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ROBERT G. OSHIMA, PH.D.
Program co-Director, Professor
Tumor Development
858.646.3147 (phone)
858.795.5268 (fax)
rgoshima@burnham.org
Research Focus
Cancers arise from mistakes in sending, receiving or interpreting the molecular instructions intended to construct or maintain the tissues of the body. The Oshima laboratory investigates the role of the Ets2 nuclear regulatory molecule in breast and colon cancer using mouse genetic models. Decreasing the amount of Ets2 results in mice in which breast cancers progresses slower. This effect is not due to the action of Ets2 in the tumor, but rather in the normal host tissues surrounding the lesion. In contrast to mammary tumors, decreasing Ets2 results in increasing colon cancers in the mouse. This repressive effect in colon cancer is linked to the role of Ets2 in regulating the self renewal of normal stem cells of the placenta. The formation of trophoblast stem cells from human embryonic stem cells and the possible stem cell origins of breast cancer are additional topics under investigation.
Biography
Robert Oshima earned his Ph.D. in biology from the University of California at San Diego in 1973. He did postdoctoral work at UC San Diego and the Centre National de la Recherche Scientifique, Gif-sur-Yvette, France. Dr. Oshima was a visiting scientist at Massachusetts Institute of Technology before joining the Burnham Institute for Medical Research in 1982. He is Co-Director of the newly formed Tumor Development Program.
Selected Publications
Allen, S. D., J. T. Garrett, et al. (2007). "Peptide vaccines of the HER-2/neu dimerization loop are effective in inhibiting mammary tumor growth in vivo." J Immunol 179(1): 472-82.
Cecena, G., F. Wen, et al. (2006). "Differential sensitivity of mouse epithelial tissues to the polyomavirus middle T oncogene." Am J Pathol 168(1): 310-20.
Hebbard, L. W., M. Garlatti, et al. (2008). "T-cadherin supports angiogenesis and adiponectin association with the vasculature in a mouse mammary tumor model." Cancer Res 68(5): 1407-16.
Jaksch M, Munera J, Bajpai R, Terskikh A, Oshima RG. Cell cycle dependent variation of a CD133 epitope in human embryonic stem cell, colon cancer and melanoma cell lines. Cancer Res; in press
Kairouz-Wahbe, R., H. Biliran, et al. (2008). "Anoikis effector Bit1 negatively regulates Erk activity." Proc Natl Acad Sci U S A 105(5): 1528-32.
Ke, Y., J. Lesperance, et al. (2006). "Conditional deletion of Shp2 in the mammary gland leads to impaired lobulo-alveolar outgrowth and attenuated Stat5 activation." J Biol Chem 281(45): 34374-80.
Ke, Y., D. Wu, et al. (2007). "Role of Gab2 in mammary tumorigenesis and metastasis." Oncogene.
Liu, M., A. Howes, et al. (2005). "Anti-tumor activity of rapamycin in a transgenic mouse model of ErbB2-dependent human breast cancer." Cancer Res 65(12): 5324-5336.
Okada, Y., Y. Ueshin, et al. (2007). "Complementation of placental defects and embryonic lethality by trophoblast-specific lentiviral gene transfer." Nat Biotechnol 25(2): 233-7.
Oshima, R. G. (2007). "Intermediate filaments: a historical perspective." Exp Cell Res 313(10): 1981-94.
Papadaki, C., M. Alexiou, et al. (2007). "Transcriptional Repressor Erf Determines Extraembryonic Ectoderm Differentiation." Mol Cell Biol.
Toivola, D. M., I. Nakamichi, et al. (2008). "Keratin Overexpression Levels Correlate with the Extent of Spontaneous Pancreatic Injury." Am J Pathol 172(4): 882-892.
Tynan, J. A., F. Wen, et al. (2005). "Ets2-dependent microenvironmental support of mouse mammary tumors." Oncogene 24(46): 6870-6876.
Wen, F., J. A. Tynan, et al. (2007). "Ets2 is required for trophoblast stem cell self-renewal." Dev Biol 312(1): 284-99.
List of Publications via PubMed
(NIH National Library of Medicine)
Research Report
Control of Trophoblast Differentiation and Functions
The development of embryos within placental mammals requires solutions to several potentially serious problems. First, a genetically dissimilar, rapidly proliferating mass of increasing cellular complexity must evade host defenses to avoid being rejected. Second an efficient mechanism of supplying nutrients and controlling exposure to hormones and growth factors must be established and continually expand its capacity to accommodate the embryo without compromising the life of the host. These problems are confronted by the first differentiated cells to appear during development, the trophoblast which establishes the embryo-maternal boundary and participates in the embryo-host circulatory interface. The complexity of the differentiation of trophoblasts and their critical interaction with host cells results in placenta development being a common stage at which many genes reveal their essential functions.
Ets2 Regulation of Placenta and Trophoblast Stem Cell self renewal
Early mouse placental development is dependent on the function of the Ets2 transcription factor (Yamamoto et al., 1998). Ets2 is one of a family of transcription factors which all utilized a conserved Ets protein domain for DNA binding (Galang et al., 2004) Ets2, like its Drosophila homologs pointed and yan is regulated by growth factor and oncogene signaling that use Ras signaling pathways. The phosphorylation of a single threonine residue in an evolutionarily conserved protein docking domain of Ets2 results in transcriptional activation and the induction of Ets2 dependent genes. We have investigated the function of Ets2 in trophoblast differentiation by combining molecular genetic methods for gene targeting and manipulation with the use of trophoblast stem cells and their differentiated derivatives in cell culture. By gene targeting methods we have generated several different Ets2 alleles. A knockout allele was created by deleting exons coding for the DNA binding domain and nuclear localization signals (Yamamoto et al., 1998). In addition, we have performed a knock-in that replaced the single amino acid which is phosphorylated by mediators of the Ras pathway (Man et al., 2003). This reinforced the importance of Ras pathway activation on Ets2 activity that was deduced from the Neu/ErbB2 activation of Ets2 signaling (Dankort et al., 2001) Recently we have generated a conditional inactivating deletion that uses the Cre loxP recombination system that permits the study of the function of the gene in both trophoblast cells and in adult tissues (Wen et al 2007). Ets2 regulates trophoblast stem cells self renewal and thus placental development. One of genes regulated by Ets2 in TS cells in the Cdx2 homeobox transcription factor. Because Cdx2 has previously been implicated as a suppressor to colon tumors, we have begun a study of the function of Ets2 in suppressing colon tumors. Combinations of thes different engineered mutations has facilitated the investigation of the role of Ets2 in controlling the growth and differentiation of TS cells and of the epithelial and stromal contributions of Ets2 to mammary tumors.
Trophoblast Stem Cell formation by Human Embryonic Stem Cells
We have very recently initiated a California Institute for Regenerative Medicine supported project to derive human trophoblast stem cells from embryonic stem cells. We are building a fluorescent reporter gene for Cdx2 expression into hES cells and have begun characterizing the cytoskeletal characteristics of hES cells.
Keratin Dependent Resistance of Trophoblast Cells to Apoptosis
Trophoblast giant cells form a boundary between embryonic and material environments. The embryonic lethality of keratin 8 (K8) deficient embryos is associated with a maternal, TNFa dependent process which is modeled by non-specific activation of the maternal immune system of pregnant mothers (Jaquemar et al., 2003) The increased sensitivity of keratin deficient epithelial cells to death receptor mediated apoptotic challenge (Caulin et al., 2000) is consistent with the hypothesis that some keratins provide trophoblast giant cells resistance to intrinsic apoptotic challenges in utero. Immunological challenges of trophoblast derivatives may be a common cause of pregnancy failure in humans.
An Ets2 Dependent, Stromal Restriction of Mammary Tumors
Mouse mammary tumors caused by the transgenic expression of the Polyoma virus middle T antigen or an activated form of Neu/ErbB2 are dependent upon on Ets2 because decreasing Ets2 by even half limits the appearance of such tumors (Man et al., 2003; Neznanov et al., 1999) This dependence on Ets2 is due, at least in part, to a host effect because malignant tumors transplanted directly into the fat pad of mice with deficient Ets2 grow in direct response to the activity of the combination of Ets2 host alleles (Man et al., 2003) We are currently investigating the role of Ets2 in endothelial cells during mammary tumor development.
We showed that the disruption of mammary epithelial polarity is tightly associated with the expression of the Neu oncogene. Increased expression of VEGF by Neu-transformed epithelial cells led to a dramatic acceleration of tumor formation and metastasis (Oshima et al., 2004) Unlike the generally accepted model of metastasis, tumor cells which retained their intercellular cohesion appear to bud off into vascular spaces and may passively lodge in lung capillaries. Contributions of this type of non-invasive metastasis maybe an important contribution to the well documented correlation of increased vascularity and metastasis. This accelerated model of breast cancer may be particularly useful for testing angiogenesis therapeutics because of the increased vessel density and the rapid and predictable progression of the disease.
Mammary Epithelial Stem Cells and Breast Cancer
In collaboration with Dr. Alexey Terskikh, we are investigating the role of the Maternal Embyronic Leucine zipper Kinase (Melk) in normal mammary epithelial stem cells and mouse models of breast cancer. Using a transgenic reporter gene for Melk expression we have found that Melk expression appears to be preferentially expressed in proliferative, mammary epithelial progenitor cells and tumor cells. We are using mammary transplantation methods, cell culture assays and mouse genetic tools to expand the investigation of the function of this candidate cancer therapeutic target.
