Abstract

In the past few years it has become possible to mobilize Sleeping Beauty (SB), a member of the Tc1/mariner class of transposons, in mouse somatic cells, at frequencies high enough to induce cancer. Cancer results from SB-induced insertional mutagenesis of oncogenes and tumor suppressor genes and the SB insertion sites in these tumors serve to mark the location of candidate cancer genes. Cancer gene discovery continues to drive current cancer research with the promise of identifying new diagnostic markers and therapeutic targets by elucidating novel genetic interactions that promote or sustain tumor formation. More recently, we have been able to develop a conditional floxed SB transposase allele that can be activated tissue-specifically by Cre recombinase, which has made it possible to selectively model virtually any human solid tumor in mice using SB mutagenesis. Using this conditional SB transposition system, often in combination with sensitizing mutations such as activated Kras or mutant Apc, P53 or Smad4, we have been able to model 15 different human cancers affecting 11 organ sites in our laboratory in Singapore. In my talk I will summarize the main lessons we have learned from these studies in addition to the challenges we face in using this new type of genomic information to develop new and/or better cancer therapeutics.