Case Western Reserve University

Barbara Bedogni, Ph.D.

Visiting Assistant Professor

Education

• Ph.D.: Catholic University, Rome, Italy
• Postdoc: Department of Radiation Oncology, Stanford University, Stanford, CA

Research Interests

The goal of our lab is to understand how the interaction between the tissue microenvironment and oncogenes contributes to melanoma development and progression.

Melanoma results from the interaction of altered intracellular tumor suppressors and oncogenes with the microenvironment in which these changes occur. Normal human and mouse skin is mildly hypoxic and melanocytes are localized in areas of hypoxia, suggesting that skin hypoxia might represent a permissive environment for melanocyte survival and a promoting factor that contributes to melanocyte transformation. In fact, Akt is able to transform melanocytes only when in the presence of a mild hypoxic environment normally found in skin and this is mediated by the transcription factor HIF-1α (Hypoxia Inducible Factor-1α).

The Notch signaling pathway lies at the convergence of the signaling cascade triggered by hypoxia and Akt and is required for melanocyte transformation and melanoma development. The Notch signaling pathway is an evolutionarily conserved signaling cascade that affects cell fate decisions and many differentiation processes during both embryonic and postnatal development, including proliferation, survival, EMT/MET (epithelial-mesenchymal transition/mesenchymal-epithelial transition) in both normal and tumor cells.

One of the research interests of our lab is to understand how Notch signaling contributes to melanoma development and progression. We have evidence suggesting that the Notch signaling pathway is elevated in melanoma. The goal of our research is to dissect the mechanism by which Notch1 and its effectors and other Notch receptors and ligands affect melanomagenesis. These studies will benefit from a vast array of melanoma cell lines and both melanoma orthotopic and transgenic mouse models for studies in vivo.

Our lab is also interested in understanding what role hypoxia and the Hypoxia Inducible Factors (HIF-1α and HIF-2α) play in the survival and maintenance of melanocyte precursor cells and whether they contribute to melanomagenesis. Our hypothesis is that normal tissue hypoxia creates a permissive niche for stem/precursor cells via regulation of specific genes (e.g. Oct-4) and that, by maintaining cells in a more precursor-like state may contribute to tumorigenesis. These studies will take advantage of conditional KO mice where HIF-1α and/or HIF-2α can be excised specifically in the melanocytic lineage and of transgenic melanoma mouse models for the study of melanomagenesis in vivo.

The ultimate goal of our research is to understand the genetics of melanoma in order to gain new knowledge that can lead to new therapeutic approaches.

Selected References

• Bedogni B, Warneke JA, Nickoloff BJ, Giaccia AJ, Powell MB.
  “Notch1 is a mediator of Akt and Hypoxia in melanoma development.”
  J. Clin. Invest. 118 (11): 3660-70, (2008)
• Bedogni B, Welford SM, Kwan AC, Ranger-Moore J, Saboda K, Powell MB.
  “Inhibition of PI3Kinase and MEK1/2 prevents melanoma development and promotes melanoma regression in the transgenic TPRas mouse model.”
  Mol Cancer Ther 5: 3071-7 (2006)
• Bedogni B, Welford SM, Cassarino DS, Nickoloff BJ, Giaccia AJ, Powell MB.
  “The hypoxic microenvironment of the skin contributes to Akt-mediated melanocyte transformation.”
  Cancer Cell. 8: 443-54 (2005)
• Bedogni, B, O’Neil MS, Welford SM, Bouley DM, Denko NC, Giaccia AJ, Powell M.B.
  “Topical treatment with inhibitors of the PI3Kinase/Akt and Raf/MEK/Erk pathways reduces melanoma development.”
  Cancer Res. 64: 2552-60 (2004)