Peptidylprolyl Isomerase E (PPIE/Cyclophilin E/Cyp33) in Colorectal Cancer Biology and Therapy

• Applicant: Professor Dr. Heiko Hermeking
• Subject Area: Pathology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 562046626

Despite the promising successes of targeted therapy of colorectal cancer (CRC), the treatment of metastatic CRC (mCRC) is still an unmet clinical need. Therefore, the identification of additional therapeutic targets is of high clinical relevance. In our unpublished preliminary work, we performed a bioinformatics screen of diverse, public datasets to identify molecules that may represent therapeutic targets for CRC. The criteria for selection of candidates were dependency of CRC cells on their expression, their druggability, and increased expression in tumors when compared to normal colon, and elevated expression in cancer cells compared to stromal cells. tissue. Among the top prioritized candidates were known oncogenes and therapeutic targets, such as EGFR, PIK3CA, and BRAF, showing that the screen can yield significant results. PPIE was one of the top prioritized candidates. Knockdown of PPIE markedly suppressed cell viability in all tested CRC cell lines. Notably, the silencing of PPIE resulted in stronger suppression of cell viability when compared to the silencing of the established therapeutic targets KRAS, EGFR, PIK3CA, and c-MYC. The suppression of PPIE also resulted in decreased proliferation. Finally, knockdown of PPIE completely prevented colony formation of CRC cell lines and markedly inhibited sphere formation. In addition, the suppression of PPIE induced apoptosis in cancer cells. Knockdown of PPIE in human intestinal fibroblasts resulted in a substantially lower suppression of cell viability and proliferation, and only in a minor increase in apoptosis, indicating that cancer cells are exquisitely sensitive to PPIE-inhibition. In the current proposal we suggest to determine the effect of PPIE suppression on the growth of organoids derived from primary CRC tumors and normal intestinal epithelium. In addition, we plan to determine the effect of PPIE suppression on colon tumor growth and liver metastasis formation in preclinical mouse models of CRC. Next, we plan to determine whether the enzymatic and/or the RNA-binding domain of PPIE are required for its effects on CRC cells. We will also study the mechanisms underlying the induction of apoptosis after inhibition of PPIE by performing comprehensive expression profiling after silencing of PPIE and after ectopic expression of PPIE. The regulation and role of differentially expressed, potential mediators of PPIE function will be studied in detail. In addition, we plan to elucidate the basis for transcriptional up-regulation of PPIE expression in tumors by identifying transcription factors that directly bind to its promoter. Taken together, the results of these studies are of importance for understanding the role of PPIE up-regulation in CRC and will allow to evaluate PPIE as a therapeutic target for mCRC.

• DFG Programme: Research Grants