Turning to the dark side: A study from Stanford Medicine shows how oncogenes trick immune cells.news center


Cancer-associated genes, called oncogenes, are well known to stimulate cell growth and division, leading to tumor swelling and spread. But now, researchers at Stanford University School of Medicine and Sarafan ChEM-H have discovered that a notorious oncogene called Myc also plays a direct role in hiding growing cancers from the immune system.

Myc is linked to more than 70% of human cancers, and researchers believe that blowing cover in these cancers could lead to a new class of cancer treatments.

They found that a key component of Myc-induced camouflage is sugar molecules that coat the surface of cancer cells. This sugar sends a “stop” signal to immune cells called macrophages, which normally engulf and destroy cancer cells.

This finding connects two seemingly unrelated previous observations. Cancer cells differ from healthy cells in the pattern of sugars on their surface. The Myc oncogene also somehow protects cancer cells from the immune system by increasing the production of specific proteins within the cells. To decipher this relationship, her two labs run by sugar chemist and recent Nobel Prize winner Carolyn Bertozzi, Ph.D., and her two, led by cancer expert Dean Felsher, M.D. I needed the cooperation of two labs.

Felsher, professor of medicine and pathology, said: Felscher also directs the Stanford Translational Research and Applied Medicine Center, which encourages physicians and basic scientists to collaborate and bring results into the clinic. “Many cancer treatments have been developed basically by trial and error, but this one is very different. We know exactly the mechanism and how to target this process.”

“It’s an amazing connection,” says Bertozzi, professor of Ann T. and Robert M. Bass in the Faculty of Humanities. “In my lab, we were trying to understand why cancer cells changed their surface sugar patterns and how these changes help the cells evade the immune system. , have been found to regulate the production of proteins that make these sugar molecules that trick the immune system into ignoring cancer cells.”

Bertozzi, Baker Family Director of Felsher and Sarafan ChEM-H, is senior author of the study, which was published March 10 in the online edition of the Proceedings of the National Academy of Sciences. Graduate student Benjamin Smith and instructor Dr. Anja Deutzman are the lead authors of the study.

lost gene

Oncogenes are good genes going bad. They play an important role in controlling how and when cells divide before they go to the dark side. When released from the regulatory layer, it promotes rapid cell division and tumor growth.

Like many oncogenes, Myc is a member of a class of proteins called transcription factors. Transcription factors are key regulators that regulate up and down the levels of many proteins in cells in response to external and internal signals. These proteins can prompt cells to ignore signals to stop dividing, or circumvent built-in cell-suicide programs to eliminate cell malfunction. They can also modulate the cell’s external environment, bringing unfriendly neighbors into alliance, and promoting the growth of new blood vessels to deliver much-needed oxygen to growing tumors. is fully prepared to wreak havoc when things go wrong.

Felsher has spent decades studying how Myc triggers cancerous changes inside and outside cells. Early in his career, he became suspicious that his Myc was also weakening his immune system. This was a relatively new idea at the time.

Bertozzi is an expert in analyzing the patterns of sugars or glycans that bristle from the surface of all living cells. These sugars are dizzyingly complex in their structure, mediate important interactions with other cells, and signal molecules such as hormones and pathogens such as viruses and bacteria. Research requires specialized knowledge and equipment, and Bertozzi is a world leader in this field.

I think this is very likely to lead to a completely new cancer treatment.

Felsher and Deutzmann, then postdoctoral researchers in Felsher’s lab, learned that Myc likely controlled the expression of a class of proteins called glycosyltransferases. This is necessary for building complex sugar-containing molecules on the surface of cells. But they lacked the tools and expertise to pursue their discoveries.

But in the summer of 2016, Felsher invited Bertozzi to speak at a symposium at his Center for Translational Research and Applied Medicine. Bertozzi, who had recently arrived at Stanford University, enthusiastically accepted the offer.

“I came to Stanford with great hope that I could interact directly with doctors and learn more about human disease,” said Bertozzi. So when Dean asked me to talk, I was very excited. This was all new to me. ”

At the symposium, Bertozzi talked about observations he had made in his lab.

“We know, and have known for some time, that there are changes in the pattern of sugar molecules on the surface of cancer cells. I was wondering.

As she spoke, the atmosphere in the room changed. “Our students would gather after the talk and say, ‘This all makes sense,'” she recalls Felsher. After hearing from Felsher and members of his lab about the relationship between Myc and glycosyltransferase enzymes, Bertozzi said: “We realized that this must be how sugars change.”

With Deutzmann and Felsher’s lab providing information on Myc and its role as an oncogene, and Smith and Bertozzi’s lab with expertise in sugar science, also called “glycobiology,” the lab soon agreed to cooperate.

Identify the role of Myc

The research team jointly discovered that Myc promotes the production of a glycosyltransferase called ST6GalNAc4. ST6GalNAc4 is required to make a sugar molecule called disialyl T, which is abundantly displayed on the surface of Myc-driven cancer cells. Disialyl-T binds to another molecule on the surface of macrophages, flipping them from foe to friend in one fell swoop.

This interaction is important. Leukemic cells driven by Myc expression but unable to make ST6GalNAc4 grew more slowly in experimental mice and generated stronger immune responses against tumors than cells capable of making ST6GalNAc4. Furthermore, Smith and Deutzmann found that cancer patients with high levels of both Myc and ST6GalNAc4 had a worse prognosis and fewer immune cells near their tumors than those with low levels.

“This connection between Myc and glycobiology was really eye-opening and it was in front of everyone,” said Bertozzi. “From Dean’s previous work, we know that Myc regulates cell growth and division, which is clearly important for cancer. It can promote sugar expression and avoid recognition by the immune system.”

The researchers are eager to continue the partnership to develop new cancer treatments.

“From our perspective, there are two obvious directions for research,” said Bertozzi. “First, we want to test whether other oncogenes also influence sugar structures on the surface of cancer cells. We want to see if we can raise it.”

“What Stanford University is doing — deliberately bringing together doctors and basic scientists from different fields — is exactly how we try to cure disease,” Felscher said.

Researchers at the University of British Columbia, the University of California, San Francisco, the City of Hope, and the University of Iowa also contributed to this work.

This study was funded by the National Institutes of Health (Grants R01-CA227942, R35-CA253180, R01-CA208735PQ7, U01-CA188383, R01-CA184384, R01-CA170378PQ22, F30-CA232541, NCI-CA222676, K00-CA21324) it was done. CA250324 and F30-AG060638), Stanford University School of Medicine Medical Scientist Training Program, Howard Hughes Medical Institute, Emerson Population Cancer Research Fund, Lymphoma Research Foundation, ChEM-H Stanford Interdisciplinary Graduate Fellowship, Canadian Institutes of Health, Natural Sciences and Engineering Canada Research Council, Leukemia and Lymphoma Society, American Society of Hematology, and American Cancer Society.

Bertozzi is a co-founder of Redwood Biosciences (subsidiary of Catalent), Enable Biosciences, Palleon Pharmaceuticals, InterVenn Bio, Lycia Therapeutics, and OliLux Biosciences, and a member of the Eli Lilly Board of Directors. Bertozzi, Felsher, and other co-authors are co-inventors on a patent application related to this work held by Stanford University.



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