Current Research and Scholarly Interests
The long-term goal of our laboratory is to identify novel targets for cancer therapy in order to improve the lives of cancer patients. We use genome-wide analysis tools (RNAseq, WGS, microarrays etc) to understand the consequences of oncogenic mutations at a system-wide level. We have found that comparing genome-wide changes in mouse models of cancer with those seen in primary human tumors is a fruitful approach for the discovery of novel genes and pathways important in oncogenesis. We continue to exploit such cross species comparisons as a tool for understanding cancer pathways and networks. We also use shRNA technology both in vitro and in vivo to perform functional studies of genes identified in our genomic screens. Our laboratory has a genome-wide lentiviral shRNA library available which greatly facilitates these studies.
Specific Projects Include:
Kras is one of the most frequently mutated genes in human cancer. Many signaling pathways have been described as being necessary for Kras induced oncogenic transformation. However, the specific pathways required are strongly dependent on the tissue origin (fibroblast vs epithelial cell) and the species of the model system used. Using cross-species microarray analysis, we have uncovered a gene expression profile associated with Kras mutation across species and in different tissues (Sweet-Cordero, Nature Genetics 2005). We have used shRNA- based screens to study the functional significance of this signature. For example, we identified Wt1 as a key regulator of the Kras signature and also a gene whose loss leads to “synthetic senescence” in the context of oncogenic Kras activation (Vicent et al, JCI, 2010). Current studies are focused on identifying novel critical regulators of Kras function, primarily in lung cancer.
Chemotherapy response in vivo
Despite decades of clinical use, much is still unknown about the molecular and cellular determinants of chemotherapy response in cancer. We rely on mouse models that closely recapitulate important aspects of human oncogenesis to study chemotherapy response (Oliver et al Genes and Development, 2010). We are particularly interested in uncovering why tumor-propagating cells (TPCs, also called cancer stem cells) are chemoresistant. Recently, we described and characterized a tumor-propagating population of cells that is dependent on Notch3 signaling (Zheng et al Cancer Cell 2013). Other work is focused on determining how the tumor microenvironment contributes to tumor growth (Vicent et al, Cancer Research 2012) and understanding the kinetics of TPCs in vivo (Zheng et al, Cancer Research 2013).
Modeling solid tumor translocations in vivo and in vitro
Translocations are genetic events present in many cancer types. They are particularly frequent in tumors common in pediatric patients. We use gene targeting to produce mouse models in which translocation events can be activated temporally or in specific tissues. We are using gene targeting approaches in the mouse to study the oncogenesis mediated by fusion of the gene EWS with ets family transcription factors such as Fli-1 and Erg. Such translocations are seen in Ewing’s Sarcoma, a bone tumor found mostly in children. Using human mesenchymal stem cells, we are also exploring what genetic events other than oncogenic translocation are required for tumor initiation and progression. Recently we described a role for a long non-coding RNA (lncRNA) in the pathogenesis of Ewing sarcoma (Howarth et al Journal of Clinical Investigation, 2014).
Personalized Approaches to Pediatric Oncology
Our lab is leading an effort in the division of pediatric oncology at Packard Children’s hospital to develop more focused, genomics-based approaches to the care of patients with solid tumors. This effort focuses on using WGS, RNAseq and other genomic technologies to identify novel theapies for patients with metastatic or relapsed cancer.