Investigators at Weill Cornell Medical College have identified propionate metabolism as a contributor to the ability of cancer cells to establish metastases, establishing new basic insights into cancer metastases as well as potential therapeutic targets.

They published their results in the March 20, 2022, online issue of Nature Metabolism.

The work sits at the intersection of cancer and its main risk factor aging.

At a session at the 2022 annual meeting of the American Association for Cancer Research (AACR), which is happening in New Orleans this week, first author Ana Gomes told the audience that there are two ways to think about why cancer risk increases with age.

"Maybe our body is more frail," Gomes said, and less able to nip cancer in the bud. Declining immune function is certainly a contributor to increased cancer incidence with age.

"But also," Gomes said, "the biology in our body changes – maybe these changes make our body a better host for tumors to progress."

Age-induced circulatory changes, she said, are a good place to look for specific molecules that might make the aging body a better host for cancer, because they are "a bridge between the aging process and tumorigenesis."

The circulatory system, is "the point of convergence of inputs from different organs, diet and the microbiome," and its state "a direct reflection of everything that happens in our body."

In previous work, first author Ana Gomes and her team had shown that methylmalonic acid (MMA), a specific metabolite produced in the propionate metabolism pathway, accumulated in blood serum with age. Cancer cells that were treated with the serum of old but healthy donors showed multiple changes. Compared to cells treated with serum from young donors, such cells had increased resistance to chemotherapy and the increased ability to form metastatic colonies when they were injected into the bloodstream of mice.

In the work now published in Nature Metabolism, the team took a broader approach to identifying metabolic pathways that were altered in lung metastases compared to primary tumors in a mouse model of triple-negative breast cancer (TNBC) -- though they noted that "while this experiment can provide a snapshot of potential metabolites and metabolic pathways that are important for TNBC metastasis, it probably does not account for the full spectrum of metabolic alterations that fuel metastasis."

Their experiments turned up known metabolic alterations, such as serine metabolism. But it also identified changes in the pathway for propionate metabolism one of whose metabolites is MMA. The researchers showed that MMA accumulated in cancer cell lines with the ability to metastasize, but not in locally invasive cell lines. MMA accumulation was more pronounced in TNBC than in other breast cancer subtypes.

Mechanistically, the inflammatory cytokines TGF-beta and TNF-alpha decreased expression of MCEE, an enzyme in the propionate metabolism pathway, which altered propionate metabolism to favor the accumulation of MMA.

In a commentary published along with the paper, Beatson Institute researchers Emily Kay and Sara Zanivan noted that in order to target MMA accumulation therapeutically, it will be critical to understand its mechanism of action. But the work has already demonstrated that "altered propionate metabolism in cancer cells is a key metabolic alteration that enables cancer cells to undergo [epithelia-mesenchymal transition] and, ultimately, to metastasize," they wrote. "These findings provide new potential therapeutic targets for preventing metastasis and widen the field of research on the role of metabolites in promoting tumor aggressiveness."