Breast cancer cells have been found to consume the matrix surrounding them as a source of nutrients, according to a recent study published in the open access journal PLOS Biology. The research, conducted by Elena Rainero and her team at the University of Sheffield in the UK, sheds light on a previously unknown mechanism through which cancer cells are able to survive and grow. The findings may pave the way for the development of new therapeutic targets for breast cancer treatment.
Breast cells, including tumor cells, are embedded in a meshwork known as the extracellular matrix (ECM). Due to limited blood flow, nutrients are scarce within the ECM, and become even scarcer as tumor cells continue to grow. This led the researchers to investigate how the cancer cells manage to sustain their growth despite the lack of resources.
The team conducted experiments in which breast adenocarcinoma cells were placed in different substrates, including collagen (a major component of the ECM), a commercial matrix preparation, or plastic. Some cells were also deprived of certain critical amino acids. The results showed that cells grown on plastic without the essential amino acids fared poorly compared to those grown in the matrix. The same trend was observed in other models, demonstrating that tumor cells are able to overcome the decrease in amino acids when surrounded by the matrix.
Further investigation revealed that the cells took up the ECM by ingesting it through a process called macropinocytosis, where the extracellular material is engulfed by the cell in large quantities. The researchers also discovered that the cells broke down the ingested matrix in digestive compartments called lysosomes. When the ECM was chemically treated to cross-link its components, the cells were unable to ingest it.
Analysis of the tumor cells’ metabolome showed that the breakdown of two amino acids, tyrosine and phenylalanine, played a dominant role in their metabolic changes in response to starvation. The authors noted that these two amino acids can be used as a raw material for energy production through the mitochondrial tricarboxylic acid (Krebs) cycle.
To further validate their findings, the researchers knocked down the activity of HPDL, a key enzyme in the pathway from phenylalanine to the Krebs cycle. This significantly impaired cell growth. Additionally, blocking or reducing the expression of HPDL or the macropinocytosis promoter PAK1 decreased the ability of tumor cells to migrate and invade surrounding tissue.
Elena Rainero commented, “Our results indicate that breast cancer cells take advantage of nutrients in the extracellular matrix in times of nutrient starvation, and that this process depends on both macropinocytosis and metabolic conversion of key amino acids to energy-releasing substrates.” The researchers suggest that targeting the metabolic vulnerability of breast cancer cells in nutrient-deprived microenvironments could lead to the development of new therapeutic approaches.
The study provides valuable insights into a previously unidentified mechanism utilized by breast cancer cells to survive and thrive in challenging tumor environments. As the availability of food sources becomes scarce, the cancer cells are capable of consuming and digesting components of the matrix surrounding them. The researchers have identified a crucial metabolic process required by the cells to take advantage of the matrix, which could serve as a potential therapeutic target for breast cancer treatment.
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