In a new study, pancreatic tumors in both humans and mice that had low levels of G[alpha]13 expression increased mTOR signaling, while targeting the mTOR pathway in mice reduced tumor growth and progression. The findings establish a previously undocumented tumor-suppressive role of G[alpha]13 in pancreatic cancer, and also suggest patients with pancreatic ductal adenocarcinoma (PDAC) whose tumors have G[alpha]13 loss may benefit from therapies that inhibit the mTOR signaling pathway.
The study was led by Mario A. Shields, PhD, Research Assistant Professor of Medicine in the Division of Hematology and Oncology, and Hidayatullah G. Munshi, MD, the Robert and Lora Lurie Professor of Medicine, both at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.
Detailing their findings in Cell Reports, the cancer investigators note that G[alpha]13 regulates signaling from G-protein-coupled receptors (GPCRs), which are membrane proteins that mediate the physiological functions of cells (2022; doi.org/10.1016/j.celrep.2022.110441). While previous studies suggested G[alpha]13 would be pro-tumorigenic, most involved in vitro models or cell lines injected in mouse models, according to the researchers, who were the first to genetically engineer mice with G[alpha]13 loss in epithelial tumors. The new findings in PDAC tumors also agree with mouse models of lymphoma that have demonstrated the tumor-suppressive function of G[alpha]13, the study shows.
After knocking out G[alpha]13 in a genetically engineered KRAS and TP53 (KPC) mouse model of a pancreatic tumor containing genetic mutations known to be contributors to pancreatic cancer in humans, the investigators observed increased tumor growth and decreased survival in mice. Pancreatic tumors with G[alpha]13 loss in humans and mice also shared similar increases in E-cadherin protein expression, the study showed.
When the researchers injected rapamycin into mice with pancreatic tumors, the mTOR signaling inhibitor increased tumor cell death and decreased tumor growth and progression while also establishing the tumor-suppressive role of G[alpha]13 in pancreatic cancer. The findings may help physicians stratify patients with pancreatic cancer who might benefit from drugs targeting the mTOR signaling pathway based on high and low levels of G[alpha]13 in their tumors, and despite this patient population having a history of poor response to targeted therapies.
Meanwhile, the researchers have begun looking at how G[alpha]13 affects the immune microenvironment of pancreatic tumors and whether targeting cells within it can reverse tumor progression and increase overall survival.
Recently, the Northwestern Medicine investigators, Shields and Munshi, the lead author and senior author of the study, respectively, shared additional insights about their groundbreaking research with the Oncology Times.
What inspired you to investigate this research question?
"GPCRs are targets for a third of FDA-approved therapeutic drugs. GPCR signaling regulates many processes in cancer, including angiogenesis, immunobiology, and metastasis. G proteins are a major class of proteins that directly propagate GPCR signaling activity. Like the GPCRs, G proteins are found to be altered in many cancers. However, the functions of G proteins in cancers are less understood.
"We previously reported that GNA13 (G[alpha]13) is upregulated in pancreatic cancer and is required for the invasion of pancreatic cancer cells in vitro. Others have also shown that siRNA targeting of G[alpha]13 in epithelial cancer cell lines decreases growth in vitro and when injected into a mouse model.
"However, genetic targeting of G[alpha]13 in mouse models of lymphoma, in fact, promotes tumor development, indicating that G[alpha]13 functions as a tumor suppressor in lymphoma. Thus, we were interested to understand the effects of genetic targeting of G[alpha]13 in tumors developing and progressing in their native environment in the mouse pancreas."
What were the most important findings in the study?
"Contrary to our hypothesis, we found that G[alpha]13 plays a tumor-suppressive role in pancreatic cancer. Loss of G[alpha]13 increases pancreas tumorigenesis and progression in a genetic mouse model and is associated with elevated mTOR signaling in both mouse and human tumors. We show that rapamycin, an mTOR inhibitor, reduced tumor growth and induced apoptosis in tumors with loss of G[alpha]13."
What, if anything, surprised you about the results of your research?
"We were surprised by the context-specific outcomes of targeting G[alpha]13 in pancreatic cancer. In transplantation models with cell lines, we and others have shown that G[alpha]13 can have a tumor-promoting effect.
"In the current study, we find that G[alpha]13 has a tumor-suppressive role in mouse tumors harboring mutations in KRAS and p53, while in tumors with only mutation in KRAS, G[alpha]13 had no apparent effect on tumorigenesis and progression."
What are the clinical implications, if any, of your research?
"mTOR signaling has been an attractive clinical target in cancer patients, including pancreatic cancer. Clinical trials with mTOR inhibitors for cancers have not been widely successful. Our study suggests that a population of patients with low levels of G[alpha]13 may benefit from therapeutics targeting mTOR such as everolimus."
What further research needs to be done on this topic?
"We are actively investigating what are the consequences of elevated mTOR signaling in G[alpha]13-deficient tumors. Particularly, how mTOR signaling regulates mitochondrial metabolism and the immune microenvironment.
"Our ongoing investigations suggest aspects of the mitochondrial function are disrupted in G[alpha]13-deficient pancreas tumors. Consistent with another recent publication, we found a profound effect of G[alpha]13-loss on inflammation, thus we plan to further investigate changes in the immune microenvironment of G[alpha]13-deficient tumors and the impact of mTOR signaling in this context (Science 2021; doi: 10.1126/science.abg5784).
Is there anything else about the study that you would like to add?
"There are no current pharmacological inhibitors for G[alpha]13, and tremendous effort is underway to find specific inhibitors to G-proteins to further understand their functions in normal physiology and diseases. Our study suggests that an inhibitor for G[alpha]13 might not provide benefits to pancreatic cancer patients."
Chuck Holt is a contributing writer.
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