Microbial and host biomarkers in colorectal cancer oncogenesis

PROJECT SUMMARY Colorectal cancer (CRC) is the second leading cause of cancer death in the U.S. Fusobacterium nucleatum (Fn), a gram-negative oral anaerobe, is one of the most prevalent species implicated in CRC. Our previous work demonstrated that Fn stimulates colorectal cancer growth via its unique adhesin FadA, which binds E-cadherin and activates Wnt/?-catenin signaling. FadA undergoes dramatic biochemical changes to become amyloid-like under stress and disease conditions, converting Fn from a benign commensal to a virulent pathogen. Amyloid FadA preferentially binds to cells expressing Annexin A1 (ANXA1), which is upregulated in proliferating CRC cells and is critical for CRC growth. Upon binding to CRC cells, Fn further stimulates ANXA1 expression via amyloid FadA worsening prognosis. We hypothesize that amyloid-like FadA and ANXA1 are novel biomarkers in CRC oncogenesis. To test this hypothesis, we propose the following interrelated aims: (i) Mechanistic and therapeutic investigation of amyloid-like FadA in CRC; and (ii) Mechanistic and therapeutic investigation of ANXA1 in CRC. Results from this study will significantly advance our understanding of microbes in CRC and identify potential therapies, thus will have tremendous translational potential.