Principal Investigator Tyler Jacks
Using advanced gene targeting methods, generating mouse models of cancer that accurately reproduce the genetic alterations present in human tumors is now relatively straightforward. The challenge is to determine to what extent such models faithfully mimic human disease with respect to the underlying molecular mechanisms that accompany tumor progression. Working with the Golub lab at the Broad Institute, we have developed a method for comparing mouse models of cancer with human tumors using gene expression profiling. We applied this method to the analysis of our model of Kras-mediated lung cancer and found a good relationship to human lung adenocarcinoma, thereby validating the model (Sweet-Cordero et al., 2005). The K-ras lung cancer model has also been used in collaboration with the Golub laboratory to perform miRNA profiling experiments. The data from the model are consistent with human data, demonstrating a general down regulation of miRNA expression in tumors compared to normal tissue (Lu et al., 2005 and see below).
We have also developed a program in metastasis. Metastasis represents the cause of 90% of cancer-associated mortality, yet it is among the least well understood of the multiple processes of cancer pathogenesis. New insights suggest that cancer cells use biological programs that are normally operative during embryogenesis to become metastatic. There are two major subtypes of lung cancer in humans: non-small cell lung cancer (NSCLC), which comprises 80% of the total, and small cell lung cancer (SCLC), which comprises the remaining 20%. We are studying models of both diseases with a specific interest in understanding their metastatic spread. Soft tissue sarcomas are mesenchymal tumors that kill approximately 30% of patients because of lung metastasis. We have generated a mouse model of soft tissue sarcoma (Kirsch et al., 2007) in which primary sarcomas resemble human sarcomas at the genetic, histological, and the ultrastructural level. Like human sarcomas, these murine tumors metastasize to the lung, but not to lymph nodes. We are currently performing genomic analyses of primary tumors and metastases from the lung models and the sarcoma model. Information gained from these studies will be compared against data arising from the study of metastasis in humans, with the goal of understanding the genes and pathways that regulate metastatic spread.