Soft tissue sarcomas are mesenchymal tumors that kill approximately 30% of patients because of lung metastases. To study sarcoma biology and to develop better treatments for sarcomas, we have generated a mouse model of soft tissue sarcoma. We have utilized mice with conditional mutations in genes that are also mutated in human sarcomas: the oncogene K-ras and the tumor suppressor gene p53. This mouse model faithfully recapitulates human sarcomas at the genetic, histological, and ultra-structural levels.

Figure I,J, K, L  Like human sarcomas these primary murine tumors (I) showed a predilection for lung metastases (J,K,L)

Mechanisms of DNA Damage Response after Radiation

Approximately half of all patients with cancer are treated with radiation therapy. However, how radiation therapy controls cancer and the way radiation damages normal tissues remain unclear. Indeed, the critical cellular target and the key molecular mechanism of cell death regulating these processes remain controversial. Therefore, we are interested in understanding the response to radiation at the molecular, cellular, and whole organ level. We have a particular interest in the role that the p53 tumor suppressor pathway plays in this process. We have recently shown that p53 is required for tumor maintenance in primary lymphomas and sarcomas in mice. When normal p53 function was restored in these tumors, we observed that lymphomas regressed by apoptosis, but sarcomas appeared to regress as a consequence of cell cycle arrest and cellular senescence. Therefore, we hypothesize that the cellular response to p53 activation by radiation therapy may also depend on the tumor type.

We are combining state-of-the-art small animal imaging with sophisticated mouse genetics using models of soft tissue sarcoma and non-small cell lung cancer.