Role of ZC3H15 in Pancreatic Cancer Pathogenesis and Therapeutic Response - Project Summary/Abstract Pancreatic cancer is a very lethal malignancy. More than 95% cases of pancreatic cancer cases are pancreatic ductal adenocarcinoma (PDAC). Although the annual pancreatic cancer cases account 3% of total cancer cases, their death rate is more than 8%. According to an estimate by 2030, pancreatic cancer will be the second leading cause of cancer-related death in the United States. The key factors responsible for the high lethality of PDAC include late detection, early metastasis, and the extremely resistant nature of this cancer to existing therapies. The root cause of these factors is a poorly understood molecular mechanism and limited therapeutic options available for the patients. So, a better understanding of molecular pathogenesis by identification of novel regulators and designing novel therapeutic combinations on the basis of new molecular insights may lead to better management of PDAC patients. We observed that among all the RNA-binding proteins, the zinc finger protein ZC3H15 expression was significantly upregulated in therapy-resistant pancreatic cancer cells' transcriptome. Further, we observed increased expression of ZC3H15 in chemotherapy-treated tumors, and increased expression of this correlates with poor survival of pancreatic cancer patients. By utilizing integrative metabolomics, transcriptomics, and physiological approaches, we have demonstrated that ZC3H15 regulates pancreatic tumor growth and therapeutic response in in vitro as well as in vivo models of pancreatic cancer. The Zinc-finger protein with three cysteine motifs is considered an RNA-binding protein, but the RNA-binding function of the ZC3H15 was completely unknown. By the RIP-Seq method, we identified the RNA-binding partners of the ZC3H15. Further, we observed that ZC3H15-mediated stabilization of KDM3A regulates the cholesterol metabolism of pancreatic cancer cells, which drives the EMT phenotype and therapeutic response in these cells. Further, in proposed studies, we will study the in-depth molecular mechanism of ZC3H15-mediated pancreatic cancer progression, therapy response, and regulation of Zc3H15 expression in pancreatic cancer cells. In Aim 1, using a genetically engineered mouse model of pancreatic cancer, we will evaluate the role of ZC3H15 in cancer progression by combining Zc3h15 flox/flox mice with other genetic perturbations. We will also evaluate the gene regulation of ZC3H15. In Aim 2, we will decipher the molecular mechanism of ZC3H15-mediated modulation of cholesterol metabolism and EMT phenotype. In Aim 3, we will evaluate the novel therapeutic combination of cholesterol biosynthesis inhibitor rosuvastatin with FOLFIRINOX (combination of 5- fluorouracil, leucovorin, irinotecan, oxaliplatin) in different physiologically relevant models such as organoid model, orthotopic implantation model, genetically engineered mouse model, and patient-derived xenograft (PDX) models of pancreatic cancer. In summary, the proposal is focused on understanding the molecular mechanism of ZC3H15-mediated PDAC pathogenesis and deciphering the role of epigenetic-metabolic crosstalk in chemotherapeutic response. Animal models are required for this study to evaluate pancreatic cancer pathogenesis and therapeutic response in a more physiologically and biologically relevant system, which cannot be achieved with any alternative.
