Interactions between two signaling pathways are raising hopes for a new way to treat cancer, researchers at Vanderbilt University Medical Center and the Sanford Burnham Prebys Discovery Institute of La Jolla, California, have reported.
“It’s super exciting,” said Ray Blind, PhD, Ingram Assistant Professor of Cancer Research at VUMC, who co-led the research with Brooke Emerling, PhD, at the Sanford Burnham Presbys Cancer Center. “There are medications currently in development that could be therapies for patients who have mutations in this pathway.”
Their findings, published May 28 in the journal Science Signaling, focused on the Hippo signaling pathway, which regulates organ size. Mutations that “dysregulate” this intracellular pathway can trigger cancer and other diseases.
The study connected the Hippo pathway to phosphoinositides, a particular type of lipid, or fat molecule, which regulates cell functions that are critical in cancer, obesity and diabetes.
Previous work from Blind’s lab has shed light on phosphoinositide structure, while Emerling and her colleagues have advanced current understanding of enzymes, called PI5P4Ks, which make these lipids. More specifically, her group has established the function of PI5P4Ks in cancer metabolism.
Joining forces, the two research teams discovered that two enzymes in the Hippo pathway, MST1 and MST2, inhibited PI5P4Ks in cells.
“Our hypothesis is that MST1 and MST2 keep PI5P4Ks in check,” Emerling said in a news release. “So, when you lose MST activity in cancer cells, they can keep turning on PI5P4K, and then you get more aggressive metastatic tumors.”
The researchers also found that “knocking out” the gene for PI5P4K led to a decline in the activity of the Yes-associated protein, YAP. Located at the end of the Hippo pathway, “YAP is often used in the clinic as a biomarker for aggressive tumors,” Emerling said.
“For many different reasons, proteins like YAP are difficult to target with drugs,” Blind noted.
However, said Emerling, “we see a lot of potential in trying instead to inhibit PI5P4K as a possible treatment for cancers that have YAP activation. Several compounds have already been developed to inhibit PI5P4K and could be used in future studies to explore this approach.”
Emerling is co-director and associate professor of the Cancer Metabolism and Microenvironment Program at Sanford Burnham Presbys, a leading research institute named for philanthropists T. Denny Sanford, Malin and Roberta Burnham, and Conrad Prebys.
Blind has a primary appointment in the Department of Medicine and secondary appointments in the departments of Biochemistry and Pharmacology in the Vanderbilt University School of Medicine. He also directs the Vanderbilt Quantitative & Chemical Biology PhD program and is associate DEI director for Vanderbilt-Ingram Cancer Center.
“It was a fantastic, easy collaboration with many more papers to come,” Blind said.
Emerling’s group made the initial discoveries, performed the biological assays, and established the relevance of the interacting pathways to cancer, while Blind’s team conducted computational, biochemical, and structural biology studies to support a mechanistic basis for the findings.
Their paper was accompanied by a commentary by an internationally known expert in the field, Emilio Hirsch, PhD, and colleagues at the University of Torino, Italy.
VUMC co-authors are:
- Zeinab Haratipour, PhD, a former postdoctoral fellow in Blind’s lab who is now assistant professor of chemistry at Austin Peay State University in Clarksville, Tennessee.
- Woong Jae Choi, a former undergraduate researcher and research associate in Blind’s lab currently enrolled in the Tri-Institutional MD-PhD Program at Weill Cornell Medicine in New York.
This work was supported by National Institutes of Health grants R01CA237536, R01GM143583, T32CA211036, R01GM132592, R21CA243036, T32DK007673, and T32HG008341, the American Cancer Society and the V Foundation for Cancer Research.
