Iyamu Pilot Project Summary

Pancreatic cancer has one of the highest cancer-related deaths in the United States due to advanced-stage diagnosis and ineffective treatment options. To find new treatment options, there is a need to understand the molecular pathways involved in pancreatic cancer progression, identify novel biological targets, and develop new therapeutics. Dysregulation of ferroptosis, a type of regulated cell death that contributes to uncontrolled cell growth, is one of the pathways involved in cancer development and progression. Ferroptosis is regulated by protein methylation, and methyltransferase-like 9 (METTL9) is a methyltransferase overexpressed in pancreatic cancer cells, and its upregulation correlates with poor prognosis. This enzyme recognizes and specifically methylates the N1 (π) position of the imidazole in histidine within an "xHxH" motif (where H is histidine and x denotes a small amino acid residue). METTL9 is a gene regulator, and its expression has been shown to upregulate the levels of solute carrier family 7 member 11 (SLC7A11), a known ferroptosis inhibitor in cancer. Additionally, some molecules involved in ferroptosis harbor the recognition motif of METTL9.

This project aims to elucidate the molecular mechanisms and specific pathways through which METTL9 suppresses ferroptosis in pancreatic cancer through the comparative transcriptomics of cells with and without genetic modulation of METTL9 expression levels. I will evaluate different pancreatic cancer cells for the biochemical markers of ferroptosis, including iron concentration, reactive oxygen species levels, and evidence of lipid peroxidation. Furthermore, an antiproliferation and cell viability assay will be employed to evaluate the effect of METTL9 knockdown on different pancreatic cancer cells. Lastly, the RNA of the different prostate cancer cells will be extracted and sequenced to identify and compare the differentially expressed genes (DEGs) in normal pancreatic cancer cells versus pancreatic cancer cells with METTL9 knockdown. The genes that are differentially expressed could represent the rate-limiting steps along the pathways that control cancer progression. Analysis of the DEG will elucidate the connection between METTL9 and the ferroptosis pathway in pancreatic cancer. I have employed structure-based drug design to develop potent inhibitors that inhibit the activity of METTL9 in a biochemical assay. In addition to establishing the mechanisms of METTL9-mediated ferroptosis suppression in pancreatic cancer, this project will identify new therapeutic targets and the METTL9 inhibitors already designed that could serve as a starting point for drug discovery for novel pancreatic cancer treatment.