The study, published Jan. 2 in Nature Immunology, may lead to therapies that target the earliest stages of cancer. The findings bolster the idea that the inflammasome has a dual role — it promotes inflammation associated with poor outcomes in late cancer stages, but early on, it can help prevent cells from becoming cancerous in the first place.

“What was striking was that the innate immune system, which includes the inflammasome, has a role beyond infection,” said Dr. Julie Magarian Blander, the Gladys and Roland Harriman Professor of Immunology in Medicine and a member of the Jill Roberts Institute for Research in Inflammatory Bowel Disease at Weill Cornell Medicine. “We found that it functions in maintaining homeostasis in the tissue, keeping an eye on whether stem cells are proliferating too much. By doing so, it prevents cells from becoming cancerous and this activity is independent of inflammation.”

The co-first authors of the study are Dr. Andrew Kent, an assistant professor of medicine-hematology at the University of Colorado School of Medicine and Dr. Kristel Joy Yee Mon, a postdoctoral associate in Dr. Blander’s lab.

Origin Story

By the time patients typically go to the doctor with cancer symptoms, tumors have already formed. As a result, very little is known about cancer’s beginnings.

To get a better understanding of how the disease takes hold, Dr. Blander and her colleagues chose to study a mouse model of B-cell lymphoma called Eµ-myc, which has a mutation in the Myc oncogene. These mice have a long delay before tumors develop, giving researchers a chance to observe what happens early on in cancer. Because B-cell lymphoma develops in a type of white blood cell, the team examined their precursors, called hematopoietic stem cells, in the mice.

Genetically disrupting inflammasome activity in the Eµ-myc mice greatly accelerated stem cell proliferation and tumor development. The investigators were surprised to find that stem cells in control mice that lacked the inflammasome also proliferated at a fast pace compared with wild-type mice, suggesting that the complex has an important role in healthy cells, too. The team found that without the inflammasome, the stem cells have high levels of the protein Ras, which is another oncogene product. This protein can work together with mutant Myc to drive cancer, so the inflammasome’s normal job of keeping Ras in check delays tumorigenesis.

Ground zero for the protective activity was not the hematopoietic stem cells themselves, but the bone marrow stroma, a collection of many cell types surrounding and nurturing the stem cells.

Higher levels of soluble tumor necrosis factor (TNF) receptors were found in the stroma of control mice compared with the inflammasome-deficient mice. “It turned out that TNF receptors were being shed from stem cells in control mice, and they were being retained on stem cells from inflammasome-deficient mice. Higher TNF receptor levels lead to increased stem cell proliferation. Maintaining a healthy level of TNF receptors becomes important for these stem cells to maintain homeostatic control of proliferation,” said Dr. Blander. “We think that the inflammasome in the stroma is orchestrating something where it’s cleaving TNF receptors, shaving them off the stem cells.”

Next steps

Next, the team will test for the inflammasome’s protective effects in other tissues. In addition, they will determine which of the stromal cell types is responsible for the activity, and which molecules the inflammasome is using to suppress cell growth.

Ultimately, the researchers hope that the study will lay the groundwork for a therapeutic that would stave off cancer. “A therapy could target the inflammasome, but it should be directed only to the inflammation side of its activity that is associated with tumor progression,” said Dr. Blander, who is also a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine. “You want to protect the inflammasome’s beneficial function of delaying tumorigenesis.”

New research led by The University of Texas at Arlington emphasizes that studying the impacts of past tropical storms can help communities better prepare for future storms. A key part of the study is analyzing the types and quantities of storm-related precipitation in affected regions to understand its role on local water resources. By mitigating excessive damage, such preparation could enable more people to remain in their home countries. This is increasingly urgent as climate change is expected to make tropical storms 10-15% more frequent and intense.

“We already know that tropical storms have a huge impact on water resources in communities, but few studies have examined the water runoff from these events and how they impact local populations — that’s where our research comes in,” said Ricardo Sánchez-Murillo, lead author of the study and associate professor of earth and environmental sciences at UTA.

Dr. Sánchez-Murillo and his team, in collaboration with international partners from hurricane-prone regions in the Bahamas, Costa Rica, the Dominican Republic, El Salvador, Honduras, Jamaica, Mexico, Nicaragua, and Trinidad and Tobago, analyzed water “fingerprints” known as isotopic compositions. By studying isotopic data from past storms, they provided new insights into how storm-related precipitation influences regional water cycles, adding depth to our understanding of these weather events.

“Our comprehensive analysis of isotopic compositions in tropical storm-derived precipitation offers a deeper understanding of the role these weather systems play in regional water cycles and climate predictions,” said Sánchez-Murillo. “These results underscore the significance of accounting for storm-related precipitation. We feel that understanding precipitation impacts will help communities better prepare for extreme storms and manage local water resources both before and after the storms.”

The research team, which includes researchers from Brown University, Clemson University, Florida International University, Humboldt University, Oberlin College, Rice University, the University of Aberdeen, the University of Houston, the University of Tennessee and Washington State University, plans to expand its work. Future studies will investigate evaporation and groundwater recharge patterns resulting from tropical storms, as well as how storm paths might shift due to climate change.

“This research has broad implications for improving our understanding of how tropical storms impact water resources and climate, leading to better predictions and management strategies,” Sánchez-Murillo said.

This research was funded in part from grants from the International Atomic Energy Agency and an Early Career Fellowship from the Gulf Research Program of the National Academics of Science, Engineering, and Medicine.

The finding could be particularly important to the study and treatment of diseases such as cystic fibrosis, in which the mucus that lines the lungs becomes more concentrated, often causing bacterial infections that take hold in that mucus to become life threatening. This discovery could also have implications in studies of polymer-secreting conglomerations of bacteria known as biofilms — the slippery goo on river rocks, for example — and in industrial applications where they can cause equipment malfunctions and health hazards.

The work is described in a paper published on January 17 in the journal Science Advances.

“We’ve discovered that when many bacteria grow in fluids containing spaghetti-like molecules called polymers, such as mucus in the lungs, they form cable-like structures that intertwine like living gels,” says Sujit Datta, a professor of chemical engineering, bioengineering, and biophysics at Caltech and corresponding author of the new paper. “And, interestingly, there are similarities between the physics of how these structures form and the microscopic physics underlying many nonliving gels, like Purell or Jell-O.”

Datta recently moved to Caltech from Princeton University. One of his graduate students at Princeton, Sebastian Gonzalez La Corte, is lead author of the paper. He and Datta had been interested in how mucus concentration changes in the lungs and guts of cystic fibrosis patients — in whom more polymers than usual are present. Working with mucus samples provided by colleagues at MIT, Gonzalez La Corte grew E. coli bacteria (commonly used in laboratory studies) in regular liquid and in cystic fibrosis-like samples and then observed the specimens under a microscope to watch how the bacterial cells grew in each case.

He focused on cells that had lost the ability to swim, as is the case for many bacteria in nature. Under normal circumstances, when such a cell divides into two, the resulting cells separate and diffuse away from each other. However, Gonzalez La Corte found that in a polymeric solution, the copied cells remained stuck to each other, end to end.

“As cells continue to divide and stick to each other, they start to form these beautiful long structures that we call cables,” Gonzalez La Corte says. “At some point, they actually bend and fold on each other and form an entangled network.”

The team found that the cables continue to elongate and grow as long as the cells have the nutrients they need, eventually creating chains that are thousands of cells long.

Subsequent experiments showed that it does not seem to matter which bacterial species are introduced, nor does the type of organic polymer solution make a difference; once enough polymer surrounds the bacterial cells, the cables grow. The researchers even saw the same result with bacteria in synthetic polymers.

Although the initial motivation for the study was to better understand the growth of infections in patients with cystic fibrosis, the findings are more broadly relevant. Mucus plays an important role in the human body, not only in the lungs but also in the gut and in the cervicovaginal tract. And Datta says the work is also important in the context of biofilms, groupings of bacteria that grow an encapsulating polymer matrix of their own. There are biofilms in the human body, such as dental plaque, but they are also extremely common in soil and in industrial settings, where they can damage equipment and cause health hazards.

“That polymer matrix that they’ve secreted is what makes biofilms so tough to remove from surfaces and treat with antibiotics,” Datta says. “Understanding how cells grow in that matrix could be key to discovering how to better control biofilms.”

Understanding the Physics Behind the Cables

Through carefully designed experiments, the team found that the external pressure exerted by the polymers surrounding the dividing cells is what forces the cells together and holds them in place. In physics, such an attractive force that is under the control of an outside pressure is called a depletion interaction. Gonzalez La Corte used the theory of depletion interaction to create a theoretical model of bacterial cable growth. The model can predict when a cable will survive and grow in a polymeric environment.

“Now we can actually use established theories from polymer physics, which were developed for completely different things, in these biological systems to quantitatively predict when these cables will arise,” Datta says.

Why Do the Bacteria Form These Cables?

“We discovered this interesting, unusual, very unexpected phenomenon,” Datta says. “We can also explain why it happens from a mechanistic, physics perspective. Now the question is: What are the biological implications?”

Interestingly, there are two possibilities: The bacteria could be clumping together to form this network of living gel in an effort to make themselves larger and therefore more difficult for immune cells to engulf and destroy. Alternately, cable formation could actually be harmful to the bacteria. After all, the secretions from the host cause the bacteria to build the cables. “Mucus isn’t static; for example, in the lungs, it’s being constantly swept up by little hairs on the surface of the lungs and propelled upward,” Datta says. “Could it be that when bacteria are all clumped together in these cables, it’s actually easier to get rid of them — to expel them out of the body?”

For now, no one knows which possibility is correct, and Datta says that is what makes this project remain interesting. “Now that we have found this phenomenon, we can frame these new questions and design further experiments to test our suspicions,” he says.