Northwestern Medicine investigators have discovered that targeting the G alpha 13 protein in pancreatic tumors promotes tumor growth and progression, according to a study published in Cell Reports.
They also showed that human and mice pancreatic tumors with reduced G alpha 13 exhibited increased mTOR signaling, and targeting the mTOR signaling pathway reduced tumor growth in the mice.
“We believe that pancreatic cancer patients whose tumors have a reduced expression of G alpha 13 might benefit from therapies targeting the mTOR signaling pathway,” said Mario A. Shields, ’12 PhD, research assistant professor of Medicine in the Division of Hematology and Oncology and lead author of the study.
The G alpha 13 protein regulates cell signaling from G-protein-coupled receptors, a large class of membrane proteins that mediate many physiological functions and can be dysregulated in diseases.
Previous work utilizing in vitro models has shown that inhibiting the G alpha 13 protein in epithelial cancer cells decreased their ability to grow and invade, while other work in lymphomas showed that G alpha 13 functioned as a tumor suppressor. However, the specific impact of targeting G alpha 13 in mouse models of epithelial cancer had not been previously studied.
In the current study, investigators employed genetically engineered a mouse model of pancreatic cancer containing Kras and Tp53 genetic mutations, both of which contribute to pancreatic cancer in humans. They found that knocking out G alpha 13 promoted tumor growth and reduced survival in the mice.
Next, the team found that human tumors with reduced G alpha 13 expression exhibited increased mTOR signaling and E-cadherin protein expression. To corroborate their findings, they demonstrated that similar to the human tumors, mouse tumors with reduced G alpha 13 expression exhibited increased mTOR signaling and increased E-cadherin expression.
The team then administered the drug rapamycin — an mTOR inhibitor — to mice with established pancreatic tumors, finding that rapamycin increased tumor cell death and decreased the growth of tumors with reduced G alpha 13 expression.
The findings establish a previously unrecognized tumor-suppressive role of Galpha13 in pancreatic cancer and suggests that targeting the mTOR signaling pathway in human pancreatic tumors with decreased expression may be efficacious.
“We thought G alpha 13 would be pro-tumorigenic because of past research, but most of these studies involved looking at in vitro models or in cell lines injected in mouse models. Nobody had genetically engineered mice with G alpha 13 loss in epithelial tumors. Our findings in pancreatic cancer agree with mouse models of lymphoma where G alpha 13 also has a tumor-suppressive function,” Shields said.
While most patients with pancreatic cancer have historically responded poorly to targeted therapies, including rapamycin, the current findings may help better identify pancreatic cancer patients who could benefit from therapies targeting the mTOR signaling pathway.
“Targeted therapies are increasingly being developed for cancer treatments, but most targeted therapies have been unsuccessful when it comes to pancreatic cancer. This work suggests stratifying pancreatic cancer patients with low and high G alpha 13 tumor expression and using rapamycin to treat pancreatic patients with reduced G alpha 13 expression,” said Hidayatullah G. Munshi, MD, the Robert and Lora Lurie Professor of Medicine and senior author of the study.
According to Shields, the team also wants to investigate how G alpha 13 expression affects the immune microenvironment in pancreatic tumors and determine whether targeting cells in the tumor immune microenvironment can reverse tumor progression and prolong patient survival.
Munshi and Shields are members of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.
This work was supported by National Cancer Institute (NCI) grants R01CA217907 and R21CA255291; a merit award I01BX002922 from the U.S. Department of Veterans Affairs; an H Foundation award and APA/APA Foundation 2020 Young Investigator in Pancreatology grant; a Mander Foundation award; a Harold E. Eisenberg Foundation award from the Robert H. Lurie Comprehensive Cancer Center; and a National Institutes of Health/NCI training grant T32CA070085.
