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New Study Reveals Starving Cancer Cells Change Food Source By Breaking Down Protein

The environment in which cancer cells grow does not have enough nutrients so the cancerous cells overcome this challenge by changing their metabolism to make use of proteins as an alternative "food." It is using this mechanism that an international group of scientists identified the protein LYSET as part of the way, which allows cancer cells to make the switch. The research findings are now published in the journal Science.

Amino acids are known to be the building blocks of proteins and are the important nutrients for cell growth and proliferation. A good understanding of how cells use amino acids in different environments is a basic question in biology and cancer research. Tumor tissues often have a limited blood supply, and to grow under such conditions, cancer cells switch their metabolic activities. In particular, they switch from taking up nutrients delivered by blood vessels to taking alternative nutrients, like breaking down neighbouring proteins as a food source, when they are deprived of food. However, researchers are yet to find the mechanism, which helps the cancer cells make the switch so easily.

To better understand the molecular pathways, which underly this nutrient change in cancer, two groups of scientists with similar expertise joined forces to find answers. Wilhelm Palm of the German Cancer Research Center or DKFZ in Heidelberg is a leading expert in cancer metabolism, Johannes Zuber at the Research Institute of Molecular Pathology or IMP in Vienna have enough experience in functional cancer genetics. The scientists set up their study with tightly controlled nutrient conditions to mimic amino acid starvation as it happens in tumors. Then they used the "gene scissors" CRISPR-Cas9 to disrupt the expression of almost every gene in the genome, which helped them narrow down several pathways involved in the nutrient switch.

Among them, the scientists spotted an uncharacterized gene that was only required for cell survival when cancer cells were feeding on extracellular proteins. This gene, which the scientists re-named as LYSET or Lysosomal Enzyme Trafficking Factor, turned out to be important for the working of lysosomes, which are small organelles that function as the stomach of cells where proteins are digested.

More study in the functioning of LYSET revealed that the gene acts as a core component of the so-called mannose-6-phosphate pathway, which is needed for filling lysosomes with digestive enzymes. In the absence of LYSET, cancer cells do not have the enzymes in their lysosomes and can no longer digest proteins.

Following this, scientists used mouse models to study the function of LYSET in real tumors. They found that the loss of LYSET affected tumor development in several types of cancer, while it was normal under normal nutrient conditions. Wilhelm Palm, whose lab was among the first who described the ability of cancer cells to feed on extracellular proteins, says, "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."

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