NOVA publishers, 2014; ISBN: 978-1-63117-657-9.

Patents

  • Therapeutic compositions and uses thereof, # WO 2014163513 A1. The patent characterizes propolis complexes and their application; it is filed by Manuka Health New Zealand Limited (Auckland, New Zealand).

Education

Bachelor – St. Kliment Ohridski University, Sofia, Bulgaria
Master – St. Kliment Ohridski University, Sofia, Bulgaria
PhD – Fordham University, Bronx, NY
Postdoctoral – Yale University School of Medicine, New Haven, CT