Energy-Starved Breast Cancer Cells Scavenge From Their Surroundings

Breast cancer cells can consume their surroundings to overcome starvation and continue cell growth, according to University of Sheffield researchers. The new study – published in PLOS Biology – describes a previously unknown method of cancer cell survival, which may represent a new target for anti-cancer therapies.

How do cancer cells overcome starvation?

Breast cancer cells grow in tumors surrounded by an extracellular matrix (ECM). This is a kind of scaffold produced by cells, made up of a network of non-cellular components such as macromolecules and proteins. This provides structural support and interacts with cellular receptors.

The ECM forms part of the tumor microenvironment (TME), and a growing body of evidence indicates that the TME can promote tumor growth.

However, when tumors grow to a large size, blood flow in the TME can be restricted. This reduces the amount of nutrients that reach the energy-hungry cancer cells – yet they continue to grow.

The researchers in the current study investigated how these tumors continue to supply themselves with the raw materials needed to sustain their growth.

“We know that tumors grow in an unfavorable environment, which normally lacks oxygen and nutrients,” explains senior author and lecturer at the University of Sheffield, Dr. Elena Rainero, speaking to Technology Networks. “If we look at breast cancer, we can see that the tumors are very fibrotic, meaning that in addition to cancer cells, there is an accumulation of ECM, the main component of which is collagen. We hypothesized that breast cancer cells might feed on the ECM, to obtain nutrients to support their growth.”

Breast cancer cells can “scavenge” from the ECM

The researchers grew breast cancer cells either on a plastic surface or on an ECM-like material such as collagen or a commercially available matrix preparation.

When these cells were grown without the presence of several important amino acids – effectively starving them – those cultured on the plastic surface had much lower growth rates than those grown on collagen or matrix preparation. Therefore, when surrounded by matrix, the cancer cells were able to scavenge from it and grow despite a lack of nutrient supply.

“We found that breast cancer cells, but not normal breast cells, are able to take up extracellular matrix components from their surrounding environment and digest them inside the cells,” Rainero adds.

Adding fluorescent labels to the collagen matrix revealed that the cells ingested the ECM and broke it down within the cells’ digestive compartments, known as lysosomes.

Analysis of changes in the cells’ metabolism showed that the largest changes involved amino acids tyrosine and phenylalanine, which can both be used as raw materials to generate energy via the Krebs cycle. The researchers could significantly impair cell growth when they blocked the expression of HPDL, an important enzyme involved in feeding phenylalanine into the Krebs cycle.

Potential implications for other cancer types?

“I believe that other highly fibrotic cancers, such as pancreatic cancers, are likely to use similar mechanisms,” says Rainero. “We are now working on expanding this work to other cancer types, as well as understanding whether there is synergy between the inhibition of the metabolic pathway that we identified and other drugs currently used in breast cancer, with the aim of developing a novel combination strategy to prevent breast cancer growth.”

“We believe that it is possible to target the metabolic enzyme that we have identified, and we demonstrated that a drug targeting this blocks cell growth in the lab. Further work is needed to demonstrate that this also works in whole organisms,” Rainero explains, discussing how the study’s findings could highlight a potential therapeutic target.

Reference: Nazemi M, Yanes B, Martinez ML, et al. The extracellular matrix supports breast cancer cell growth under amino acid starvation by promoting tyrosine catabolism. 2024. PLOS Biology. doi: 10.1371/journal.pbio.3002406

Dr. Elena Rainero was speaking to Dr. Sarah Whelan, Science Writer for Technology Networks.

About the interviewee:

Dr. Elena Rainero is a lecturer at the University of Sheffield, UK. Her research interests focus on understanding the role of the ECM in cell migration and growth, as well as supporting breast cancer metabolism. She earned a PhD in human biotechnology from the University of Eastern Piedmont, Italy, in 2010.