Embedded in a thick wall of collagen and other extracellular matrix materials, cancer cells starve when out of reach of the blood supply that transports vital nutrients (1). In the case of breast cancer, hungry tumor cells survive by consuming the extracellular matrix surrounding them, according to a recent study published in PLOS Biology (2). 

Lead investigator and biotechnologist Elena Rainero at the University of Sheffield studied how the extracellular matrix around cancer cells affected how cancers spread, but an interesting observation made her refocus her efforts: “I started to notice that the [cancer] cells were not just binding to the matrix, but they were also taking it inside,” she said. “If they're doing that, they must have a reason.” What she and her team found sheds light on a potential vulnerability in cancer cells and suggests possible new targets for therapeutic interventions.

Rainero’s team cultured a human breast cancer cell line and a metastatic breast cancer cell line on three different materials: collagen I, Matrigel, or plastic. Collagen I is an extracellular matrix component, while Matrigel is a protein mixture designed to mimic the extracellular matrix.  To find out how cancer cells grow under starvation, they used either nutrient-rich media or media lacking amino acids. Compared to plastic, collagen I and Matrigel supported cell growth even when nutrients were scarce, suggesting that the extracellular matrix partially rescues cell growth during nutrient deprivation. 

Rainero was surprised at the results. “I was expecting that if you removed a lot of nutrients, the cells would just die,” she said. “Apparently, cancer cells don't do that. They are really efficient at using whatever they have access to.”

When the team fluorescently labeled the collagen to track its journey inside the cancer cells, the researchers found that the ingested material accumulated inside lysosomes. There, it was degraded and used to derive essential amino acids, such as phenylalanine and tyrosine, which the cancer cells used to continue growing. “It’s always a bit surprising how fast the extracellular matrix can degrade in a tumor,” said Paolo Provenzano, a biomedical engineer at the University of Minnesota, who was not involved in the study. “This could be part of that missing puzzle; it's not all just getting degraded by classical enzymatic approaches. Instead, a lot of it is being metabolized by the cancer cells themselves.”

I was expecting that if you removed a lot of nutrients, the cells would just die. Apparently, cancer cells don't do that. They are really efficient at using whatever they have access to. 
– Elena Rainero, University of Sheffield

Rainero’s team showed that one possible mechanism through which cancer cells ingested extracellular matrix material was macropinocytosis, a form of endocytosis through which cells engulf extracellular molecules (3). Blocking or reducing expression of the macropinocytosis promoter p21-activated kinase reduced Matrigel uptake and cancer cell growth under nutrient deprivation conditions. 

In future experiments, Rainero’s team plans to inhibit amino acid metabolism in an animal cancer model to see whether tumor growth is affected. In parallel, they would also like to test whether extracellular matrix uptake occurs in other highly fibrotic cancer types such as pancreatic tumors. Provenzano added, “I suspect that a lot of [the] mechanisms [these researchers uncovered] are applicable to a broad range of breast cancer cells, and even to broader cancers, but we [need] the experiments to find out.”

References

1. Kamphorst, J. J. et al. Human pancreatic cancer tumors are nutrient poor and tumor cells actively scavenge extracellular protein. Cancer Res  75, 544–553 (2015).
2. Nazemi, M. et al. The extracellular matrix supports breast cancer cell growth under amino acid starvation by promoting tyrosine catabolism. PLOS Bio  22, e3002406 (2024).
3. Kay, R. R. Macropinocytosis: Biology and mechanisms. Cells Dev  168, 203713 (2021).