Energy-starved breast cancer cells consume their environment for fuel, study finds

Breast cancer cells ingest and consume the matrix around them to overcome starvation, according to a new study published January 16 in the open access journal. Biology PLOS, by Elena Rainero of the University of Sheffield, UK, and colleagues. This discovery elucidates a previously unknown mechanism of cancer cell survival and could provide a new target for the development of therapies.

Breast cells, including tumor cells, are embedded in a network called the extracellular matrix (ECM). Nutrients are scarce in the ECM, due to limited blood flow, and become even scarcer as tumor cells grow. And yet, they continue to grow, which led the authors to study how tumor cells provide themselves with the raw materials necessary for their growth.

To do this, they seeded breast adenocarcinoma cells in collagen (a major component of ECM) or in a commercial matrix preparation, or on plastic, with or without certain essential amino acids. Without these amino acids, cells on plastic fared poorly compared to those on either matrix. Similar results were observed with other matrix models: tumor cells were able to overcome amino acid reduction when surrounded by matrix.

Then, by fluorescently labeling the collagen and observing its journey through the cell, the authors showed that the cells took up the ECM and broke it down into digestive compartments called lysosomes; when ECM was chemically treated to cross-link its components, cells were unable to ingest it.

Further investigation indicated that absorption occurs through an ingestion process called macropinocytosis, in which the cell engulfs large quantities of extracellular material.

What were the tumor cells like next? Analysis of their metabolome indicated that the supply and degradation of two amino acids, tyrosine and phenylalanine, dominated the metabolic changes in response to starvation. The authors noted that these two elements can serve as raw materials for energy production via the mitochondrial tricarboxylic acid (Krebs) cycle.

When they destroyed HPDL, a central enzyme in the pathway from phenylalanine to TCA, cell growth was significantly impaired. Blocking or reducing the expression of HPDL, or the macropinocytosis promoter PAK1, reduces the ability of tumor cells to migrate and invade surrounding tissues.

“Our results indicate that breast cancer cells take advantage of extracellular matrix nutrients in times of nutritional deprivation, and that this process depends on both macropinocytosis and the metabolic conversion of key amino acids into energy-releasing substrates. ” Rainero said.

“HPDL-mediated tyrosine and phenylalanine metabolism could represent a metabolic vulnerability of cancer cells growing in a nutrient-deprived microenvironment.”

The authors add: “This study identified a new mechanism used by breast cancer cells to survive in the harsh environment in which they find themselves within tumors. As food sources are scarce, cancer cells gain the ability to eat and digest components of the matrix around them. “.

“Here, we identified a key metabolic process that cells need to be able to take advantage of the matrix, which could represent a new therapeutic target.”