Scientists at the Weizmann Institute of Science and their research partners have found that cancer cells sometimes skip an essential ingredient in protein-producing recipes – a phenomenon that has hitherto been known in bacteria and viruses, but not in multicellular organisms.
When following a complicated recipe for a cake, you are sometimes tempted to give up one of the ingredients or try to find a replacement in the home pantry. The result may be successful, but most tasters will feel the difference. From a new study by scientists at the Weizmann Institute of Science and their research partners published today in the scientific journal NatureIt appears that cancer cells sometimes skip an essential ingredient in protein-producing recipes – a phenomenon that has hitherto been known in bacteria and viruses, but not in multicellular organisms. The result of this process is short, disrupted protein sequences that, like the products of an unsuccessful recipe, may allow our immune system to “feel the difference,” that is, to identify and fight the cancer cells.
The new generation of cancer treatments in general – and melanoma skin cancer in particular – is based on harnessing our immune system against malignancies. These treatments, called immunotherapy, work, among other things, by removing barriers that prevent our immune system cells from detecting cancerous growth cells. Despite the great promise of these treatments, they are now yielding results in only a few cases – and many research laboratories around the world are looking for ways to make these treatments more effective.
One of the ways in which cancerous tumors deceive our immune system is the overproduction of an enzyme called IDO1. This enzyme breaks down an essential component in the production of proteins – the amino acid tryptophan – leaving behind a trail of by-products that suppress the immune response. Clinical trials examining the possibility of blocking the activity of the enzyme have so far not yielded the desired results – but have left open the question of how do cancer cells themselves function in a tryptophan-poor environment?
To answer this question, Prof. Jordana Samuels’ research group from the Department of Molecular Biology, which specializes in melanoma research, joined the research groups of Prof. Reuven Agami of the Dutch Institute for Cancer Research, Dr. Noam Stern-Ginosar of the Institute of Molecular Genetics, D. Rabbi Yishai Levin of the National Center for Personalized Medicine at the Institute and of Prof. Johanna Ulvaus of the University of Oslo. The international research team found that melanoma cells deal with tryptophan deficiency through a trick known as “frameshift” which has hitherto been known exclusively in bacteria and viruses.
In the process of producing proteins in a cell, organs called ribosomes make up amino acid after amino acid according to a recipe encoded in messenger RNA molecules. In healthy cells when the amino acid needed for the recipe is missing, the production process gets stuck and a kind of “traffic jam” is created. Surprisingly, the ribosomes in the cancer cells manage to skip one of the letters in the recipe, so that in practice proteins are formed based on completely new recipes. This deliberate disruption of the recipe produces short and unusual protein sequences (peptides) some of which are then displayed on the outer membranes of the cancer cells. “In fact, we found in the study new clues that spread the cancer cells – these clues may help the immune system cells identify the tumor and fight it,” explains Dr. Osnat Bartok of Prof. Samuels’ group.
These abnormal peptides produced by melanoma cells have not been identified so far, as they do not result from DNA mutations, which like hundreds of melanoma cells, but from a deliberate disruption of the recipe at the production stage itself. “We hypothesize that this flexibility in translating messenger RNA molecules encourages tumor growth and its degree of violence,” says Prof. Agami, whose laboratory is currently investigating whether this phenomenon also characterizes other cancers. “These findings reveal a whole new dimension in the picture of proteins displayed on cell membranes, so they will allow us to better understand the interrelationships between the immune system and healthy and malignant cells alike,” says Prof. Samuels, adding: “Apart from basic science, the findings also point to On new and exciting directions for the development of immunotherapeutic drugs. “
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