Characterization of intestinal Amyloid Precursor Protein in the pathogenesis of colorectal cancer

• Applicant: Dr. Maria de los Reyes Gamez Belmonte
• Subject Area: Gastroenterology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 531560612

Amyloid precursor protein (APP) and Presenilin1 (PSEN1) axis constitutes the core paradigm in our understanding of Alzheimer´s disease. Unexpectedly, in our recent study that set the stage for this proposal, we demonstrated that, beyond the brain, PSEN1 is highly expressed in the intestinal epithelial cells (IEC). Surprisingly, we identified PSEN1 as a key driver of intestinal tumor development and growth. Given this unexpected finding, we now aim to uncover the connection of the PSEN1/APP axis in intestinal tumorigenesis. Our preliminary findings reveal that APP mRNA and protein is highly expressed in the intestinal epithelium in mouse and human gut tissues. Moreover, the expression of APP as well as its proteolytic processing are augmented during intestinal tumorigenesis. Finally, preliminary functional analyses reveal that APP deletion in colorectal cancer cell lines sensitizes to apoptosis in vitro. Based on our preliminary data, we hypothesize that APP in IECs influences intestinal tumor development and that modulation of APP or its processing might have therapeutic potential in colorectal cancer. To evaluate this hypothesis, we will determine the role of epithelial APP in intestinal tumorigenesis in vivo and decipher APP-regulated pathways in tumor IECs. Furthermore, we will characterize APP expression and proteolytic processing in human colorectal cancer. Finally, the potential therapeutic advantage of APP modulation in colorectal cancer will be investigated.

• DFG Programme: Research Grants