MDA B4.4511 (Unit 072)
The University of Texas MD Anderson Cancer Center
Department of Hematopathology
My research focuses on the problem of chemoresistance in diffuse large B cell lymphoma (DLBCL), in particular in cellular adaptation at the membrane level and its contribution to drug resistance as well as cellular responses to established treatment modalities. Drug resistance is arguably one of the least understood aspects of cancer, especially when the emphasis is placed on the mechanisms leading towards resistance as opposed to the resulting changes in already established oncogenic pathways.
Smoothened (SMO) is a transmembrane protein that is overexpressed in lymphoma, and in other cancers. We found that SMO expression is highly induced in doxorubicin-resistant lymphoma cells. In addition, our findings reveal for the first time that SMO is a raft resident protein and that depletion of SMO results in a decrease of multiple cytokine/growth factor receptors in lymphoma and other cancer cells. Furthermore, silencing SMO quantitatively and qualitatively alters cell signaling involved in proliferation and cell survival such as PI3K/AKT. Although SMO localizes in cilia to function as Hedgehog signal transducer, our data support that SMO localizes in lipid rafts and mediates the assembly of a TRAF6 E3 ligase-dependent machinery that enhances AKT signaling, establishing a potential link to chemoresistance.
We are evaluating whether SMO levels and its activation state directly modulates the properties of lipid rafts with regard to expression of surface receptors or overall lipid raft composition. We are also exploring whether changes in SMO driven compartmentalization of signaling proteins enhances activation of survival pathways contributing to lymphoma progression and chemoresistance.
Education & Training
M.D. - University Complutense of Madrid - 1992
Ph.D. - University of Navarra - 1997