Tian Xu, PhD

Metastasis is the major cause of mortality for cancer patients. Given that alterations causing metastasis are late events and that multiple genetic alterations occur in late stage cancers, traditional approaches have not been fruitful in identifying genes involved in metastasis. We have performed a genome-wide genetic screen for mutations promoting tumor progression and metastasis in Drosophila and have identified mutations in more than 50 genes. We have found that apicobasal polarity mutations in collaboration with oncogenic Ras mutation produce fly tumors with a full spectrum of metastatic phenotypes observed in human malignant cancers. Mutation of cell polarity genes activates JNK signaling and down-regulates the E-cadherin/b-catenin adhesion complex. Furthermore, JNK and Ras signaling cooperate in promoting tumor growth. The concept that tumor-initiating alterations contribute to the development of metastasis, provides an explanation why tumors of distinguish origins have vast different metastatic potential.

Our work has also revealed that tumor cells hijack normal invasive developmental process to achieve progression. Elements of the invasion machinery, including JNK-induced MMP expression, are shared by both developmental and tumor invasion processes. Preventing BM degradation completely blocks both tissue and tumor invasion, indicating that modulation of BM is essential for invasion. The pathways regulate invasion during development and tumor progression are excellent targets for cancer therapy. Our work on tumor growth have shown that tumor suppressors such as TSC, PTEN, and LATS regulate tissue and organism size during development and propose that deregulation of size-control mechanisms is essential for tumorigenesis. We have showed that TSC and PTEN genes function in the PI3K/Akt pathway and reduction of S6K activity levitates TSC defects. These findings have helped to define one of the major cancer pathways in humans and have lead to clinical trials for TSC and LAM diseases. One of our long term goal is to develop methodologies in mammals for interrogating the genome by forward genetics. We have successfully adapted the piggyBac transposon for transgenesis and insertional mutagenesis in mammals. This has led to the development of a highly efficient single transposon mutagenesis strategy and to the near-production of the first set of genome-wide insertional mutants in mice, which will provide an unprecedented opportunity for deciphering mammalian biology and disease.