Functional role of nuclear PLAC8 mRNA in PDAC cells and therapeutic potential of antisense-mediated PLAC8 inhibition

• Applicant: Professor Dr. Malte Buchholz
• Subject Area: Gastroenterology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 549320039

Pancreatic ductal adenocarcinoma (PDAC) exhibits the poorest prognosis of all solid tumors, as most patients present with advanced disease, chemotherapies show only limited efficacy, and personalized treatment approaches are woefully lacking. It is therefore of utmost importance to further unravel the molecular basis underlying the aggressive biology of PDAC tumors and to develop novel concepts for personalized therapy. We have previously shown that the PLAC8 gene is strongly ectopically expressed in PDAC as well as a subset of pancreatic neuroendocrine tumors (PanNET). The PLAC8 gene codes for a small protein (115 AA) of so far unknown molecular function which is evolutionarily highly conserved. Based on results from a series of different experimental approaches we are now able to demonstrate that the PLAC8 mRNA has its own cellular functions which are completely independent of the encoded protein. In particular, pancreatic tumor cells are addicted to the expression of the mRNA, but not the protein, for maintenance of cell proliferation and viability, and knockdown of nuclear PLAC8 mRNA induces massive DNA damage and subsequent cell death. To the best of our knowledge, both aspects (separate functions of mRNA and encoded protein, and a central role of an mRNA in maintaining genome stability) have not previously been described in the literature, and thus represent novel paradigms in human (patho)physiology. However, the molecular mechanisms underlying these biological phenomena remain enigmatic. In this proposal, we therefore aim to: i) characterize the cellular mechanism(s) through which PLAC8 mRNA mediates genome stability; ii) elucidate which segments of the PLAC8 transcript are functionally relevant in this context; and iii) assess the therapeutic potential of antisense-based approaches targeting PLAC8 mRNA in ex vivo and in vivo models of PDAC. We expect the results of these experiments to not only significantly enhance our understanding of the molecular basis underlying the aggressive biology of PDAC tumors, but also directly pave the way for translation of our findings into clinical application.

• DFG Programme: Research Grants