The influence of the folate on the interaction between macrophages and the neural stroma in colorectal cancer

• Grant number: 25/02807-6
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: August 01, 2025
• End date: December 31, 2028
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Rodrigo Nalio Ramos
• Grantee: Cauã Pacheco de Lima
• Host Institution: Unidade São Paulo. Instituto D'Or de Pesquisa e Ensino (IDOR). Rede D'Or São Luiz (RDSL). São Paulo , SP, Brazil
• Associated research grant: 24/04450-5 - FOLR2+ macrophages as immuno-modulators during the carcinogenesis onset: a molecular and spatio-temporal approach, AP.JP

Abstract

Colorectal cancer (CRC) is the second leading cause of cancer-related mortality worldwide, making it a public health issue. The number of people under 50 receiving this diagnosis has increasing. Its incidence is associated with lifestyle factors, often characterized by tobacco and alcohol consumption, obesity, stress, and a sedentary lifestyle. Various studies indicate that adopting a balanced diet with increased folate intake reduces the risk of cancer. The colon and rectum are highly innervated organs with the presence of sympathetic, parasympathetic, and vagal nerve fibers. Tumor cells can invade nerve fibers, using them as tunnels to reach the bloodstream and spread to other parts of the body. This mechanism is known as perineural invasion (PNI) and represents an important metastatic pathway, similar to blood vessels and lymph nodes. In the tumor microenvironment (TME) surrounding the nerves, in addition to tumor cells, tumor-associated macrophages (TAMs) can also be found. These cells are responsible for tissue homeostasis, but in cancer, various macrophage subtypes can be identified, including those with pro-tumorigenic properties. With the advent of modern technologies, new molecular profiles of macrophages have been characterized, among them, tissue-resident macrophages (TRMs) expressing folate receptor (TRM FOLR2+). Although many studies investigate the benefits of dietary folate in CRC carcinogenesis, the relationship between TRM FOLR2+ and migratory cells under the influence of folate metabolism remains poorly explored. In this project, we aim to apply spatial transcriptomics methodology to cohorts of CRC patients from the biobank of the national pathology network of Rede D'Or. Additionally, we will conduct in vitro assays with primary macrophages to assess the modulation of these cells upon folate exposure. Furthermore, we will use an in vivo tumor model to validate the molecular signatures identified in folate-rich diets. Thus, by mapping the spatial and molecular profile of nerve fibers and macrophages in the TME, we seek to uncover new molecular biomarkers that correspond to changes in the neural microenvironment in CRC.