The function and functional interaction of APN / CD13 and PAR2 in the development and progression of colon cancer

• Applicants: Professorin Dr. Elke Beate Krüger, since 8/2024; Professor Dr. Bernhard Hermann Rauch
• Subject Area: Pharmacology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 494088392

Colon cancer (carcinoma) is one of the most frequent sex-independent carcinomas worldwide and a major public health problem. A major limitation of many chemotherapeutic protocols and thus of a longer-term remission is that tumor stem cells evade the effects of therapeutic agents. Due to their unlimited ability to self-renewal, they are crucial for the development, progression and metastasis of tumors. The aminopeptidase N (APN/CD13) is a membrane-bound ectopeptidase associated with cellular functions such as proliferation, differentiation, invasion, angiogenesis, and the immune response and has been identified as a stem cell marker. Elevated expression and activity of APN/CD13 has been reported in aggressive and rapidly growing cancer types and in colon cancer is associated with a reduced survival time. Preliminary results by the applicants indicate a to date unexplained therapeutically relevant function and interaction of APN/CD13 with the protease-activated receptor-2 (PAR2) in colon cancer. PAR2 belongs to a family of G protein-coupled receptors, which are responsive to proteases such as the activated coagulation factor X or to trypsin. In addition to (patho) physiological functions in vascular biology, inflammation and hemostasis, a growth-promoting effect in colon cancer was demonstrated for PAR2 - also in the preparatory work of the applicants. Therefore, the current proposal aims to clarify to what extent APN/CD13, PAR2 and their interaction regulate colon cancer growth in vivo i) in genetic models (APN-, PAR2- and APN/PAR2-deficiency) and ii) by pharmacological modulation of APN/CD13 and iii) affects number and phenotype of stem cells, and iv) aims to identify underlying molecular mechanisms and the responsible signaling pathways. The application consistently aims to establish the pharmacological modulation of APN/CD13 and PAR2 as a therapeutic option for the treatment of colon cancer. Accordingly, a considerable benefit for the individual patient, but also for the health economic system, can be expected.

• DFG Programme: Research Grants
• Ehemaliger Antragsteller: Professor Dr. Uwe Lendeckel, until 8/2024