Breast Cancer Cells Unveil a Stealthy Survival Mechanism: Ingesting Matrix to Overcome Starvation

In a groundbreaking study published on January 16 in PLOS Biology, researchers led by Elena Rainero from the University of Sheffield, UK, have uncovered a previously unknown survival strategy employed by breast cancer cells. The study reveals that these cells consume the matrix surrounding them to counteract nutrient scarcity, shedding light on a potential target for future therapy development.

Understanding the Battle Within:

Breast cells, including tumor cells, reside within a meshwork known as the extracellular matrix (ECM). The ECM, however, is a challenging environment for nutrient availability due to limited blood flow, a situation exacerbated as tumor cells proliferate. Despite this scarcity, tumor cells persist in their growth, prompting the researchers to investigate how they manage to sustain this relentless expansion.

Decoding the Survival Tactics:

To unravel the mystery, breast adenocarcinoma cells were seeded into collagen (a major ECM component), a commercial matrix preparation, or onto plastic. The study compared their performance with or without specific critical amino acids. The findings revealed that cells on plastic struggled without these amino acids, while those in the matrix showcased resilience. Similar results were replicated across various matrix models, indicating the tumor cells' ability to overcome amino acid reduction when surrounded by the matrix.

Using fluorescence to trace collagen within the cells, the researchers observed that the cells ingested the ECM and broke it down within lysosomes. When the ECM was chemically altered to inhibit this process, the cells were unable to consume it.

Further investigations highlighted that the uptake occurred through a process called macropinocytosis, where the cell engulfs substantial amounts of extracellular material.

Unveiling the Nutrient Hunt:

Metabolomic analysis revealed that, in response to starvation, the tumor cells focused on procuring and breaking down two amino acids: tyrosine and phenylalanine. These amino acids served as crucial raw materials for energy production through the mitochondrial tricarboxylic acid (Krebs) cycle.

When the researchers suppressed HPDL, a central enzyme in the phenylalanine-to-TCA pathway, cell growth was significantly hindered. Inhibiting HPDL or macropinocytosis promoter PAK1 reduced the tumor cells' ability to migrate and invade surrounding tissues.

Potential Therapeutic Implications:

Elena Rainero explained, "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 study identifies a novel survival mechanism employed by breast cancer cells facing nutrient scarcity within tumors. Rainero concludes, "Here we have identified a key metabolic process that the cells need to be able to take advantage of the matrix, which could represent a novel therapeutic target."