RESEARCH

/RESEARCH
RESEARCH2019-03-21T02:07:12+00:00

The Rosetta Institute of Biomedical Research is an independently funded medical research institute founded by Dr. Ryan Holzer, PhD.  The institute is funded by internally generated revenue, and by private donations.

We conduct basic and translational research on cell death in multiple myeloma and lung cancer, with the ultimate goal of identifying novel driver mutations responsible for tumorigenesis and the emergence of chemoresistant clones. The primary model system is molecular evolution in response to various cytotoxic agents, including agents that disturb proteostasis, senolytics, and inhibitors of DNA replication. Under this umbrella, multiple overlapping themes are being investigated, including: 1) discovering novel mechanisms of bortezomib (Velcade) resistance in multiple myeloma and the identification of the bortezomib-resistant subclone, 2) transcriptomic analysis and miRNA profiling of clonal evolution in cancer, 3) the discovery of novel roles for IL-6 family cytokines in hematologic malignancies, 4) The identification of novel alternatively spliced transcripts that contribute to tumor progression and the RNA-binding proteins that regulate rare exon inclusion/exclusion, 5) the role and regulation of autophagy during proteotoxic stress, 6) adaptation to endoplasmic reticulum (ER) stress and mechanisms of ER stress-induced apoptosis, 7) the role of cell differentiation in drug resistance and the identification and characterization of the stem cell compartment, 8) the role of hypoxia in drug sensitivity and clonal evolution, 9) the role of senescence in drug resistance/drug sensitivity and the identification and characterization of the senescence-prone subclone, 10) the genetic basis for the co-emergence of the drug resistance and epithelial-mesenchymal transition (EMT) phenotypes, 11) The role of innate antiviral defense mechanisms in myeloma pathogenesis/progression and treatment response. A variety of techniques are being used at the Institute to address these questions, including tissue culture, bioinformatic analyses, CRISPR/Cas9 gene editing, and mass spectrometry. In addition, we are engaged in a drug discovery program to identify novel small molecules that combat cancer, neurodegenerative disorders, aging and other diseases related to senescence, splicing errors or disturbances in proteostasis.

PUBLICATIONS

  • Holzer RG, MacDougall CA, Atwood C, Courtright G, Green JE, and Jorcyk CL: Development and characterization of a progressive series of mammary
    adenocarcinoma cell lines derived from the C3(1)/SV40 Large T-antigen transgenic mouse model. Breast Cancer Res and Treatment 77: 65-76, 2003
  • Holzer RG, Ryan RE, Tommack M, Schlekeway E and Jorcyk CL. Oncostatin M stimulates the detachment of a reservoir of invasive mammary carcinoma cells: role of cyclooxygenase-2. Clin Exp Metastasis 21: 167-76, 2004
  • MacDougall CA, Vargas M, Soares CR, Holzer RG, Ide AE, Jorcyk, CL. Involvement of HGF/SF-Met signaling in prostate adenocarcinoma cells: evidence for
    alternative mechanisms leading to a metastatic phenotype in Pr-14c. Prostate 21: 167-76, 2004
  • Queen MM, Ryan RE, Holzer RG, Keller-Peck CR, Jorcyk, CL. Breast cancer cells stimulate neutrophils to produce oncostatin M: potential implications for
    tumor progression. Cancer Res 65: 8896-904, 2005
  • Jorcyk CL, Holzer RG, Ryan RE. Oncostatin M induces cell detachment and enhances the metastatic capacity of T-47D human breast carcinoma cells.
    Cytokine 33: 323-36, 2006
  • Gallagher E, Tenzler T, Matsuzawa A, Anzelon-Mills A, Otero D, Holzer R, Janssen E, Gao M, Karin M. Kinase MEKK1 is required for CD40-dependent
    activation of the kinases Jnk and p38, germinal center formation, B cell proliferation and antibody production. Nat Immunology 8: 57-63, 2007
  • Park EJ, Lee JH, Yu G-Y, He G, Ali SR, Holzer RG, Österreicher CO, Takahashi H, Karin M. Dietary and genetic obesity promote liver inflammation and
    tumorigenesis by enhancing IL-6 and TNF expression. Cell 140: 197-208, 2010
  • Holzer RG, Park EJ, Tran H, Choi C, Li N, Solinas G, Karin M. Saturated fatty acids activate JNK by inducing c-Src clustering within intracellular membrane
    subdomains. Cell 147: 173-184, 2011.
  • Li N, Wu X, Holzer RG, Lee J-H, Park E-J, Ogata H, Gukovskaya AS, Gukovsky I, Moscat J, Dia-Meco M, Deerinck T, Dawson D, VandenBerg S, Karin M. Loss of acinar cell IKKα triggers spontaneous pancreatitis in mice. Journal of Clinical Investigation 123: 2231-43, 2013.
  • Tawara K, Scott H, Emathinger J, Ide A, Fox R, Greiner D, LaJoie D, Hedeen D, Nandakumar M, Oler AJ, Holzer R, Jorcyk C.  Co-Expression of VEGF and IL-6 family cytokines is associated with decreased survival in HER2 negative breast cancer patients: subtype-specific IL-6 family cytokine-mediated VEGF secretion.  Translational Oncology  12: 245-255, 2018.