by UT Southwestern Medical Center

These images show co-localization of AKT3 (red) and the transcription factor Snail (green) in human pancreatic cancer. The presence of AKT3 and Snail in human pancreatic cancer was detected by immunohistochemistry (IHC). DNA was stained in blue as a counterstain. Credit: UT Southwestern Medical Center

A team led by UT Southwestern scientists has discovered a mechanism that promotes metastasis in pancreatic, breast, and potentially other cancers, along with a new druggable therapeutic target to block it. The findings, published in Science Signaling, represent an important lead in developing new drugs to prevent tumors from spreading, the cause of death among most patients with cancer.

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“Metastases from many solid tumors are very challenging to prevent or eliminate with existing tools. This research defines a new target for fighting metastatic disease,” said study leader Rolf Brekken, Ph.D., Professor of Surgery and Pharmacology and in the Hamon Center for Therapeutic Oncology Research at UT Southwestern. He is also an Effie Marie Cain Research Scholar and a member of the Harold C. Simmons Comprehensive Cancer Center.

While primary tumors can be controlled through surgery or radiation therapy, most patients die from the metastatic spread of tumor cells to other sites in the body. Metastasis is the process by which cancer cells separate from a primary tumor and migrate elsewhere in the body, forming new tumors at a distance from their original location. Pancreatic cancer is particularly deadly because metastasis can occur early in the disease before the primary cancer is diagnosed. In fact, only 12% of pancreatic cancer patients survive five years after diagnosis.

One key feature of metastasis, Dr. Brekken explained, is epithelial-to-mesenchymal transition (EMT), in which cancer cells adopt an appearance and behavior that mimics fibroblasts and stem-like cells that migrate and invade other tissues.

Previous research has shown that stimulating a cell surface receptor called AXL can prompt EMT. Another protein in cancer cells, called TBK1, can also drive EMT and appears to be triggered by AXL. TBK1 itself appears to activate the AKT family of proteins, which has three members—AKT1, AKT2, and AKT3. But how these proteins work together to cause EMT has been a mystery.

To learn more about this process, the Brekken Lab worked with James Lorens, Ph.D., Professor of Biomedicine at the University of Bergen in Norway and a Visiting Professor in the Hamon Center for Therapeutic Oncology Research and Pharmacology at UT Southwestern, along with collaborators elsewhere to determine the role each of these proteins plays in EMT.

The researchers started their investigation by examining how the bookends of this cascade, AXL and AKT, relate to each other. Using a database and their own experiments, they found that pancreatic and breast cancer cells tend to co-produce AXL and only one member of the AKT family, AKT3, suggesting that AKT3 contributes to EMT. Further research showed that if they genetically removed AKT3, they could dramatically block invasion and metastases, making AKT3 a potential therapeutic target.

Using advanced techniques, Norwegian researchers on the team developed the first AKT3-specific molecule inhibitor, allowing the investigators to shut down AKT3 in models of pancreatic and breast cancer. Loss of AKT3 expression in pancreatic cancer cells significantly decreased the number of metastases in mice with pancreatic tumors but did not affect the size of the primary tumor. Importantly, the UTSW group found that high AKT3 expression is associated with metastatic disease and worse outcomes in patients with breast and pancreatic cancer.

Together, Dr. Brekken said, these results suggest that AXL, TBK1, and AKT3 work in a cascade to stabilize proteins in the cell nucleus that regulate EMT. Although AXL and TBK1 are already being investigated as targets to fight metastasis in a variety of cancer types, AKT3 represents a new target against metastatic disease. Additionally, AKT3 in the nucleus of cancer cells could serve as a biomarker for patients at high risk of metastasis, Dr. Brekken notes. He and his colleagues plan to continue studying this signaling cascade to develop new ways to monitor and combat metastasis.

More information: Emily N. Arner et al, AXL-TBK1 driven AKT3 activation promotes metastasis, Science Signaling (2024). DOI: 10.1126/scisignal.ado6057

Journal information:Science Signaling

Provided by UT Southwestern Medical Center

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