Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and deadly known cancers. This disease begins in the cells of specific small ducts in the pancreas. It progresses silently, sometimes with no symptoms, until advanced tumors form and obstruct the ducts. It can also spread to other places. PDAC is difficult to diagnose and doesn’t respond well to existing treatments. Researchers have noted that PDAC cells can survive radiotherapy using mechanisms that are largely unknown.
Dr. Sumitaka Hasegawa and colleagues Motofumi Suzuki and Mayuka Anko, part of the Radiation and Cancer Biology Group of the National Institutes for Quantum and Radiological Science and Technology, Japan, are studying what makes PDAC cells so radiation-resistant. In their latest study, published in the International Journal of Radiation Oncology, Biology, Physics, they’ve uncovered some of the mysteries underlying the relationship between treatment resistance in PDAC, the cell cycle, and a process called autophagy–or “self-digestion.”
Every cell in our body completes countless cell cycles. Each cell cycle is a chemically orchestrated sequence of phases in which many proteins actively control the growth of the cell and ensure it divides safely. When DNA damage is encountered, the cell cycle is stopped at the G2 checkpoint, and cell division is postponed until the problem is fixed.
The G2 checkpoint activates after irradiation which increases resistance to therapy.
Autophagy is the natural mechanism by which a cell digests some of its damaged organelles and proteins to reclaim nutrients and maintain proper internal conditions. It is essential for healthy cells, but researchers have found that autophagy increases in cancer cells right after radiation treatment, and that helps them endure and survive therapy.
Autophagy and the G2 checkpoint share some of the same chemical signals, and it is believed that these two processes are interrelated. “Although a relationship exists, the mechanics were unclear. Thus, in our recent study, we sought to understand more about the link between these processes, especially in PDAC cells,” explains Dr. Hasegawa.
After numerous experiments in PDAC cell cultures, the team of scientists led by Dr. Hasegawa determined that irradiation-induced autophagy is dependent on the G2 checkpoint being activated. Moreover, they showed that autophagy helped the irradiated PDAC cells generate more energy (in the form of a molecule called ATP), which assists their survival. Thus, the team analyzed what happened to irradiated PDAC cells when the G2 checkpoint was chemically inhibited. The irradiated cells could not activate the G2 checkpoint and did not undergo autophagy.
These promising results were then tested in mice where PDAC cells were transplanted to produce tumors. By treating these mice with both radiation and the G2 checkpoint inhibitor, the scientists significantly suppressed tumor growth compared to when irradiation was administered alone. In essence, this means that suppressors of the G2 checkpoint, which also mitigate autophagy, could be effectively used as tools to lower the radiation resistance of PDAC cells. “Our research,” concluded Dr. Hasegawa, “should facilitate the development of new radiotherapeutic strategies for PDAC. In turn, this could largely improve the survival rate of patients with this type of cancer.”
Further studies will be needed to understand better the connection between the G2 checkpoint and autophagy and how these processes make cancer cells more resistant. Let us hope scientists eventually find ways to effectively combat challenging cancer types, such as PDAC, and add more years of life to affected people.
Research Article: Radiation-induced autophagy in human pancreatic cancer cells is critically dependent on G2 checkpoint activation: a mechanism of radioresistance in pancreatic cancer, International Journal of Radiation Oncology, Biology, Physics, Motofumi Suzuki, Mayuka Anko, Maki Ohara, Ken-Ichiro Matsumoto, and Sumitaka Hasegawa, DOI: https://doi.org/10.1016/j.ijrobp.2021.04.001
Sumitaka Hasegawa is a physician-scientist and a group leader of the Radiation and Cancer Biology Group at the National Institutes for Quantum and Radiological Science and Technology, Japan. He graduated from Nagasaki University Graduate School of Biomedical Sciences after graduating from the medical school of Nagasaki University. He has published many publications in cancer research, radiation oncology, and nuclear medicine, including prestigious journals such as Nature, Science, Journal of the American Chemical Society, and the Proceedings of the National Academy of Sciences of the United States America.
The National Institutes for Quantum and Radiological Science and Technology (QST) was established in April 2016 to promote quantum science and technology comprehensively and integrated. QST’s mission is to raise the level of quantum and radiological sciences and technologies through its commitment to research and development into quantum science and technology, the effect of radiation on humans, radiation emergency medicine, and the medical use of radiation. To ensure that research and development deliver significant academic, social, and economic impacts and maximizes the benefits from global innovation, QST strives to establish world-leading research and development platforms and explore new fields. Website: https://www.qst.go.jp/site/qst-english/