Activated mTOR signaling promotes the expression of PGC1α and mortalin in pancreatic neuroendocrine tumours

Abstract

Pancreatic neuroendocrine tumors (panNETs) are a rare malignancy that is difficult to treat. Since a considerable number of panNETs exhibit high mTOR pathway activity, current therapeutic strategies for advanced panNETs often involve the use of mTOR inhibitors. Recently, there has been discussion regarding the potential benefits of combining mTOR inhibition with therapies targeting cellular metabolism. These are based on observations that mTOR signalling also impacts mitochondrial functions and the expression of nuclear-encoded mitochondria-related genes. However, the precise interaction between mTOR and mitochondrial function, particularly in the context of panNETs, remains poorly understood. Consequently, the objective of this study is to identify proteins that connect these two systems and assess the functional implications of this relationship. In the present study, a well-characterized cohort of 157 panNETs was established. We identified pS6 as a reliable biomarker for the mTOR pathway activity in panNET, as we revealed that 22 % of the investigated panNET exhibit mTOR pathway activity by expression analysis of pS6. We could verify this finding by identifying the mTORc1 pathway as the most upregulated pathway in panNET with activated mTOR pathway using RNA-sequencing and gene set enrichment analysis (GSEA). In addition, we were able to identify two mitochondria related proteins as targets of mTOR in panNET. RNA sequencing of panNET tissue and cell lines highlighted PGC1α as the most significantly upregulated gene in tumors with activated mTOR and in the BON1 cell line control group that was compared to BON1 cells treated with mTOR inhibitors. Furthermore, mortalin was found to be highly upregulated in high-grade panNETs with elevated mTOR activity. Interestingly, PGC1α was shown to influence mTOR pathway activity, while mortalin did not impact mTOR signaling. We could not find any correlation between somatic mutations in the mitochondrial DNA and the mTOR pathway activity In summary, these findings offer valuable insights into the molecular interactions between mTOR signalling and the mitochondria-related proteins mortalin and PGC1α in panNETs. This may pave the way for new treatment options for this rare tumor entity, offering benefits for patients.