Princeton researchers discover previously unknown organelle that plays a role in bone metastasis

Some leading Princeton cancer researchers were set to discover that what they thought was a straightforward study of how cancer spreads through the body – metastasis – turned evidence of liquid-liquid phase separation: the new field of biological analysis that studies how liquids of blobs of living materials coalesce into each other, similar to the movements seen in a lava lamp or in beer mercury.

We believe this is the first time that stage separation has been implicated in cancer metastasis. “

Yibin Kang, Warner-Lambert / Parke-Davis Professor of Molecular Biology

He is the lead author of a new paper that appears on the cover of the current issue of Nature’s cell biology.

Not only does their work link stage separation to cancer research, but the merging blobs turned out to form more than the sum of their parts, assembling themselves into an organelle. previously unknown (actually the organ of the cell).

Finding a new organelle is very moving, Kang said. He compared it to finding a new planet inside our solar system. “Some of the organs we’ve known for 100 years or more, and then all of a sudden, we’ve found a new one!”

This will move some basic ideas about what a cell does and does, said Mark Esposito, Ph.D. alumnus and postdoc routine in Kang lab the first author of the new paper. “Everyone goes to school, and they learn ‘Mitochondria are the powerhouse of the cell,’ and a lot of other things about a few organelles, but now, our classic definition is on what ‘s inside a cell, on how a cell organizes and controls its behavior, begins to move, “he said.” Our research marks a step forward in very hard there. “

The work grew out of a collaboration between researchers in the laboratory of three Princeton professors: Kang; Ileana Cristea, professor of molecular biology and leading expert in live cosmetic spectroscopy; and Cliff Brangwynne, June K. Wu ’92 Professor of Chemical and Biological Engineering and director of the Princeton Bioengineering Initiative, who began a study of phase differentiation in biological processes.

“Ileana is a biochemist, Cliff is a biologist and an engineer, and I am a cancer biologist – a cell biologist,” Kang said. “Princeton is just an amazing place for people to connect and collaborate. We have very little campus. All the science departments are side by side. Ileana’s lab is actually on the same floor of Lewis Thomas as mine! , among very diverse research areas, allows us to introduce technologies from many different angles, and allows developments to understand the mechanisms of metabolism in cancer – its progression, metastasis and the immune response – and also create new ways to target it. “

The latest fragment, in which the organelle remains unnamed, adds a new understanding of the Wnt signal pathway, a system that led to the 1995 Nobel Prize for Eric Wieschaus, Princeton’s Squibb Professor of Molecular Biology and professor at Lewis. -Sigler Institute for Integrative Genomics. The pathway of Wnt is crucial for the development of early growth in countless organisms, from small invertebrates to humans. Wieschaus discovered that cancer can co-select this pathway, essentially impairing its ability to grow as fast as embryos, to grow tumors.

Subsequent research has shown that the Wnt signaling pathway has several roles in healthy bone growth as well as metastasizing cancer to bone. Kang and his colleagues were studying the complex interplay between Wnt, a signaling molecule called TGF-b, and a relatively unknown gene called DACT1 when they discovered this new organelle.

Think of it as buying panic before a storm, Esposito said. Buying bread and milk before a blizzard isn’t just human features – or stacking a hand sanitizer and toilet paper when a pandemic is looming. They occur at the cellular level, too.

Here’s how it works: DACT1 is the panic buyer, and TGF-ß is the panic (or pandemic). Casein Kinase 2 (CK2) is the bread and hand sanitizer, and in the presence of a storm, DACT1 picks up as much as they can, and the newly discovered organelle removes them. By collecting CK2, the buyer prevents others from making sandwiches and cleaning their hands, ie interrupting the healthy functioning of the Wnt pathway.

Through a series of detailed and complex experiments, the researchers put together the story: bone tumors first stimulate Wnt signals, to spread (spread) through the bone. TGF-b, which is abundant in bones, then stimulates the purchase of panked, eliminating Wnt symptoms. The tumors then stimulate the growth of osteoclasts, which scrape away old bone material. (Healthy bones are always replenished in a two-part process: osteoclasts scrape away a layer of bone, then osteoblasts rebuild the bone with new material.) This increases increased TGF-b concentration, encouraging even greater DACT1 accumulation and subsequent Wnt overdose that has been shown to be important in further metastasis.

By discovering the roles of DACT1 and this organelle, Kang and his team have discovered potential new targets for cancer drugs. “For example, if we have a way to prevent a DACT1 complex, the tumor may spread, but it will not be able to‘ grow up ’to be a life – threatening metastasis. That’s the hope, ”Kang said.

Kang and Esposito recently co – founded KayoThera to develop medicines for patients with late or metastatic cancers, based on their joint work in the Kang laboratory. “The kind of basic study that Mark is doing is both mimicking the results of modern science and can lead to medical advances,” Kang said.

The researchers have found that DACT1 plays many other roles as well, which their team is only beginning to study. The massive spectrometry collaboration with Christ’s team revealed more than 600 different proteins in the secret organelle. Mass spectrametry allows scientists to discover the exact components of almost any content designed on a microscope slide.

“This is a more dynamic signal node than just controlling Wnt and TGF-b.” said Esposito. “This is just the tip of the iceberg on a new field of biology.”

This bridge between stage differentiation and cancer screening is still in its infancy, but there is already great potential, said Brangwynne, who co – authored the paper.

“The role that biomolecular condensates play in cancer – both its genesis but specifically their spread through metastasis – is still poorly understood,” he said. “This study provides new insights into the interplay of cancer signaling pathways and condensate biophysics, and will open up new therapeutic pathways.”