Variable expression of an enzyme in the initial tumor has been identified as an early step in the process of migration and growth of cells to form remote metastases in breast cancer.

The enzyme in question is phosphoglycerate dehydrogenase (PHGDH), which initiates synthesis of the amino acid serine. The gene encoding PHGDH is frequently present at higher-than-normal numbers in several types of cancer, and it has been shown that PHGDH suppression limits the growth of primary tumors.

Now, new research has shown that while tumors with high expression of PHGDH are more likely to undergo primary tumor growth, they were less likely to metastasize.

In a mouse model of breast cancer, cells with low PHGDH expression in the primary tumor exhibited greater metastatic activity than cells with high expression of the enzyme. But once low-PHGDH cells migrated from the primary tumor, growth at secondary sites again required high expression of PHGDH.

"We know there is quite a bit of heterogeneity in the metabolism of cancer cells, but this is relatively understudied," said Sarah-Maria Fendt, professor of oncology at the Center for Cancer Biology, KU Leuven, Belgium, and an author of a paper describing the findings in Nature, May 18, 2022.

"Here we find that in breast cancer patients lower levels of PHGDH expression in primary tumors are associated with a higher chance of metastasis. This suggests that metabolic processes contribute significantly to the aggressiveness of certain cancers," Fendt said.

"This could explain why patients whose triple-negative breast tumors are heterogeneous, or low in PHGDH protein expression, have worse metastasis-free survival compared to patients with homogeneous and high [PHGDH-expressing] primary tumors," she told BioWorld Science.

To unpick why low PHGDH expression promotes early metastasis, the researchers measured gene expression in cells with and without PHGDH.

They showed cells lacking the enzyme had higher expression of genes associated with migration and invasion, and of the mesenchymal cell state that is a hallmark of metastatic cells.

In human tumors, cells with the lowest levels of PHGDH expression had the highest expression of these genes. That directly links metabolic heterogeneity with gene expression proteins associated with metastasis.

In support of this link, cells with low PHGDH were consistently more migratory than cells from the same tumor with high PHGDH.

Other enzymes involved in the synthesis of serine were expressed at constant levels and there was no increase in migratory activity if their suppression was blocked.

That indicates PHDGH's role in promoting metastasis is unrelated to the part it plays in the production of serine, despite the fact this amino acid is critical to cell metabolism.

Rather, the researchers showed that PHGDH takes on a moonlighting role, interacting with phosphofructokinase in the pathway by which glucose normally is converted to pyruvate and redirecting it to a pathway that synthesizes sialic acid.

The result is to modify cell surface integrin proteins which facilitate migration. The researchers showed that blocking sialic acid synthesis reversed the effects of low PHGDH on cancer cell migration and metastasis.

Therapeutic significance

Fendt would not be drawn on the possible therapeutic relevance of this. "I see the significance of our work in better predicting and understanding metastasis risk. Whether sialylation can be targeted requires additional studies, especially given that sialylation also occurs in immune cells," she said.

Turning to the question of the circumstances under which a subset of tumor cells reduces PHGDH expression, the researchers found that cells with low levels of the enzyme cluster around vascular tissue. Factors secreted by endothelial cells lining the vascular tissue suppressed PHDGH expression, thus linking proximity to the vasculature to the acquisition of migratory properties.

It is suggested the tumor cells withstand a reduction in PHGDH, and the subsequent reduction in serine production, because they are supplied with the amino acid by the vasculature.

That fits with previous research indicating distance from the vasculature sparks the establishment of metabolic heterogeneity in cells of the same tumor.

"It has emerged over the last decade that metabolic rewiring is a requirement for tumor progression," Fendt said. "The role of intra-tumor heterogeneity of metabolism we are just beginning to understand."

The direct demonstration that metabolic heterogeneity is important for tumor growth highlights the contribution of this variation across the course of tumor development. It opens up the possibility that specific metabolic pathways might have stage-specific effects.

Fendt said that her next move is to try to further understand the basis of metabolic intra-tumor heterogeneity and how this is linked to metastasis formation.

As the researchers note, there is an extensive body of evidence showing increased PHGDH activity is important for cancer cell proliferation and is associated with poor prognosis.

Showing that heterogeneous and low PHGDH expression is associated with increased metastasis in breast cancer does not contradict this previous data, but it does highlight the importance of differential regulation of gene and protein expression.

"Tumors with increased or amplified PHGDH gene expression may be more aggressive because they can switch between proliferation and metastatic dissemination by modulating PHGDH protein expression, resulting in intra-tumor heterogeneity," the researchers say.