Cancer Cells Devour Surroundings For Survival, Offering New Therapy Target

Starving breast cancer cells feast on their surroundings in order to survive while inside tumors, a new study suggests.

Scientists behind the study hope the findings may offer a new target for therapy development.

The cells were found to take advantage of nutrients in the ‘extracellular matrix’ of the breast when food became scarce.

The previously unknown discovery of the survival tactic ostensibly debunks the mechanism of how the cells survive, according to the study published in the journal PLOS Biology,

The multinational research team from the UK, Singapore and France, sought to find out the survival mechanisms of cancerous cells in the breast. These cells, including tumor cells, are embedded in a meshwork called the extracellular matrix (ECM), where nutrients are scarce due to limited blood flow and become even scarcer as tumor cells grow.

Yet these cells continue to grow, leading researchers to investigate how tumor cells supply themselves with the raw materials to support this growth.

The research team seeded breast adenocarcinoma cells into either collagen – a major component of the ECM – or a commercial matrix preparation, or onto plastic, with or without certain critical amino acids. Without these amino acids, the cells on plastic fared poorly compared to those in either matrix.

Similar results were observed with other matrix models; the tumor cells were able to overcome the reduction of amino acids when surrounded by the matrix. By fluorescently labeling the collagen and watching its journey through the cell, the researchers found that the cells took up ECM and broke it down in digestive compartments called lysosomes.

But when the ECM was chemically treated to cross-link its components, the cells were unable to ingest it.

Further investigation indicated that this ingestion was completed through a process called macropinocytosis, in which the cell engulfs large quantities of extracellular material.

Analysis of the tumor cells’ metabolome indicated that procurement and breakdown of two amino acids, tyrosine, and phenylalanine, dominated the metabolic changes in response to starvation. The researchers noted that these two can serve as the raw material for energy production through the mitochondrial tricarboxylic acid (Krebs) cycle.

When they knocked down HPDL – a central enzyme in the pathway from phenylalanine to the TCA – they found cell growth was significantly impaired.

Blocking or reducing the expression of HPDL, or the macropinocytosis promoter PAK1, reduced the ability of tumor cells to migrate and invade surrounding tissue.

Dr. Elena Rainero, a lecturer at the University of Sheffield’s School of Biosciences, explained that the results of the study demonstrated how cancer cells survived in the ‘challenging’ environment within tumors.

The lead author of the study said: “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.

“HPDL-mediated metabolism of tyrosine and phenylalanine could represent a metabolic vulnerability of cancer cells thriving in a nutrient-deprived microenvironment,” said the study.  “This study identified a novel mechanism employed by breast cancer cells to survive in the challenging environment they are in within tumors.

“As sources of food are scarce, cancer cells gain the ability to eat and digest components of the matrix around them.

“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,” said the study.

Produced in association with SWNS Talker