A Tiny Molecule’s Big Role in Cancer
Researchers uncover a possible molecular mechanism for recurrent ovarian cancer
Image credit: iStock
by Rena Kingery
June 10, 2022
Ovarian cancer is the deadliest cancer of the female reproductive system. While health providers are beginning to recognize its subtle symptoms — bloating, abdominal discomfort, pelvic pain — no reliable screening tool exists for the cancer, and many women ignore their symptoms or are misdiagnosed until tumors are advanced. “It’s a very horrible and devastating disease, and the vast majority of patients eventually die of the disease,” says Riccardo Fodde, professor of experimental pathology at the Erasmus Medical Center in Rotterdam, Netherlands.
Historically, the National Cancer Institute and nonprofits have devoted a smaller share of research and advocacy funding to gynecological malignancies than to more common but less deadly cancers such as those of the prostate and breast. Thus, advances in ovarian cancer screening and treatment have lagged. Oncologists still turn to platinum-based chemotherapy to fight the cancer, even though 80% of patients with advanced disease develop resistance to it and experience recurrence.
A team of researchers led by Analisa DiFeo, an associate professor in the department of pathology and obstetrics and gynecology at the University of Michigan, aims to improve screening and treatment for ovarian cancer by examining its underlying molecular causes. In a study published in Cancer Research in April 2021, the team identified a minuscule molecule as a potential driver for chemotherapy-resistant forms of ovarian cancer. The culprit appears to be one of the thousands of fragments of genetic material, called microRNAs, or miRNAs, that swirl within human cells and influence processes throughout the body.
If the human genome were a beach, miRNAs would be the size of individual grains of sand. One human chromosome, for example, contains between 50 million to 250 million nucleotides (the building blocks of DNA and RNA). However, one strand of miRNA contains just 22 nucleotides, on average, and is roughly 500 times smaller than a single red blood cell.
Decades of research following the discovery of miRNA in 1993 revealed that the tiny molecules are essential for healthy growth and development across numerous species, including humans. Diseases such as HIV, lupus, Type 2 diabetes, and cancers of the breast, lung, colon, and others are linked to abnormal levels of miRNAs.
DiFeo’s team found that one miRNA, miR-181a, often overexpressed in ovarian cancer, activates a process called the Wnt/beta-catenin signaling pathway, a series of proteins that regulate growth and development in nearly all animals, from house flies to humans. You could think of the Wnt (pronounced “wint”) pathway as a dammed river whose flow is tightly regulated by a series of spillways. The spillways only open when necessary, just as the Wnt pathway is only activated when normal growth processes are needed.
Follow MicroRNA’s possible role in ovarian cancer. (Image credit: Tara Holley)
Sometimes, a defective protein in the pathway activates Wnt when it should be dormant, causing unchecked growth of cells. Abnormal activation of Wnt signaling is linked to cancer of the liver, stomach, skin, and many others. “We discovered a new mechanism by which this extremely relevant cancer pathway was activated [in ovarian cancer],” says DiFeo.
The Wnt pathway also helps determine the stemness of cells, or the ability of cells to become different tissues such as bone, skin, or other organs. When Wnt signaling is activated in ovarian and other cancers, it generates cancer stem cells, which produce tumors that can outwit the immune system, evade chemotherapy, and spread to nearby tissues.
The team began investigating miR-181a’s role in Wnt signaling because they noticed that recurrent, therapy-resistant ovarian tumors always contained high levels of the miRNA, DiFeo says. When they inserted human ovarian cancer cells into mice, they demonstrated that as miR-181a in the cells increased, so too did levels of Wnt activation.
In most cancers, mutations in the proteins that control the Wnt pathway cause it to activate, but not in ovarian cancer. “For many years, people did not think the Wnt signaling pathway was relevant in ovarian cancer, because there are no mutations,” DiFeo says. But the team’s study revealed that miR-181a, and not a mutation, is responsible for switching on the cancer-causing conduit.
Despite their minute size, miRNAs influence the body in big ways by switching off genes. Genes produce strands of messenger RNA, or mRNA, that code for proteins, molecules that perform essential tasks for the cell. While miRNAs don’t code for proteins, they do control protein production by clinging to the messengers, triggering the mRNA to break down or blocking it from being translated.
The team found that in ovarian cancer, miR-181a turns on Wnt by blocking the production of a protein that shuts down the pathway in healthy cells. In other words, miR-181a is like a glitch in the dam’s operating system that causes one of the spillways to get stuck open. But if it could be repaired, the spillway could once again hold back the flow. The Michigan team showed that they could shut off the flow of Wnt and halt tumor growth in mice by targeting miR-181a so that it could no longer interfere with the inhibitor protein. The results reveal a potential strategy for treating the deadly disease.
“It’s a very solid paper in terms of the experiments that they’ve done,” says Fodde, who was not involved in the study. “They show a reduction in the incidence of cancer in those mouse models, but that does not immediately and directly mean you can apply this to human beings,” he says, adding that the team used mice with suppressed immune systems to perform the research.
That’s why DiFeo is teaming up with colleague Dr. Kathleen Cho, a professor of pathology at the University of Michigan who has genetically engineered mice that spontaneously develop the most common and deadly form of ovarian cancer. DiFeo will use the models to study the natural progression of the disease and its potential treatments in rodents with fully functioning immune systems.
Currently, DiFeo and her team are using a specially designed procedure to find small molecules that could reduce miR-181a in the novel mouse models. “Targeting miRNA has become kind of a hot topic right now,” DiFeo says, adding that recent research into mRNA vaccines for protection against SARS-CoV-2, the virus that causes COVID-19, has been a boon for miRNA therapeutics. If the DiFeo lab finds a molecule that works against miR-181a, the results could have implications for all cancers antagonized by the specific miRNA. For ovarian cancer, the micro findings could lead to macro changes that transform it from a deadly threat into a manageable nuisance.
Rena Kingery
Rena Kingery is a freelance science writer and fact-checker based in Bellingham, WA. She writes for Discover Magazine Online and Facing Our Risk of Cancer Empowered, a non-profit that provides education, support, and advocacy for people facing hereditary cancer. She is in her final semester of the MA in Science Writing Program at Johns Hopkins University. A former environmental educator, Rena enjoys exploring the mountains, forests, and waterways of the Pacific Northwest.