No abstract

Summary Metastases arising from tumors have the proclivity to colonize specific organs, suggesting that they must rewire their biology to meet the demands of the organ colonized, thus altering their primary properties. Each metastatic site presents distinct metabolic challenges to a colonizing cancer cell, ranging from fuel and oxygen availability to oxidative stress. Here, we discuss the organ-specific metabolic adaptations cancer cells must undergo, which provide the ability to overcome the unique barriers to colonization in foreign tissues and establish the metastatic tissue tropism phenotype.

Highlights d Metastasis inducers lead to a decline in CAF-1 suppressing canonical H3 incorporation d EMT and metastatic colonization occur as a function of CAF-1 levels d Histone H3.3 variant is essential for tumor progression and aggressive phenotypes d HIRA-mediated H3.3 gap filling induces a pro-metastatic transcriptional reprogramming

The alteration of metabolic pathways is a critical strategy for cancer cells to attain the traits necessary for metastasis in disease progression. Here, we find that dysregulation of propionate metabolism produces a pro-aggressive signature in breast and lung cancer cells, increasing their metastatic potential. This occurs through the downregulation of methylmalonyl-CoA epimerase (MCEE), mediated by an ERK2-driven SP1/EGR1 transcriptional switch driven by metastatic signaling at its promoter level. The loss of MCEE results in reduced propionate-driven anaplerotic flux and the intracellular and intratumoral accumulation of methylmalonic acid (MMA), a byproduct of propionate metabolism that promotes cancer cell invasiveness. Altogether, we present a previously uncharacterized dysregulation of propionate metabolism as an important contributor to cancer and a valuable potential target in the therapeutic treatment of metastatic carcinomas.