Mechanisms of Epigenetic Modulation in Pancreatic Neuroendocrine Tumors (PanNET)

• Applicant: Dr. Julia Weißbach
• Subject Area: Gastroenterology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 549339442

Pancreatic neuroendocrine tumors (PanNETs) represent a rare and heterogeneous tumor entity, in contrast to the most common and well-studied classical pancreatic adenocarcinoma. In addition to surgical interventions, several therapeutic approaches involving biotherapy, target therapy or chemotherapy are applicable. However, tumor progression and resistance mechanisms in PanNET patients are still challenging. Recent genome-wide sequencing analyses in PanNETs have identified a large number of mutated genes involved in epigenetic modulation, such as post-translational histone modifications, mediated by histone acetyl transferases (HATs) and histone deacetylases (HDACs). Moreover, transcriptomic analyses have shown that long non-coding RNAs (lncRNAs) are frequently dysregulated in cancer thereby acting as putative oncogenes or tumor suppressors. Our preliminary in vivo and in vitro data indicate an important role of epigenetic mechanisms in regulating tumor cell proliferation and apoptosis in PanNET. In Rip1Tag2 mice, a transgenic model for neuroendocrine insulinoma, intervention with the non-selective HDAC-Inhibitor Panobinostat (PB) reduces the number, size and invasiveness of tumors. In the human PanNET cell lines QGP1 (primary tumor) and BON-1 (metastasis), PB inhibits proliferation and induces apoptosis of tumor cells. Thus, epigenetic modulations are relevant for the persistence of PanNETs. Targeting epigenetic modulators by PB-mediated HDAC inhibition would be a promising therapeutic approach for PanNET patients. However, despite the obvious cytotoxic effect, a subpopulation of tumor cells survives even at high PB concentrations. Own RNAseq data show several altered mRNAs, lncRNAs and miRNAs under PB. Therefore, in this project we hypothesize that (1) these regulatory RNAs are key drivers for either the pro-apoptotic or the therapy-resistant phenotype in PanNET cells. To investigate the physiological role of identified RNA candidates in mediating the pro-apoptotic or the therapy-resistance phenotype of PanNET cells, we will perform knockdown and overexpression analyses. Furthermore, we will (2) investigate previously uncharacterized non-coding lncRNA and miRNA candidates by binding partner analyses regarding their physiological function in PanNET. (3) Potentially relevant RNA candidates will be validated in resistant escaper cells, which will be specifically selected beforehand. In addition, further analyses can validate our in vitro findings in the Rip1Tag2 mouse model as well as tissue samples from PanNET patients in vivo to prove the relevance across species.

• DFG Programme: Research Grants
• Co-Investigator: Professor Dr. Sebastian Krug