Chemotherapy Response in Vivo
Despite decades of use in clinical medicine, much is still unknown about the molecular and cellular determinants of chemotherapy response in cancer. Why are some tumors sensitive to chemotherapy treatment whereas others are highly resistant? To what extent are these properties due to genetic mutations in tumor cells (i.e, p53 loss) and to what extent are they determined by the cellular context and microenvironment in which the tumor exists? It is by now well established that important differences exist between how tumor cell in a plastic dish respond to therapy and how tumors in an organism respond to therapy. Therefore, we rely on mouse models that closely recapitulate important aspects of human oncogenesis to study chemotherapy response.
Our group published one of the first studies to comprehensively analyze the response to chemotherapy in a well-characterized mouse model of lung cancer (Oliver et al, Genes and Development, 2010). In this study, we found that p53 loss did not decrease the effect of cisplatin therapy in this model. Furthermore, we found that repeated doses of cisplatin led to the emergence of resistant tumors that showed evidence of increased genomic instability. Using gene expression profiling, we uncovered a role for PIDD in this process.
Current studies in our laboratory are focused on determining whether cancer stem cells or tumor re-initiating cells (TRICS) play a role in mediating chemoresitance in murine lung cancer. Using patient-derived xenograft models we are also extending these studies to human cancer using both lung cancer and osteosarcoma as models.