A team of international scientists led by the German Cancer Research Center (DKFZ) in Heidelberg, Germany has identified a new protein called LYSET which allows cancer cells to survive in low-nutrient environments by switching food sources.
The deregulation of cellular metabolism is one of the hallmarks of cancer. As tumor tissues often have a limited blood supply, cancer cells need to switch their metabolism to alternative nutrients such as the breakdown of surrounding proteins in order to proliferate and survive. However, the mechanisms behind this switch have remained largely unknown.
In the new study published in Science, the team of researchers has identified a key regulator of the metabolic switch using the “gene scissors” CRISPR-Cas9 to silence almost all metabolic pathways in cancer cells in order to identify the exact ones enabling the nutrient switch. Using this method, they discovered a previously uncharacterized gene which they re-named Lysosomal Enzyme Trafficking Factor “LYSET”.
“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, ” said Wilhelm Palm, Group Leader at the DKFZ in Heidelberg, Germany and senior author of the study in a press statement.
The researchers found that LYSET is critical for the normal function of lysosomes, small organelles responsible for protein digestion. The gene plays an important role in the mannose-6-phosphate pathway, required for providing lysosomes with digestive enzymes. When LYSET is not present, cancer cells are unable to digest proteins and generate amino acids, revealing the protein as a key regulator in the nutrient switch.
“This is what made the discovery so exciting,” said Johannes Zuber, Senior Group Leader at the Research Institute of Molecular Pathology in Vienna and co-author of the study in a press statement. “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.”
The researchers also used mouse models in order to study the function of LYSET in real tumor tissues. In the models, the loss of LYSET strongly diminished tumor development in several cancer types. However, under regular nutrient conditions the protein was well-tolerated by the cells.
Previous research published in Cell identified the protein mTORC1 as another possible regulator of the metabolic switch by inhibiting the uptake of extracellular proteins for digestion in cancer cells as an alternative food source, also representing a possible target for the suppression of cancer cell metabolism and their proliferation.
“LYSET represents a core component of the lysosomal enzyme trafficking pathway, underlies the pathomechanism for hereditary lysosomal storage disorders, and may represent a target to suppress metabolic adaptations in cancer,” the authors conclude in their research paper, marking the protein as an important target for future research.
