SUMMARY (30 lines max)
The vast majority of cancer mortality is due to metastases. A major unmet need in oncology is how to predict
and prevent metastatic progression. To address this need, it is imperative we advance our understanding of how
tumor cells acquire metastatic capability. Epithelial-to-mesenchymal transition (EMT) is a normal physiologic
process in wound healing and development by which polarized epithelial cells undergo biochemical, metabolic,
and epigenetic changes and convert to a mesenchymal phenotype, characterized by enhanced migratory and
invasive capacity. Cancers co-opt this reprogramming to acquire metastatic ability. Understanding how tumor
cells undergo EMT is critical to unraveling how cancer becomes metastatic. Historically, studies have primarily
focused on genetic mutations or gene expression changes that trigger EMT and metastasis. But recent work has
suggested that non-genetic factors such as metabolites can promote cancer progression, suggesting unexplored
areas of cancer biology. To gain a deeper understanding of EMT and capture the sequential changes necessary
for cancer to become metastatic, we performed proteomics, metabolomics and transcriptomics at multiple time
points as cells underwent EMT. Our multifaceted approach revealed rich new insights. We found that propionate
metabolism was dysregulated during EMT. Indeed, we observed increased propionyl-CoA and methylmalonic
acid (MMA), a dicarboxylic acid by-product of propionate metabolism, during early EMT. To test the functional
effect of elevated MMA, we treated lung and breast cancer cells with MMA. Strikingly, we found that MMA
triggered EMT and enhanced migratory and invasive capacity. Prior to our discovery, little was known about
propionate metabolism and MMA other than propionate metabolism is dysregulated in rare inborn errors of
metabolism collectively referred to as “methylmalonic acidemias.” Some recent studies have also shown that
MMA increases in serum with age and is linked to age-related, all-cause mortality. To our knowledge, our findings
are the first to demonstrate that propionate metabolism plays a role in EMT and cancer cell progression. This
led us to study how propionate metabolism is altered during EMT. Our long-term goals are to define how this
pathway is regulated by multiple inducers of metastasis and at multiple points in the pathway, and to define how
MMA produced by cancer cells can also influence the tumor microenvironment. Our proposed studies will
address a critical need for a greater understanding of the molecular basis of metastasis. Our expectations are
that successful completion of the proposed work will impact cancer biology by shifting the paradigm and
highlighting critical non-genetic factors that drive cancer progression. Consequently, our work will identify new
biomarkers and therapeutic targets that can be exploited to prevent and inhibit metastases.