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Demetri D. Spyropoulos

Title
InstitutionMedical University of South Carolina
DepartmentPathology and Laboratory Medicine
AddressP.O. Box MSC 908
CRI207
Children's Research Inst. - 173 Ashley Ave.
Phone843-792-1625
Fax843-792-5002
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    My laboratory performs Biomedical Research at the interface between genetics and the environment through investigations that find common ground in embryonic development and adult disease. We study master regulators (homeobox, PPAR/RXR and Ets family genes), whose activities control cell type specification or ‘fate decisions’ and are in turn controlled epigenetically by exposures to agents, including natural and anthropogenic endocrine disrupting compounds (EDCs). The increase in bulk and variety of anthropogenic EDCs appears to closely parallel a variety of human health issues, including cancer, obesity, inflammation/immunity, cardiovascular and neurological diseases. For this work, we have relied heavily on animal model and cell-based systems and have created tools that act as surrogates for studying genetic interactions and cell fate determination as they pertain to human health trajectories. Sophisticated transgenic, knockout and xenograft rodent mammalian models have shown us the roles of particular homeobox and Ets genes in thoracic/urogenital patterning and epithelial cell fate, especially related to breast, lung and prostate carcinogenesis. For example, we observe that common estrogenic/anti-androgenic contaminants profoundly alter homeobox expression patterns in the embryo and cancer cells and are pursuing an understanding of these exposures on long-term health. Also, Hox homeobox and Ets1 gene disruptions have shown us that genetic background (i.e. modifier loci) can profoundly change whether a loss or gain in gene function is embryonic lethal or produces a minimal phenotype, pushing us to view “one size fits all” diagnostics and/or therapeutics with caution. Thus, we seek to improve these models to go beyond the investigation of common biomolecular mechanisms to patient-specific ‘humanized’ models that bridge the gap from basic research to diagnosis, prognosis and treatment-based pre-clinical/clinical trials. Towards this end, we have developed a method for freezing freshly excised human tissues, such that when thawed these tissues behave as if freshly isolated (live cells and intact 3-D architecture). Currently, we are using these patient-derived tissues for improved xenograft animal and ex vivo organ culture models to develop diagnostics (e.g. molecular signatures in parent tumors that indicate metastatic potential) and therapeutics (e.g. cancer cell resistance testing in native 3-D microenvironments). We use human induced pluripotent stem cells (iPSCs) as surrogates for studying the impact of environmental agents on embryonic cell type determination. Most recently, we have used human iPSCs to show that a major component of COREXIT, the solution used to disperse the Gulf Oil Spill, is a potent ‘obesogen’ that drives stem cell fate towards adipogenesis at the expense of osteogenesis (via altered PPARg/RXRa activities). This is potentially quite important given that 1.2 million gallons of COREXIT were used in the Gulf for oil spill clean up and since the obesogenic component is widely used in household cleaning products. This underscores our need to realize that while we are excellent builders of tools to solve specific problems we are not yet at a level to understand the influences of our tools on complex system-based levels. In this work on gene-by-environmental interactions, we hope provide tools to test novel dispersants; new tools that go beyond organism/cell toxicity testing to cell fate testing in order to more fully understand their potential to perturb long-term health trajectories.

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    embryonic development, adult disease, animal models

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    Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Faculty can login to make corrections and additions.
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    1. Temkin AM, Bowers RR, Ulmer CZ, Penta K, Bowden JA, Nyland J, Baatz JE, Spyropoulos DD. Increased adiposity, inflammation, metabolic disruption and dyslipidemia in adult male offspring of DOSS treated C57BL/6 dams. Sci Rep. 2019 Feb 06; 9(1):1530. PMID: 30728429.
      View in: PubMed
    2. Wang K, Xu R, Schrandt J, Shah P, Gong YZ, Preston C, Wang L, Yi JK, Lin CL, Sun W, Spyropoulos DD, Rhee S, Li M, Zhou J, Ge S, Zhang G, Snider AJ, Hannun YA, Obeid LM, Mao C. Correction: Alkaline Ceramidase 3 Deficiency Results in Purkinje Cell Degeneration and Cerebellar Ataxia Due to Dyshomeostasis of Sphingolipids in the Brain. PLoS Genet. 2018 01; 14(1):e1007190. PMID: 29360825.
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    3. Williams CE, McNabb NA, Brunell A, Lowers RH, Katsu Y, Spyropoulos DD, Kohno S. Feminizing effects of exposure to Corexit-enhanced water-accommodated fraction of crude oil in vitro on sex determination in Alligator mississippiensis. Gen Comp Endocrinol. 2018 09 01; 265:46-55. PMID: 29208362.
      View in: PubMed
    4. Wu M, Ingram L, Tolosa EJ, Vera RE, Li Q, Kim S, Ma Y, Spyropoulos DD, Beharry Z, Huang J, Fernandez-Zapico ME, Cai H. Gli Transcription Factors Mediate the Oncogenic Transformation of Prostate Basal Cells Induced by a Kras-Androgen Receptor Axis. J Biol Chem. 2016 Dec 02; 291(49):25749-25760. PMID: 27760825.
      View in: PubMed
    5. Toyota K, McNabb NA, Spyropoulos DD, Iguchi T, Kohno S. Toxic effects of chemical dispersant Corexit 9500 on water flea Daphnia magna. J Appl Toxicol. 2017 02; 37(2):201-206. PMID: 27225887.
      View in: PubMed
    6. Bowers RR, Temkin AM, Guillette LJ, Baatz JE, Spyropoulos DD. The commonly used nonionic surfactant Span 80 has RXRa transactivation activity, which likely increases the obesogenic potential of oil dispersants and food emulsifiers. Gen Comp Endocrinol. 2016 11 01; 238:61-68. PMID: 27131391.
      View in: PubMed
    7. Bilir B, Osunkoya AO, Wiles WG, Sannigrahi S, Lefebvre V, Metzger D, Spyropoulos DD, Martin WD, Moreno CS. SOX4 Is Essential for Prostate Tumorigenesis Initiated by PTEN Ablation. Cancer Res. 2016 Mar 01; 76(5):1112-21. PMID: 26701805.
      View in: PubMed
    8. Wang K, Xu R, Schrandt J, Shah P, Gong YZ, Preston C, Wang L, Yi JK, Lin CL, Sun W, Spyropoulos DD, Rhee S, Li M, Zhou J, Ge S, Zhang G, Snider AJ, Hannun YA, Obeid LM, Mao C. Alkaline Ceramidase 3 Deficiency Results in Purkinje Cell Degeneration and Cerebellar Ataxia Due to Dyshomeostasis of Sphingolipids in the Brain. PLoS Genet. 2015 Oct; 11(10):e1005591. PMID: 26474409.
      View in: PubMed
    9. Temkin AM, Bowers RR, Magaletta ME, Holshouser S, Maggi A, Ciana P, Guillette LJ, Bowden JA, Kucklick JR, Baatz JE, Spyropoulos DD. Effects of Crude Oil/Dispersant Mixture and Dispersant Components on PPAR? Activity in Vitro and in Vivo: Identification of Dioctyl Sodium Sulfosuccinate (DOSS; CAS #577-11-7) as a Probable Obesogen. Environ Health Perspect. 2016 Jan; 124(1):112-9. PMID: 26135921.
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    10. Lottes RG, Newton DA, Spyropoulos DD, Baatz JE. Lactate as substrate for mitochondrial respiration in alveolar epithelial type II cells. Am J Physiol Lung Cell Mol Physiol. 2015 May 01; 308(9):L953-61. PMID: 25747963.
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    11. Wiles WG, Mou Z, Du Y, Long AB, Scharer CD, Bilir B, Spyropoulos DD, Jenkins NA, Copeland NG, Martin WD, Moreno CS. Mutation of murine Sox4 untranslated regions results in partially penetrant perinatal lethality. In Vivo. 2014 Sep-Oct; 28(5):709-18. PMID: 25189881.
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    12. Shojaii R, Bacopulos S, Yang W, Karavardanyan T, Spyropoulos D, Raouf A, Martel A, Seth A. Reconstruction of 3-dimensional histology volume and its application to study mouse mammary glands. J Vis Exp. 2014 Jul 26; (89):e51325. PMID: 25145969.
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    13. Baatz JE, Newton DA, Riemer EC, Denlinger CE, Jones EE, Drake RR, Spyropoulos DD. Cryopreservation of viable human lung tissue for versatile post-thaw analyses and culture. In Vivo. 2014 Jul-Aug; 28(4):411-23. PMID: 24982205.
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    14. Atanelishvili I, Liang J, Akter T, Spyropoulos DD, Silver RM, Bogatkevich GS. Thrombin increases lung fibroblast survival while promoting alveolar epithelial cell apoptosis via the endoplasmic reticulum stress marker, CCAAT enhancer-binding homologous protein. Am J Respir Cell Mol Biol. 2014 May; 50(5):893-902. PMID: 24279877.
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    15. Lottes RG, Newton DA, Spyropoulos DD, Baatz JE. Alveolar type II cells maintain bioenergetic homeostasis in hypoxia through metabolic and molecular adaptation. Am J Physiol Lung Cell Mol Physiol. 2014 May 15; 306(10):L947-55. PMID: 24682450.
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    16. Temkin AM, Spyropoulos DD. Induced pluripotent stem cell technology and aquatic animal species. Comp Biochem Physiol C Toxicol Pharmacol. 2014 Jun; 163:3-13. PMID: 24548888.
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    17. Chatterjee S, Bacopulos S, Yang W, Amemiya Y, Spyropoulos D, Raouf A, Seth A. Loss of Igfbp7 causes precocious involution in lactating mouse mammary gland. PLoS One. 2014; 9(2):e87858. PMID: 24505323.
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    18. Sutter AG, Palanisamy AP, Kurtz N, Spyropoulos DD, Chavin KD. Efficient method of genotyping ob/ob mice using high resolution melting analysis. PLoS One. 2013; 8(11):e78840. PMID: 24236058.
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    19. Cryopreservation and in vitro culture of primary cell types from lung tissue of a stranded pygmy sperm whale (Kogia breviceps). Comp Biochem Physiol C Toxicol Pharmacol. 2012 Jan; 155(1):136-42. PMID: 21501697.
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    20. Moussa O, LaRue AC, Abangan RS, Williams CR, Zhang XK, Masuya M, Gong YZ, Spyropoulos DD, Ogawa M, Gilkeson G, Watson DK. Thrombocytopenia in mice lacking the carboxy-terminal regulatory domain of the Ets transcription factor Fli1. Mol Cell Biol. 2010 Nov; 30(21):5194-206. PMID: 20823267.
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    21. Grek CL, Newton DA, Spyropoulos DD, Baatz JE. Hypoxia up-regulates expression of hemoglobin in alveolar epithelial cells. Am J Respir Cell Mol Biol. 2011 Apr; 44(4):439-47. PMID: 20508070.
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    22. Grek CL, Newton DA, Qiu Y, Wen X, Spyropoulos DD, Baatz JE. Characterization of alveolar epithelial cells cultured in semipermeable hollow fibers. Exp Lung Res. 2009 Mar; 35(2):155-74. PMID: 19263283.
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    23. Ellett JD, Evans ZP, Zhang G, Chavin KD, Spyropoulos DD. A rapid PCR-based method for the identification of ob mutant mice. Obesity (Silver Spring). 2009 Feb; 17(2):402-4. PMID: 18948969.
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    24. Zhang XK, Moussa O, LaRue A, Bradshaw S, Molano I, Spyropoulos DD, Gilkeson GS, Watson DK. The transcription factor Fli-1 modulates marginal zone and follicular B cell development in mice. J Immunol. 2008 Aug 01; 181(3):1644-54. PMID: 18641300.
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    25. McCabe CD, Spyropoulos DD, Martin D, Moreno CS. Genome-wide analysis of the homeobox C6 transcriptional network in prostate cancer. Cancer Res. 2008 Mar 15; 68(6):1988-96. PMID: 18339881.
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    26. Higuchi T, Bartel FO, Masuya M, Deguchi T, Henderson KW, Li R, Muise-Helmericks RC, Kern MJ, Watson DK, Spyropoulos DD. Thymomegaly, microsplenia, and defective homeostatic proliferation of peripheral lymphocytes in p51-Ets1 isoform-specific null mice. Mol Cell Biol. 2007 May; 27(9):3353-66. PMID: 17339335.
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    27. Schweinfest CW, Spyropoulos DD, Henderson KW, Kim JH, Chapman JM, Barone S, Worrell RT, Wang Z, Soleimani M. slc26a3 (dra)-deficient mice display chloride-losing diarrhea, enhanced colonic proliferation, and distinct up-regulation of ion transporters in the colon. J Biol Chem. 2006 Dec 08; 281(49):37962-71. PMID: 17001077.
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    28. Smith BT, Mussell JC, Fleming PA, Barth JL, Spyropoulos DD, Cooley MA, Drake CJ, Argraves WS. Targeted disruption of cubilin reveals essential developmental roles in the structure and function of endoderm and in somite formation. BMC Dev Biol. 2006 Jun 20; 6:30. PMID: 16787536.
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    29. Burger AM, Leyland-Jones B, Banerjee K, Spyropoulos DD, Seth AK. Essential roles of IGFBP-3 and IGFBP-rP1 in breast cancer. Eur J Cancer. 2005 Jul; 41(11):1515-27. PMID: 15979304.
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    30. Mitas M, Almeida JS, Mikhitarian K, Gillanders WE, Lewin DN, Spyropoulos DD, Hoover L, Graham A, Glenn T, King P, Cole DJ, Hawes R, Reed CE, Hoffman BJ. Accurate discrimination of Barrett's esophagus and esophageal adenocarcinoma using a quantitative three-tiered algorithm and multimarker real-time reverse transcription-PCR. Clin Cancer Res. 2005 Mar 15; 11(6):2205-14. PMID: 15788668.
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    31. Grund EM, Spyropoulos DD, Watson DK, Muise-Helmericks RC. Interleukins 2 and 15 regulate Ets1 expression via ERK1/2 and MNK1 in human natural killer cells. J Biol Chem. 2005 Feb 11; 280(6):4772-8. PMID: 15563472.
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    32. Zhang XK, Gallant S, Molano I, Moussa OM, Ruiz P, Spyropoulos DD, Watson DK, Gilkeson G. Decreased expression of the Ets family transcription factor Fli-1 markedly prolongs survival and significantly reduces renal disease in MRL/lpr mice. J Immunol. 2004 Nov 15; 173(10):6481-9. PMID: 15528390.
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    33. Masuya M, Moussa O, Abe T, Deguchi T, Higuchi T, Ebihara Y, Spyropoulos DD, Watson DK, Ogawa M. Dysregulation of granulocyte, erythrocyte, and NK cell lineages in Fli-1 gene-targeted mice. Blood. 2005 Jan 01; 105(1):95-102. PMID: 15367440.
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    34. Maroulakou IG, Spyropoulos DD. The study of HOX gene function in hematopoietic, breast and lung carcinogenesis. Anticancer Res. 2003 May-Jun; 23(3A):2101-10. PMID: 12894584.
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    35. Spyropoulos DD, Bartel FO, Higuchi T, Deguchi T, Ogawa M, Watson DK. Marker-assisted study of genetic background and gene-targeted locus modifiers in lymphopoietic phenotypes. Anticancer Res. 2003 May-Jun; 23(3A):2015-26. PMID: 12894574.
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    36. Kawada H, Ito T, Pharr PN, Spyropoulos DD, Watson DK, Ogawa M. Defective megakaryopoiesis and abnormal erythroid development in Fli-1 gene-targeted mice. Int J Hematol. 2001 Jun; 73(4):463-468. PMID: 11503960.
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    37. Bartel FO, Higuchi T, Spyropoulos DD. Mouse models in the study of the Ets family of transcription factors. Oncogene. 2000 Dec 18; 19(55):6443-54. PMID: 11175360.
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    38. Garcia-Gasca A, Spyropoulos DD. Differential mammary morphogenesis along the anteroposterior axis in Hoxc6 gene targeted mice. Dev Dyn. 2000 Oct; 219(2):261-76. PMID: 11002345.
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    39. Spyropoulos DD, Pharr PN, Lavenburg KR, Jackers P, Papas TS, Ogawa M, Watson DK. Hemorrhage, impaired hematopoiesis, and lethality in mouse embryos carrying a targeted disruption of the Fli1 transcription factor. Mol Cell Biol. 2000 Aug; 20(15):5643-52. PMID: 10891501.
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    40. Rogner UC, Spyropoulos DD, Le Novère N, Changeux JP, Avner P. Control of neurulation by the nucleosome assembly protein-1-like 2. Nat Genet. 2000 Aug; 25(4):431-5. PMID: 10932189.
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    41. de la Cruz CC, Der-Avakian A, Spyropoulos DD, Tieu DD, Carpenter EM. Targeted disruption of Hoxd9 and Hoxd10 alters locomotor behavior, vertebral identity, and peripheral nervous system development. Dev Biol. 1999 Dec 15; 216(2):595-610. PMID: 10642795.
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    42. Papas TS, Bhat NK, Spyropoulos DD, Mjaatvedt AE, Vournakis J, Seth A, Watson DK. Functional relationships among ETS gene family members. Leukemia. 1997 Apr; 11 Suppl 3:557-66. PMID: 9209455.
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    43. Spyropoulos DD, Capecchi MR. Targeted disruption of the even-skipped gene, evx1, causes early postimplantation lethality of the mouse conceptus. Genes Dev. 1994 Aug 15; 8(16):1949-61. PMID: 7958869.
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    44. Spyropoulos DD, Stallard V, Roberts BE, Cohen LK. Utilization of DNA recombination for the two-step replacement of growth factor sequences in the vaccinia virus genome. J Virol. 1991 Sep; 65(9):4609-18. PMID: 1870191.
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    45. Lautenberger JA, Schulz RA, Garon CF, Tsichlis PN, Spyropoulos DD, Pry TW, Rushlow KE, Papas TS. The transforming sequences of avian myelocytomatosis virus (MC29). J Supramol Struct Cell Biochem. 1981; 16(2):193-207. PMID: 6271982.
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