Metabolic rewiring that fuels tumorigenesis
Cancer metabolism has emerged as an increasingly significant area of study in cancer research, as it influences cancer progression through various mechanisms such as regulating signaling pathways, protein modifications, and impacting cancer cell states. Over the years, our laboratory has dedicated substantial efforts to investigate cancer metabolism, leading to a realization that its functions extend beyond our initial expectations. Recently, we have been particularly intrigued by a novel metabolic pathway, the propionate metabolism pathway, which is conserved in numerous organisms. At its core, propionyl-CoA, a central metabolite, serves as a common product of several nutrients’ metabolism, including odd chain fatty acids, amino acids (valine, isoleucine, threonine, and methionine), cholesterol, and propionate. (Check the figure below for the propionate metabolism pathway)
Previous studies on the propionate metabolism pathway have primarily focused on inborn errors of metabolism, specifically methylmalonic acidemia and propionic acidemia, caused by mutations in key enzymes of this pathway. Our research group stands as the first to uncover the significance of this pathway and its metabolites in cancer progression. Our findings have revealed the following key points:
1) Tumor cells demonstrate a striking capability to modify the expression of enzymes within this pathway, specifically downregulating MCEE and upregulating PCCA as they transition into a more aggressive state. This alteration significantly enhances the plasticity of tumor cells, empowering them to exhibit heightened metastatic potential and increased resistance to therapy. (Click here for the paper)
2) Methylmalonic acid (MMA), a byproduct in this pathway, plays a crucial role in promoting cancer metastasis and drug resistance by inducing epithelial to mesenchymal transition (EMT) in tumor cells. (Click here for the paper)
3) Additionally, MMA can activate normal fibroblasts, transforming them into cancer-associated fibroblasts (CAFs). This transformation fosters effective communication between tumor cells and the stromal environment through extracellular vesicles to further support cancer metastasis. (Click here for the paper)
Through our research, we have shed light on the previously unexplored implications of this pathway in cancer biology, revealing its multifaceted contributions to cancer progression and cellular interactions within the tumor microenvironment. (Check the figure below)
Interestingly, findings from the large cohort population study indicate a positive association between aging and an increase in the serum level of MMA. MMA correlates with cardiovascular diseases and all-cause mortality, both of which are closely associated with the aging process. As age represents one of the most significant risk factors for cancer incidence and mortality, our findings strongly indicate that MMA and propionate metabolism play pivotal roles in the aging-induced enhancement of metastasis.
To gain a comprehensive understanding, ongoing studies are dedicated to characterizing the regulation of this metabolism pathway and its functional impact on aging and cancer metastasis. Our research aims to shed further light on this intriguing relationship, opening avenues for potential therapeutic interventions and enhancing our knowledge of the aging-cancer connection.
