Molecular mechanisms of NFIB in small cell lung cancer metastasis - PROJECT SUMMARY
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.
