When sufficient nutrients are available from the blood, our body’s cells import free amino acids, the building blocks of proteins, as a preferred food. However, tumors are often insufficiently supplied with blood, which means that the cancer cells have few nutrients at their disposal. They can react to this with metabolic adjustments and switch to alternative nutrient sources when they are hungry. Under these conditions, they primarily use the breakdown of proteins from their environment as a source of food. However, the mechanisms by which cancer cells achieve this have not been adequately researched.
In order to better understand the molecular steps underlying this metabolic adaptation, scientists from the German Cancer Research Center (DKFZ) in Heidelberg and the Research Institute for Molecular Pathology (IMP) in Vienna have joined forces. The team studied cancer cells under tightly controlled nutrient conditions that mimicked an amino acid deficiency found in many tumors. Using the CRISPR-Cas9 “gene scissors”, the researchers switched off the expression of almost all genes in the genome individually. This enabled them to identify the genetic components of the signaling pathways involved in switching to the new nutrient source.
The researchers discovered a previously uncharacterized gene that is only required for survival when the cancer cells feed on extracellular proteins. The gene provides the blueprint for the membrane protein “LYSET” (lysosomal enzyme trafficking factor), which has been shown to be crucial for the function of the lysosomes. These small cell structures serve as the cell’s stomach and digest proteins.
LYSET turned out to be a core component of the so-called mannose-6-phosphate pathway, which is required for the filling of the lysosomes with digestive enzymes. In the absence of LYSET, cancer cells lack the enzymes in their lysosomes and are no longer able to switch nutrient sources. This has dramatic effects on the growth of tumors: the researchers were able to show in mice in which cancer had been induced that a loss of LYSET greatly slows down tumor development.
Wilhelm Palm from the DKFZ says: “With LYSET we have discovered a central component of a metabolic pathway that enables cancer cells to adapt to different nutrients. This is their key ability to survive and grow in a sparse tumor environment.”
“That’s what makes the discovery so exciting,” says Johannes Zuber from the IMP. “LYSET and the mannose-6-phosphate pathway turn out to be particularly important for cancer cells and could therefore be a molecular target to therapeutically target an important metabolic bottleneck in cancer.”
Catarina Pechincha, Sven Groessl, Robert Kalis, Melanie de Almeida, Andrea Zanotti, Marten Wittmann, Martin Schneider, Rafael P. de Campos, Sarah Rieser, Marlene Brandstetter, Alexander Schleiffer, Karin Müller-Decker, Dominic Helm, Sabrina Jabs, David Haselbach , Marius K. Lemberg, Johannes Zuber, Wilhelm Palm: Lysosomal enzyme trafficking factor LYSET enables nutritional usage of extracellular proteins.
Science 2022, https://doi.org/10.1126/science.abn5637
The Research Institute of Molecular Pathology (IMP) in Vienna is a basic life science research institute largely sponsored by Boehringer Ingelheim. With over 200 scientists from 40 countries, the IMP is committed to scientific discovery of fundamental molecular and cellular mechanisms underlying complex biological phenomena. The IMP is part of the Vienna BioCenter, one of Europe’s most dynamic life science hubs with 2,650 people from over 80 countries in six research institutions, three universities, and 41 biotech companies.
www.imp.ac.at, www.viennabiocenter.org