Abstract
It is well accepted that malignant transformation is associated with unique metabolism. Malignant transformation involves a variety of cellular pathways that are associated with initiation and progression of the malignant process that remain to be deciphered still. Here we used a mouse model of mutant p53 that presents a stepwise progressive transformation of adult Mesenchymal Stem Cells (MSCs). While the established parental p53Mut-MSCs induce tumors, the parental p53WT-MSCs that were established in parallel, did not. Furthermore, tumor lines derived from the parental p53Mut-MSCs (p53Mut-MSC-TLs), exhibited yet a more aggressive transformed phenotype, suggesting exacerbation in tumorigenesis. Metabolic tracing of these various cell types, indicated that while malignant transformation is echoed by a direct augmentation in glycolysis, the more aggressive p53Mut-MSC-TLs demonstrate increased mitochondrial oxidation that correlates with morphological changes in mitochondria mass and function. Finally, we show that these changes are p53Mut-dependent. Computational transcriptional analysis identified a mitochondrial gene signature specifically downregulated upon knock/out of p53Mut in MSC-TLs. Our results suggest that stem cells exhibiting different state of malignancy are also associated with a different quantitative and qualitative metabolic profile in a p53Mut-dependent manner. This may provide important insights for cancer prognosis and the use of specific metabolic inhibitors in a personalized designed cancer therapy.
Highlights
A correlation between alterations in metabolism and carcinogenesis is well accepted [1, 2]
By analyzing a previous RNA sequencing dataset [10] comparing the p53Mut-Mesenchymal Stem Cells (MSCs)-TLs with their corresponding p53MutpMSCs by Gene Set Enrichment Analysis (GSEA), we found nine sets of genes involved in fundamental mitochondrial function significantly enriched in the aggressive p53Mut-MSC-TLs (Fig. 5i)
We detected an annotation cluster of genes associated with the Mitochondrion (Benjamini 3.24E-6, FDR 1.17E-4) among other annotation clusters. These results demonstrate that the oncogenic p53Mut plays a central role in coordinating both mitochondrial mass and the expression of multiple genes associated with fundamental mitochondrial metabolic processes in p53Mut-MSC-TLs
Summary
A correlation between alterations in metabolism and carcinogenesis is well accepted [1, 2]. The Warburg effect, already reported last century, showed that cancer. Mutant p53-dependent mitochondrial metabolic alterations in a mesenchymal stem cell-based model of. Model derived from either bone marrow of parental wild type p53 (p53WT) or parental Mutp (p53Mut) expressing mice carrying the R172H hotspot mutation. The latter, developed tumors in vivo [9]. The murine R172H mutation corresponds to the R175H hotspot mutation in human and it is a well-known mutant protein with GOF activity [9, 10]
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