Yibin Kang, correspondent of the paper and professor of molecular biology at Princeton University, said: "We think this is the first time that phase separation is related to cancer metastasis."
Their research not only links phase separation with cancer research, but also produces more things after fusion than the sum of their parts, and self-assembles into a previously unknown organelle (essentially an organ of a cell).
Kang said that the discovery of new organelles was revolutionary. He compared it to the discovery of a new planet in the solar system. "We have known some organelles 100 years or more, and then suddenly, we found a new organelle!"
Mark Esposito, the first author of the paper and a postdoctoral researcher at Kang Lab, said that this will change people's basic views on what cells are and what cells do. "Everyone will learn about organelles when they go to school, such as' Mitochondria is the energy factory of cells', but now, our classical definitions of the inside of cells and how cells self-assemble and control their own behaviors have begun to change. Our research marks a very concrete step in this regard. "
This research stems from the collaboration between researchers in the laboratories of three professors at Princeton University. The three professors are Kang and Ileana Cristea (Professor of Molecular Biology, leading expert in living tissue mass spectrometry); Cliff Brangwynne (director of bioengineering project of Princeton University, pioneer of phase separation research in biological process).
Kang said, "Ileana is a biochemist, Cliff is a biophysicist and engineer, and I am a cancer biologist and a cell biologist. Princeton University happens to be a good place for people to contact and cooperate. Our campus is very small. All the scientific research departments are next to each other. Ileana lab is actually on the same floor as my lab in Lewis Thomas! These very close relationships exist between very different research fields, enabling us to introduce technology from many different angles, enabling us to understand the metabolic mechanism of cancer-its progress, metastasis and immune response-and think about new methods for it. "
This latest breakthrough study, featuring this unnamed organelle, has added a new understanding of the role of Wnt signaling pathway. The discovery of Wnt pathway made Eric Wieschaus, a professor of molecular biology at Princeton University, win the 1995 Nobel Prize. Wnt pathway is essential for the embryonic development of countless organisms, from tiny invertebrates and insects to humans. Wieschaus found that cancer can take advantage of this pathway, which essentially destroys its ability to grow at the necessary speed of embryos, thus making tumors grow.
Subsequent studies have shown that Wnt signaling pathway plays multiple roles in healthy bone growth and cancer bone metastasis. Kang and his colleagues discovered this new organelle while studying the complex interaction between Wnt, a signal molecule named TGF-b and a relatively unknown gene DACT 1.
Esposito said that it was like panic shopping before a storm. Facts have proved that buying bread and milk before the snowstorm, or hoarding hand sanitizer and toilet paper when the epidemic comes, is not only a human characteristic. They also occur at the cellular level.
It works like this: panic shoppers are DACT 1, and snowstorms (or epidemics) are TGF? Bread and hand sanitizer are casein kinase 2(CK2). Facing the snowstorm, DACT 1 caught them as much as possible, and this newly discovered organelle hoarded them. By hoarding CK2, shoppers prevent others from making sandwiches and disinfecting their hands, which prevents the Wnt channel from running healthily.
Through a series of detailed and complicated experiments, these researchers pieced together the whole story: bone tumors initially induced Wnt signals to spread (spread) in bones. Then, TGF-b rich in bones stimulates panic shopping and inhibits Wnt signal transduction. Then, the tumor stimulates the growth of osteoclasts and removes old bone tissue. Healthy bones are constantly supplemented in two parts: osteoclasts wipe off a layer of bones, and then osteoclasts rebuild bones with new materials. This further increased the concentration of TGF-b, promoted the accumulation of DACT 1 and the subsequent Wnt inhibition, which has been proved to be important in further metastasis.
By discovering DACT 1 and the function of this organelle, Kang and his team discovered a new possible cancer drug target. Kang said, "For example, if we can destroy the DACT 1 complex, maybe the tumor will spread, but it will never grow into a life-threatening metastatic tumor. This is our hope. "
Kang and esposito recently co-founded KayoThera Company, seeking to develop drugs for patients with advanced or metastatic cancer based on their cooperation in Kang Laboratory. Kang said: "This kind of basic research done by Mark has not only brought about breakthrough scientific discoveries, but also brought about medical breakthroughs."
These researchers found that DACT 1 also plays many other roles that they have just begun to explore. The mass spectrometry analysis of Cristea team revealed more than 600 different protein in this mysterious organelle. Mass spectrometry enables scientists to find out the exact composition of almost any substance imaged on a microscope slide.
Esposito said, "This is a more dynamic signal transduction node than controlling Wnt and TGF-B ... This is just the tip of the iceberg in the new field of biology."
Brangwynne said that the bridge between phase separation and cancer research is still in its infancy, but it has shown great potential.
He said, "The role of biomolecular aggregates in cancer-its biogenesis, especially its diffusion through metastasis-is still not well understood. This study provides a new insight into the interaction between cancer signal transduction pathway and coagulation biophysics, which will open up new therapeutic approaches. " (Bioon.com Biology Valley)
References:
1.TGF-β-induced DACT 1 biomolecule condensate inhibits Wnt signal transduction and promotes bone metastasis. Natural Cell Biology, 202 1, doi:10.1038/S41556-021-00641-w.
2.TGF-β condenses and restricts WNT. Natural cell biology, 202 1, doi:10.1038/s 41556-021-00649-2.