Crosstalk between enteric nervous system and tumor-associated macrophages (TAMs) in colon cancer progression.

Colorectal cancer (CRC) development and progression is regulated by mechanisms of both innate and acquired immunity. Tumor-associated macrophages (TAMs) support growth, survival, migration, and metastatic spread of cancer cells. While the interaction between cancer cells and immune cells, including TAMs, has well been established, the presence and role of innervation in the colonic tumor microenvironment represent an unexplored field. I have obtained preliminary data suggesting a striking up-regulation of enteric glia and macrophage markers in patients with advanced disease. In addition, I have observed an intense crosstalk between enteric glia and TAMs in colonic tumors. Nerve infiltration in tumors is determined by the release of neurotrophic growth factors by both cancer cells and immune cells, including macrophages. This evidence suggests that neuro-immune interaction in the tumor microenvironment may be an overlooked process involved in cancer progression. Thus, I hypothesize that, in CRC, the enteric nervous system may be responsible for the accumulation and differentiation of TAMs, resulting into tumor progression. The main objective of my project is to elucidate and interfere with molecular pathways governing the crosstalk between enteric glial cells and TAMs to prevent tumor growth and progression. Finally, I aim to identify novel targets for potential therapeutic intervention and will develop innovative proof-of-concept tools to improve CRC prognosis and treatment.