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 apoptosis in multiple myeloma and other malignancies, with the ultimate goal of identifying novel driver mutations responsible for tumorigenesis and the emergence of chemoresistant clones. Current research projects include: 1) discovering novel mechanisms of bortezomib (Velcade) resistance in multiple myeloma, 2) characterizing pro-apoptotic signaling pathways activated by Type 1 interferon (IFN-a/b), 3) the identification and characterization of ubiquitin ligases that regulate cell survival, 4) transcriptomic analysis and miRNA profiling of clonal evolution in cancer, 5) the discovery of novel roles for IL-6 family cytokines in hematologic malignancies, 6) The identification of novel alternatively spliced transcripts that contribute to tumor progression and the RNA-binding proteins that regulate rare exon inclusion/exclusion, 7) the role and regulation of autophagy during proteotoxic stress, 8) adaptation to endoplasmic reticulum (ER) stress and mechanisms of ER stress-induced apoptosis, 9) the identification and characterization of the multiple myeloma stem cell compartment and the bortezomib-resistant subclone, 10) The role of hypoxia in drug sensitivity and clonal evolution. A variety of techniques are being used at the Institute to address these questions, including bioinformatic analyses, CRISPR/Cas9 gene editing, tissue culture and mouse models of cancer. Ultimately this knowledge will be translated into next generation therapeutics for the treatment of cancer and other diseases associated with splicing errors or disturbances in proteostasis.
- 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 IKKa triggers spontaneous pancreatitis in mice. Journal of Clinical Investigation 123: 2231-43, 2013.
- Tawara K, Scott H, Emathinger J, Ide A, Fox R, LaJoie D, Hedeen D, Nandakumar M, Oler AJ, Holzer RG, Jorcyk CL. Expression of VEGF and IL-6 family cytokines are associated with decreased survival in HER2- breast cancer: subtype specific IL-6 family cytokine-mediated VEGF secretion. Submitted for Publication.