Lysosomal Protein Found to Switch Cancer Cells’ Food Source

Cancerous cells require nutrients to grow and often switch their food source depending on availability. Tumors can begin by deriving nutrients from blood vessels, but when faced with limited blood supply, can use proteins as a food source. A team of researchers published a paper in Science further detailing this metabolic switch, specifically examining the role of a protein called LYSET.

The study was led by Wilhelm Palm of the German Cancer Research Center (DKFZ) in Heidelberg and Johannes Zuber at the Research Institute of Molecular Pathology (IMP) in Vienna. To begin their work, the team set up strict nutrient conditions to mimic amino acid starvation, similar to how it occurs in tumors. Then, they used CRISPR-Cas9 to disrupt the genome and narrow down which pathway was involved in these cells’ nutrient switch. 

After examining several pathways, they identified an uncharacterized gene required for cell survival, but only when the cancer cells absorbed nutrients from extracellular proteins. This protein, called Lysosomal Enzyme Trafficking Factor or LYSET, turned out to be critical for lysosome function and acts as a core component of the mannose-6-phosphate pathway, which is required for filling lysosomes with digestive enzymes. The team noted that, in the absence of LYSET, cancerous cells lack the enzymes necessary in their lysosomes to digest proteins, restricting their ability to use them as a viable source of nutrients.

“With LYSET, we have discovered a central component of a metabolic pathway that enables adaptations to different nutrients, a key ability of cancer cells to survive and grow in austere Tumor environments,” says Palm. Wilhelm Palm’s lab was one of the first to describe cancer cells’ ability to feed on extracellular proteins.

Additionally, the team utilized mouse models to study LYSET’s function in actual tumors. They found that losing the LYSET protein significantly impaired tumor development in several types of cancer, and it was well-tolerated under normal nutrient conditions.

“This is what made the discovery so exciting,” says Johannes Zuber. “LYSET and the mannose-6-phosphate pathway turn out to be particularly important for cancer cells and could therefore be a molecular entry point for attacking a major metabolic bottleneck in cancer.”