A newly published study from Duke Cancer Institute researchers sheds light on a long‑standing mystery in cancer biology and reveals a potential new path toward more targeted treatments for pancreatic and other solid tumors.
The work, led by Gerry Blobe, MD, PhD, leader of basic and translational science for the DCI Pancreatic Cancer Center, was recently published in Nature. The study uncovers how the loss of a protein called ALK4, present in a substantial percentage of pancreatic and breast cancers, drives tumor aggressiveness and metastasis. The research also identifies potential therapeutic strategies that may counteract this effect.
For more than 20 years, scientists have known that some pancreatic cancers carry mutations in ALK4, a receptor involved in the transforming growth factor (TGF)‑beta signaling pathway. What remained unclear was how the loss of this receptor affects cancer behavior and whether it creates vulnerabilities that clinicians can target.
Although ALK4 mutations occur in only about two percent of pancreatic cancers. Blobe and his team discovered that loss of ALK4 expression is far more common. Through mechanisms including loss of the gene itself, transcriptional downregulation, and epigenetic silencing, about 40 percent of pancreatic tumors lose ALK4 function. A similar pattern was found in breast cancer.
This loss, Blobe explains, turns out to be far from harmless. Across multiple cell‑culture studies and animal models in pancreatic and breast cancer, the team observed the same striking pattern.
“In animal studies, when ALK4 expression is lost, primary tumors do not grow faster, but they become significantly more metastatic, leading to worse outcomes,” Blobe said.
Cells without ALK4 became more migratory and invasive. This change aligned with an increase in a biological process called epithelial‑to‑mesenchymal transition (EMT), a hallmark of cancer progression.
Although ALK4 is part of the TGF‑beta family of receptors, losing ALK4 increased canonical TGF‑beta signaling, which is known to promote metastasis in advanced cancers.
Through extensive molecular studies, the researchers discovered why:
Loss of ALK4 increases glycosylation, a type of post‑translational modification that stabilizes other TGF‑beta receptors on the cell surface, essentially super‑charging the pathway. Receptors that remain become more abundant and more active, driving aggressive behavior.
This same glycosylation‑based mechanism was also found to elevate other pro‑cancer signaling pathways, including VEGF and integrin pathways.
When the team examined human tumor samples, findings from the lab held true:
Patients whose tumors had lost ALK4 expression showed higher TGF‑beta signaling and poorer outcomes.
Together, these discoveries point to several promising clinical applications.
“This marker could help identify patients at higher risk of metastasis — particularly in pancreatic and breast cancers, where ALK4 loss is most common,” Blobe said. “Also, because TGF‑beta contributes to an immunosuppressive tumor microenvironment, patients with high TGF‑beta activity caused by ALK4 loss might benefit from combinations of TGF‑beta inhibitors and immunotherapy.”
Blobe’s research continues through the postdoctoral fellow who led the study, now an independent investigator in China. Blobe remains involved as an advisor as she builds her program.
As researchers continue to build on these findings, ALK4 may become an important marker for identifying aggressive tumors and for tailoring treatments that more precisely address the biological drivers of cancer progression.
“This is one mechanism where the loss of one protein can reprogram cells and mediate wide‑scale changes in how cancer cells signal to become more aggressive and treatment‑resistant,” Blobe said.
