Researchers from ETH Zurich have developed a molecular switch controlled by light. It awakens lung cancer cells from a protective dormant state so that they are more accessible to treatment.
Cancer cells can enter a sleep-like state and thus avoid the destructive effect of cancer drugs. In some types of the disease, such as some forms of lung cancer, this condition is triggered by stress hormones in the body. Within cancer cells, glucocorticoid receptors recognize the hormones, and the cells respond by transitioning to a state in which they undergo almost no division. This makes many treatments ineffective. Scientists are trying to stop these receptors in order to wake cancer cells from sleep, making them vulnerable to attack.
Light limits the effect on the tumor
The problem is that every cell in our body contains glucocorticoid receptors, which perform important functions, including reducing… ignition And for the immune system. Eliminating all of these receptors throughout the body would have disastrous side effects, so a very specific method is needed that destroys only the glucocorticoid receptors in cancer cells.
Researchers from ETH Zurich have now found a solution by developing a system that catalyzes the destruction of these receptors. Light can be used to selectively neutralize the effect of the system in surrounding healthy tissue so that the effect is limited to the tumor. “This system builds on existing medical technology and thus offers a realistic prospect for topical treatments,” says Robin Choplin, co-first author of the publication and a doctoral student in the research group led by Katharina Gabb, MD, professor of medicine at UCLA. Epigenetics and neuroendocrinology.
Labeling ensures rapid elimination of receptors
In their approach, the researchers used the body’s naturally occurring recycling system. This system detects defective proteins and tags them for elimination by attaching a small molecule — a “garbage” tag, so to speak. The tagged proteins are then degraded in this way. Researchers have now modified this process specifically to eliminate glucocorticoid receptors on cancer cells.
To do this, they built a three-part switch: a subunit that binds to the receptor, a flexible connecting piece, and another subunit that binds to the enzyme responsible for attaching the garbage label. The trick lies in the chemical design of the attached piece: under normal lighting conditions, it is stretched so that the enzyme is at the correct distance from the receptor in order to identify it. The cell thus receives the signal to disassemble the receptor and get rid of it. When exposed to light of a certain wavelength, the connected piece becomes twisted. As a result, the enzyme and receptor no longer have the correct relative position to attach litter labels.
Lung cancer cells awakened from sleep in the laboratory
This scientific development has been made possible thanks to the collaboration between different research groups at ETH Zurich. For these experiments, organic synthesis professor Eric Carrera and his team produced multiple connected pieces. When integrated into the switch, two of these pieces exhibited exactly the desired characteristics during testing. Specifically, light can be used to flip the switch between a shape that degrades the receptor and a shape that does not.
The goal is to apply this switch in the treatment of HD in situ. To this end, it is injected into the tumor, and then light is used to specifically turn off all the switches that travel from the tumor to healthy tissue.
The activity can therefore be strictly limited to the core of the tumor, sparing the surrounding tissue and causing much fewer side effects. The effect is reversible and can be precisely controlled.”
Robin Choplin, joint first author of the publication
In laboratory cultures of lung cancer cells, researchers have already succeeded in demonstrating the expected biological effect, as the active substance leads to the rapid breakdown of glucocorticoid receptors in cancer cells. Analysis of gene activity also showed that cells wake up from hibernation as a result. “Of course, this must now be verified in living organisms as well,” says Choplin.
Applications in breast and prostate cancer
Furthermore, researchers still need to improve the system for its applications in cancer treatment. Since light only penetrates a few millimeters into the tissue, the light source should be placed close to the tumor border in order to create a protective optical barrier. In the case of lung cancer, for example, this can be easily achieved using an endoscope. For deeper-seated tumors, research teams want to develop switches that respond to longer wavelengths, such as near-infrared, which penetrate deeper and more gently into tissue.
“We have developed a modular system that we can also use to turn off other receptors,” explains Choplin. For example, receptors of interest for clinical applications include the estrogen receptor in hormone-dependent breast cancer and the androgen receptor in advanced prostate cancer. The system is already ready for use in research in order to elucidate complex signaling pathways in cancer biology.
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Magazine reference:
Friday how much? et al. (2026). Light-controlled disruption of cancer cell quiescence by phototransducible stress hormone receptor degraders. Proceedings of the National Academy of Sciences. doi: 10.1073/pnas.2528760123. https://www.pnas.org/doi/10.1073/pnas.2528760123
