MicroRNAs and cancer

Salk Institute research illustrates how tumors outsmart immune response

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LA JOLLA, Calif.—The immune system automatically destroys dysfunctional cells such as cancer cells, but cancerous tumors often survive nonetheless. A new study by Salk Institute scientists shows one method by which fast-growing tumors evade anti-tumor immunity.
According to a recent paper in Nature Cell Biology, Salk researchers have discovered a pair of gene-regulating molecules that can change cell signaling in tumor cells to survive and evade the immune system’s normal response.
Tumors often grow so rapidly that they deplete their available blood supply, which results in hypoxia, or a low-oxygen environment. While hypoxia typically causes cells to self-destruct, the tumor microenvironment can help protect the tumor.
“The immunological pressure occurring during tumor progression might be harmful for the tumor to prosper,” Salk Prof. Juan Carlos Izpisua Belmonte, senior author of the work and holder of the Roger Guillemin Chair, said in a press release. “However, the cancer cells find a way to evade such a condition by restraining the anti-tumor immune response.”
“Our findings actually indicate how cancer cells respond to a changing microenvironment and suppress anti-tumor immunity through intrinsic signaling,” he added.
Those findings hinge on microRNAs. These noncoding RNA molecules, which regulate genes by silencing RNA, are gaining attention as research elucidates the roles they play in tumor survival and progression. The Salk team screened a variety of tumor types for altered microRNA levels and identified two microRNAs—miR25 and miR93— whose levels were higher in hypoxic tumors. A series of articles published in 2016 linked miR25 to liver cancer, pancreatic and other gastric cancers, osteosarcoma, glioblastoma and even melanoma, while miR93 has a strong correlation with breast cancer.
The researchers measured levels of miR25 and miR93 in the tumors of 148 cancer patients and found that tumors presenting with high levels of those microRNAs resulted in a worse prognosis when compared to tumors with lower levels. The reverse was true for a molecule known as cGAS—they found that a patient’s prognosis worsened the lower the level of cGAS their tumor had.
Indeed, cGAS has been found to serve as an alarm for the immune system. It detects mitochondrial DNA floating around the cell—which is a sign of tissue damage—and activate the body’s immune response accordingly.
“Given these results, we wondered if these two microRNA molecules, miR25 and miR93, could be lowering cGAS levels to create a protective immunity shield for the tumor,” noted Min-Zu (Michael) Wu, first author of the paper. Wu was formerly a research associate in the Gene Expression Laboratory at Salk, and now works at Amgen.
It turned out they were right. When they tested their hypothesis in mouse models and tissue samples, the team discovered that a hypoxic state triggered miR25 and miR93 to kick off a chain of cell signaling that lowered cGAS levels. When miR25 and miR93 were inhibited in tumor cells, cGAS levels stayed high. Beyond that, inhibition of miR25 and miR93 enabled the Salk researchers to slow tumor growth as well. However, this effect was diminished in immune-deficient mice.
While these results are promising, and the discovery of a new potential target is always encouraging, the scientists caution that directly targeting microRNAs is often difficult, and a simpler route might consist of targeting the other links in the cell signaling chain between miR25 and miR93 and cGAS.
Wu reported in a news release that in the wake of these results, the team is now looking into “the different immune cells that can contribute to cancer anti-tumor immunity.”
This research complements further immune response research undertaken at Salk. In another recent study, scientists found a specific protein that influences the survival and function of regulatory T cells, known as Tregs, that show potential in both cancer immunotherapy and therapies for autoimmune diseases such as rheumatoid arthritis and type 1 diabetes.
The protein in question is the Lkb1 protein (for liver kinase B1). This kinase was previously known to have a role in cell metabolism, but until now, it wasn’t known that it also controls the functions in the immune response of Tregs. In the case of cancer, Tregs are hijacked by tumors to prevent other types of T cells from eliminating cancer cells. The Lkb1 pathway, the team found, “is responsible for supplying Tregs with energy. Without it, Tregs don’t have enough fuel to function,” said Ye Zheng, an associate professor in Salk’s Nomis Foundation Laboratories for Immunobiology and Microbial Pathogenesis.
“To boost cancer immunotherapy, we’d like to find ways to block the Lkb1 pathway,” he added. “The outcome of this inhibition would be an increased immune response from other types of T cells, which would help them to destroy tumors.”
As with miR25 and miR93, Lkb1 represents a difficult molecule to target directly, but the team has identified other molecules further downstream in its signaling pathway that are viable, druggable targets. Their work going forward will include developing drugs against those targets.

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