frodosome
© Image rendering by Mark Esposito and Gary Laevsky
Human breast cancer bone metastasis showing the newly discovered organelle (magenta) in cancer cells (cyan).
Unofficially dubbed the "frodosome" or "wise" organelle, after the hobbit hero in "Lord of the Rings," this membrane-less structure may play a role in driving bone metastasis, or the spread of cancer from other parts of the body to bones, according to a new study.

The frodosome, however, is likely not all bad. It governs very important chit-chat within and between cells, and thus likely plays an important — but still unknown — role in cell functioning, the scientists said.

Organelles are to eukaryotic cells as organs are to organisms, as they each perform a specific set of functions to keep their bigger machines running. It's rare to discover a brand-new organelle, and only a couple dozen organelles are already known to exist in cells including the mitochondria and the maze-like Golgi apparatus, said senior author Yibin Kang, a professor of molecular biology at Princeton University in New Jersey.

"This one is unlike any that we have known before," Kang told Live Science. "My hope is that it's going to be as important as other organelles, maybe one of the most important ones."

Kang and his team discovered this new structure accidentally while studying a gene called DACT1, which previous research showed could suppress critical signaling pathways — or a series of chemical and molecular reactions — in cells that both help in early bone development in utero, and influence cancer progression. Turning on the DACT1 gene seems to help cancer cells spread.

To understand why, the researchers used a fluorescent protein to tag the protein coded by DACT1 in human cells in a lab dish. They then observed where the protein went and what it did. Under the microscope, they saw that the DACT1 protein condensed, along with some other mystery substances, into what looked like droplets of oil in water.

Many of these condensates, which just looked like irregularly shaped balls — blobs if you will — drifted near each other and merged together like liquid mercury.

The blobs, or frodosomes, form by a process called "liquid-liquid phase separation," which is unusual but not unheard of among organelles. In other words, these frodosomes aren't defined by a solid membrane like the one that surrounds the most commonly known organelles, such as the mitochondria. Rather, it's a membrane-less fluid-like structure that has physical properties that allow it to separate out from the rest of the cell's cytoplasm, where all the organelles aside from the nucleus live.


The researchers think that frodosomes form when the protein DACT1 binds to other free-floating proteins and molecules in the cell. DACT1 can do that because it's such an excellent shape-shifter; it's made up of parts that can morph into different shapes that bind different types of proteins. Indeed, when the researchers deleted the DNA that codes for these morphing parts, DACT1 couldn't collect all the proteins needed to form the frodosome.

The team also tried to figure out what other mystery molecules made up the frodosome. They used mass spectrometry, which identifies unknown compounds by their molecular weight, and discovered 600 different types of proteins in the frodosome.

Frodosome's purpose

The researchers also found that when they injected tumor cells with the fluorescently-tagged DACT1 into mice, these blobs formed when the cancer spread to the bones; and when they removed the DACT1 gene from the tumor cells in mice, they could reduce bone metastasis.

To figure out the function of frodosome, the researchers looked at a pathway controlled by the DACT1 gene called the Wnt pathway. For cancer to metastasize to bones, it first needs to turn on Wnt to grow from individual cancer cells that came from other parts of the body, then turn off the Wnt signal once the tumor has started growing. At that point, turning off Wnt activates cells that break down bone tissue and make room for the growing tumor.

Kang's group found that the frodosome plays a part in the second phase of bone tumor spread: suppressing Wnt. To do so, the frodosome picks up and hoards all the free-floating casein kinase 2 (CK2), a molecule needed to keep Wnt signaling going.

"It's like a jail, it just takes it away," Kang said. Without CK2 readily available in the cell, Wnt signaling malfunctions. That gives cancer cells free rein to spread.

"It's very fair to call this a new type of organelle, which is a huge advance in basic cell biology," said Jeff Boyd, the director of the Center for Genomic Medicine at Northwell Health Cancer Institute in New York, who was not involved in the study. "While none of this work was done in humans, this is the type of unapologetic" basic cell biology research that ultimately leads to potential treatments for diseases such as bone metastasis, Boyd told Live Science.

The frodosome is bad in the context of cancer but it likely plays an important role in healthy cells, too, Kang said. He and his team are now hoping to figure out what that normal function is and whether the frodosome influences other signaling pathways in the body.

The researchers have found frodosomes in breast cancer and prostate cancer cells that have metastasized to the bone, but these organelles also show up in healthy human cells, including lung cells.

Given that the frodosome plays a central role in signaling pathways key to embronic development and maintenance, it's likely it's universal across cells, Kang said.

It's too early to say whether the frodosome will be a good drug target in metastatic cancer, but the discovery is definitely an "exciting new phenomena," Kang said. (He is the co-founder of a company KayoThera that works to develop medications for late-stage or metastatic cancers).

The findings were published March 9 in the journal Nature Cell Biology.