Most cancer patients do not die from their primary tumor but from their metastases. In spite of the morbidity and mortality associated with metastatic disease, relatively little is known about the mechanisms underlying the metastatic spread of cancer. Historically, one major reason for this lack of knowledge is limited access to metastatic samples and the difficulties associated with comparing primary tumors and metastases from the same patient. My overarching goal is to gain a better understanding of the metastatic process. To this end, I focus my research on small cell lung cancer (SCLC), an extremely metastatic form of lung cancer. While SCLC was thought for a long time to be inherently metastatic, recent studies from our lab and others have shown that upregulation of the NFIB transcription factor constitutes a metastatic switch in a majority of cases. A key aspect of these studies has been the use of genetically engineered mice that accurately model human SCLC at the genetic and histopathological levels, allowing us to bypass several limitations of human studies. Here I will use multiple pre-clinical mouse models of SCLC to focus on key unanswered questions. First, while upregulation of NFIB, by gene amplification or transcriptional activation, has been demonstrated to be sufficient to promote metastasis, whether NFIB is required for metastasis has only been tested in cell line systems that may not model metastasis in vivo. I will use two mouse models of SCLC, representing both classic and variant forms of the disease in humans, with conditional loss of NFIB to test the genetic requirement for NFIB in tumor progression and the development of metastases. Second, while the pro-metastatic functions of NFIB have been associated with changes in chromatin structure and activation of certain transcriptional programs, it remains unclear whether these changes depend directly on NFIB upregulation, especially because experiments modulating NFIB expression in cell lines have only partially validated early experiments comparing primary and metastatic tumors in mice. I will investigate the consequences of NFIB upregulation directly within primary autochthonous tumors in mutant mice using a novel fluorescent reporter allele for NFIB that I recently generated. In these studies, I will use genomic tools to conclusively determine the consequences of NFIB upregulation in SCLC cells. These studies, which I will perform in the laboratory of Dr. Julien Sage at Stanford University, will determine molecular mechanisms of SCLC metastasis, which may help identify patients at higher risk of developing metastasis and identify novel approaches to block metastatic progression in SCLC. In the course of these studies, the training plan I developed with Dr. Sage will allow me to develop new skills in animal models of cancer and in cancer genomics approaches.
Small cell lung cancer (SCLC) is one of the most metastatic forms of cancer. Here I propose to use a combination of mouse genetics and genomics approaches to elucidate the mechanisms of action of NFIB as a pro-metastatic transcription factor in SCLC. These experiments may help in the design of novel diagnosis tools and novel therapeutic options for SCLC patients.
