TI 07.001_021

Unravelling the secretome of Fusobacterium nucleatum in Nrf2-related carcinogenesis in colorectal cancer

01/10/2024 to 30/09/2025

Colorectal cancer (CRC) ranks as the third most common cancer type and second leading cause of cancer related deaths in western countries. Its pathogenesis is intricate, involving various individual and environmental risk factors such as age, male gender, genetic predisposition, lifestyle, chronic inflammation, and the microbiota composition. While hereditary syndromes are relatively rare and contribute to approximately 6% of tumors, the majority of CRC cases occur sporadically, with about two-thirds linked to inflammatory bowel disease. Recent studies have increasingly associated the gut
microbiome with bowel inflammation and the development of cancer. In vivo experiments involving the administration of fecal samples from CRC patients into mice have confirmed a direct tumor-promoting effect of intestinal microbiota. Furthermore, during chronic inflammation, various signaling molecules, including the transcription factor Nrf2, become dysregulated, leading to the expression of proinflammatory and tumor-promoting proteins that contribute to neoplastic transformation. Although the role of bacterial infection in Nrf2-related carcinogenesis remains unclear, previous research has spotted a connection to Nrf2, suggesting that the gut microbiome likely plays a crucial role in initiating, advancing, and facilitating tumor cell migration in CRC.
The current proposal will focus on Fusobacterium nucleatum (FN), a gram-negative, obligate anaerobic, fusiform rod-shaped bacterium that is notably abundant in CRC patients compared to healthy individuals. The presence of FN has been associated with increased mortality and cancer recurrence, possibly due to its role in promoting chemotherapy resistance. FN directly influences host responses by triggering the expression of
proinflammatory cytokines such as IL-6 and IL-8, NF-κB, TNF. In CRC, FN's virulence factor FadA binds to E-cadherin, activating β-catenin and promoting tumor cell proliferation. Additionally, FN enhances other signaling pathways like KRT7-AS/KRT to facilitate metastasis. Another significant virulence factor lies in its ability to produce biofilm. Bacteria residing within biofilms exhibit higher resistance to antibiotics and undergo alterations in their metabolism compared to planktonic bacteria. FN produces biofilms and can co-aggregate with various microorganism to form synergistic biofilms. In resected cancer tissues from colorectal cancer (CRC) patients, highly organized biofilm-like structures containing various bacteria have been identified, potentially contributing to tumorigenesis.