A jagged little protein appears to be key to how to stem cancer cells differentiate and enable metastasis, according to researchers at Rice University and the Duke University School of Medicine.
Rice scientists who have formed several theories on how to grow cancer and spread the dots for a more complete picture of tumor mechanics. At the center, they found JAG1, a ligand, or small protein, that interacts with a signaling pathway critical to regulating the fate of cells. Their new paper in the Proceedings of the National Academies of Sciences supported by experiments at Duke shows how and why some cells differentiate within tumors and how they spread.
The researchers led by members of Rice's Center for Theoretical Biological Physics (CTBP) extended their models of hybrid epithelial-mesenchymal cancer stem cells that have the ability to not only resist chemotherapy but also band together in small groups and metastasize.
The Rice team had already published theories on how to stem cancer stem cells communicate with each other and the outside world by taking control of the signaling pathway involved in extracellular signaling, wound healing and embryonic development.
Role of JAG1
In those studies, they discovered how to ligate that activate the pathway, go rogue to hold migrating cancer cells together and help them attach to connective tissues at new locations. The new work pulls all those hard-won discoveries together into a cohesive picture, with JAG1 as the prime suspect and inflammatory proteins in a supporting role.
The Rice researchers led by physicists José Onuchic and Herbert Levine also described for the first time how inflammatory proteins, including the cytokine interleukin 6, amplify signals between notch and jagged proteins that support hybrid epithelial-mesenchymal stem cells.
"We have a model of EMT, a model of stemness, a model of cancer metabolism and a model of notch-delta," Onuchic said. "In a real system, all these models are coupled. And in this particular case, we show that under stress, jagged's involved in all of them.
"We already knew JAG1 was paramount for cells to assume this (hybrid) state where they can send and receive signals and coordinate with other cells to migrate together," said Federico Bocci, co-lead author of the paper and a graduate student at Rice . "And we also knew these molecules correlate to the proliferation potential of cells.
The team at Duke led by Gayathri Devi saw evidence of heterogeneity in lab experiments on highly aggressive, inflammatory breast cancer cells. "This heterogeneity remains a major roadblock to any clinical advances, because no magic bullet can eradicate all types of cells in a tumor," she said. "Thus after most therapies, a few cells are left unharmed, a scenario that can lead to tumor relapse."
Duke graduate student Larisa Gearhart-Serna used a novel tumor organoid model of inflammatory breast cancer cells that is enriched with cancer stem cells developed previously in Devi's lab to show that reducing the presence of JAG1 affected the cancer stem-like properties and capacity to proliferate. The work could lead to therapies that track down and destroy those cells.
Notch signaling pathway
"JAG1 may play crucial roles in regulating this heterogeneity, and inhibiting its levels can significantly curb tumor formation," Devi said. "We are now using these patient-derived tumor organoid models to identify druggable targets in the notch signaling pathway."
Bocci said mesenchymal stem cells tend to remain near a tumor's periphery, where they are exposed to the surrounding environment, particularly the suspect inflammatory proteins. Cells in the tumor's interior tend to spread out and become hybrids that are harder for drugs to destroy.
Onuchic said jagged ligands are important to the body's inflammatory system, so reducing their numbers carries risks of its own. "We have learned that when things happen and cells are under stress, there's high levels of jagged in the neighborhood," he said. "Any therapy that comes from this work will be related to controlling the level of jagged, but you can not completely get rid of it because it has beneficial functions."
Levine suggested jagged could serve as a target for new diagnostic tools. "There's another aspect to what this work helps us, and that's to judge whether a tumor is aggressive enough to treat," he said. "There is a lot of literature based on measuring tumors to understand the chances of a person getting a metastatic disease." If we can identify features like that, tell us if a tumor is really aggressive, this will also be an important result. "