Interrogation of Wnt, Notch and Hedgehog Activity in Primary Tumor Samples

Cancer results when undifferentiated cells grow in an uncontrolled manner, crowding out
normal cells, causing morbidity and ultimately mortality. The cancer stem cell theory
suggests that most tumors undergo a process of differentiation through which a relatively
rare cancer stem or progenitor cell (CSC) gives rise to more differentiated populations of
cells (including transiently amplifying cells) comprising the bulk of the tumor. As a result
of this cellular diversity, one or more cells within the tumor are likely to be resistant to
therapy. Among cells resistant to a given therapy, only CSCs can repopulate the tumor. A key
feature of this resistant subset of CSCs is that they repopulate a tumor resistant to the
original intervention. The cellular programs driving the uncontrolled proliferation of many
solid tumors result from aberrant activity of Wnt, Shh, and/or Notch signaling pathways in
CSC. Thus, therapies that down-regulate the activity of these fundamental pathways in CSCs
will be effective in the treatment of cancer. The investigators' research program focuses on
the elucidation of signaling mechanisms, control of cellular processes and discovery of small
molecules that selectively target Wnt, Shh, and Notch signaling pathways that are fundamental
to CSCs. Our preliminary results identified a novel Notch associated protein NACK that
functions as a transcriptional co-activator of Notch. Moreover, Nack is expressed in human
solid tumors and is required for cell survival and tumor growth in notch -dependent tumor
cells. The investigators' aim is to further interrogate the link between Notch and Nack.