Globally, 3 out of 5 persons lose their lives to chronic inflammatory conditions, such as diabetes, cardiovascular disorders, cancer, chronic respiratory diseases, skin diseases, renal diseases and obesity. Inflammatory diseases are the most prevailing cause of death worldwide and the numbers keep rising.

The network focuses on reducing the burden of infectious and inflammatory diseases caused by pathogens, damaged cells, toxic compounds or radiation in order to develop new diagnostic and treatment technologies.

As a society, we need more knowledge about the correlation between e.g. inflammation and development of cancer, about biomarkers and about molecular mechanisms of autoimmunity in e.g. rheumatological conditions - not to mention chronic mucosal inflammation. In the inflammation network we collaborate interdisciplinearily in order to find answers.

We comprise a wide range of researchers with interest in diagnostic methods, epidemiological data, inflammatory markers and intracellular pathways, understanding of cell population and tissue structures, among others.

Focus groups

OMICS focus group

Paper of the Month

Joanna Maria Kalucka

Breast cancer (BC) is the most frequently diagnosed cancer in women in the US and Europe. Despite improvements in anti-tumour therapy, BC remains the second leading cause of cancer deaths in women. Metastatic relapse is the leading cause of this high mortality and occurs for long periods after removing the primary tumour. Therefore, understanding the mechanisms that control metastasis is pivotal for designing an improved and safe BC treatment regimen.

Changes in cell metabolism have been shown to be essential for several steps of metastasis: metabolism can support tumour growth and facilitate cancer-cell survival in the bloodstream and help to disseminate to distant organs. However, so far, no one has addressed whether a cellular metabolism can influence cancer cell abilities to metastasize.

In a recent study published in Nature, by Rossi et al., investigated the role of the metabolic enzyme phosphoglycerate dehydrogenase (PHGDH), which is known to be overexpressed and/or amplified in 70% of triple-negative breast cancers (TNBC). The authors report that intra-tumour heterogeneity and low expression of PHGDH protein in primary TNBC correlate with poor metastasis-free survival in patients. Strikingly loss of PHGDH in mice promotes cancer cell dissemination and metastasis formation. Furthermore, the changes in PHGDH expression associated with metastatic stage of cancer cells, for example, early metastatic lesions and circulating cancer cells, show low or no PHGDH expression, while advanced proliferating metastases express PHGDH. Furthermore, the downstream analysis revealed that cancer cells lacking PHGDH enzyme had higher expression of genes associated with cell migration, invasion and transformation. The authors also reported that cells with low PHGDH expression showed more migratory capacity than those with high PHGDH from the same tumour. These results elegantly link metabolic heterogeneity with gene-expression programs related to tumour metastasis, and these findings showcased that low enzyme levels are sufficient to induce aggressive features in cancer cells.

Mechanistically, PHGDH altered cell migration by directly binding to another metabolic enzyme:  phosphofructokinase (PFK), a key glycolytic pathway component. Upon loss of PHGDH, the activity of PFK decreases which redirects the carbon flux into another metabolic pathway: the hexosamine-sialic acid pathway. Consequently,  glycosylation (sialylation) of integrin alpha-v-beta-3, a key component for cell migration, is increased, which inhibits the invasiveness of PHGDH low cancer cells and metastasis formation.

Intriguingly, the authors report that cancer cells with low levels of the PHGDH tended to locate near vascular tissue. This implies that endothelial cells can modulate PHGDH expression and thus have an effect on cancer cell invasiveness. Even though the factors and the insights on this mechanisms still have to be defined, this study highlights a possibility of signalling from endothelial cells that directly affects the expression of a metabolic enzyme in tumour cells.

Taken together, while the catalytic activity of PHGDH supports cancer cell proliferation, low PHGDH protein expression non-catalytically potentiates cancer dissemination and metastasis formation. This study broadens our understanding of the role of metabolic heterogeneity in cancer and might point toward new approaches for targeting diverse tumour-cell populations in order to suppress tumor metastases.

Rossi, M. et al.: PHGDH heterogeneity potentiates cancer cell dissemination and metastasis