Project summary Metastasis, the dissemination of cells from the primary tumor to other organs in the body, leads to 90% of the 1,800 daily cancer deaths. Cell invasion is an essential feature of tumorigenesis, which is necessary for tumor growth, local invasion and metastatic outgrowth. The local tumor microenvironment, composed of stromal and immune cells, the vasculature and extracellular matrix, provides tumor cells with numerous chemical, biophysical and electrical cues that promote local invasion and support tumorigenesis. However, one major component of the TME whose function has not been well studied and whose therapeutic potential in cancer has not been explored is nerves. Perineural invasion has been associated with tumor aggressiveness by providing a path for cancer cell invasion, however, for a long time, these nerves were not seen as major drivers of tumor growth and metastasis. The lack of clinical approaches to prevent, diagnose and treat metastatic disease are largely due to a poor understanding of targetable pathways for preventing and treating migrating cells. My goal is to investigate a poorly studied component of tumors: their neuronal identity, which will provide new strategies for prevention and targeting of metastatic cancer. First, we will focus on elucidating the mechanisms by which neoneurogenesis of solid tumors occurs, which will lead us to evaluate the systemic effects of nerves on local invasion and metastasis. Second, we will dissect the neuronal identity of epithelial tumors, by studying how neuronal mimicry in metastasizing cells contributes to tumor progression. Together, our findings will contribute to the development of non-invasive monitoring of neuronal activity in solid tumors and the repurposing of FDA-approved drugs that target neuronal function for use in metastatic disease. The research described in this proposal has the potential to impact both our basic understanding of the role of the TME in tumor metastasis as well as lead to the development of novel detection and treatment approaches for metastatic disease. The neuronal identity of tumors is not well understood. Nerves have mostly been regarded as passive bystanders to dissemination and deemed to contribute to tumor phenotypes only via the molecules they secrete. A thorough literature review identified fewer than 40 primary papers directly investigating tumor cell-cancer crosstalk in solid tumors, and fewer than 7 papers focused on breast cancer. The majority of published studies focus on the central nervous system. With over 90% of tumors occurring outside of the brain, it is critical that we gain a better understanding of how peripheral nerves interact with tumor cells. The extensive and unique expertise of Dr. Oudin in both in neuroscience and cancer metastasis suggests her lab provides the perfect setting in which to study this novel topic.

Project Narrative The proposed work seeks to define and exploit the neuronal identity of solid tumors to prevent cancer metastasis, the leading cause of death in cancer patients. Recently, the presence of peripheral nerves in solid tumors and the upregulation of neuronal genes within tumor cells themselves were both reported be associated with poor outcome in cancer. We will use cell biology, engineering and clinically translatable approaches to understand how neoneurogenesis occurs in tumors, how the neural identity of tumors impacts the systemic regulation of metastasis and how we can leverage this information for non-invasive monitoring and treatment of metastatic disease.