Proteomic landscapes in cancer
Currently, we are developing proteomic approaches to delineate the role of the ubiquitin proteasome system (UPS) in hematopoiesis, cancer and stem cell function. For that purpose, we mainly focus on the E3 ligase Fbw7, which regulates the degradation of several important oncogenes with central roles in cell division, growth and differentiation. We have recently shown that Fbw7 acts as a tumor suppressor of T-cell acute lymphoblastic leukemia (T-ALL) by targeting Notch1 (Thompson et al, J Exp Med. 2007). Furthermore, we have shown that, by targeting c-myc, Fbw7 regulates the quiescence and self-renewal capacity of hematopoietic stem cells (HSCs); however, it is dispensable for the pluripotency abilities of embryonic stem cells (ESC), but appears to acquire a role along with cell differentiation (Reavie et al, Nat Immunol 2010).
We are now working on the identification of novel Fbw7 substrates by in-vitro tandem purifications combined with mass spectrometry. We then want to understand the role that the newly identified Fbw7:substrate pairs have in the different considered systems. In addition, we are developing strategies to perform global mass spectrometry analysis of various types of cells in which Fbw7 has been deleted by genetic engineering in order to identify additional substrates by comparing them to their controls. For these series of experiments, we include in vivo and in vitro models aiming to define the tissue and function specificity of the landscape of Fbw7 substrates. After these experiments we should be able to answer question such as: .which are the Fbw7 susbtrates involved in stem cell differentiation? or which Fbw7 substrates are upregulated after Fbw7 malfunctioning in different types of cancer?. Altogether, the ultimate goal of our research is to identify pathways that are new potential therapeutic targets in leukemia and, possibly, in other types of cancer.