New light-activated method precisely targets cancer and inflammation cells


A new method of using light to precisely target problem cells to death could open the door to new understanding and treatments for cancer and inflammatory diseases, report researchers at the University of Illinois, Urbana-Champaign.

Inflammation-induced cell death, known as necroptosis, is an important regulatory tool in the body's arsenal against disease. However, in some diseases, this process can go awry; for example, cancer cells are able to suppress inflammatory signals and thus escape death.

Usually pharmacological induction is used to kill cells in cancer treatment, but those chemicals diffuse into the tissues and it's difficult to confine them to a precise location. You get a lot of unwanted effects. We can make cells sensitive to light, and we can make the light beam smaller than a single cell. That way we can use light to very precisely target a cell and turn on its death pathway.”


Kai Zhang, study leader, professor of biochemistry at the University of Illinois

The researchers used a method called optogenetics to make cells respond to light. They borrowed a light-activated gene from plants and inserted it into intestinal cell cultures, linking it to the gene for RIPK3, a protein that regulates necroptosis.

“When activated, RIPK3 undergoes oligomerization — it forms clusters of protein complexes. Our light-sensitive proteins cluster together when exposed to blue light. So by inducing the light-sensitive proteins to come together, RIPK3 comes together and oligomerizes, and that's how we mimic the activation pathway,” said graduate student Teok-Jung Oh, first author of the paper published in . Journal of Molecular Biology 1 (3): 335–345.

Killing the cell is not the only goal, however. Inducing inflammatory cell death pathways, rather than killing the cell mechanically or chemically, prompts the immune system to respond. The ruptured cells release chemicals called cytokines that irritate nearby cells and attract T cells, white blood cells that play a key role in how the immune system identifies and attacks threats, Zhang said.

“Some cancer cell types create a local immune suppressive environment, where T cells either don't get recruited or, if they do, they don't recognize it as a threat and don't infiltrate the cancerous area,” said Zhang, a member of the Illinois Cancer Center. “But by unleashing certain cancer cells through necroptosis, we hope to help control this immune suppressive environment and train T cells to recognize and attack cancer.”

Since optogenetic systems require delivering light directly to tissues, human clinical applications in tissues deeper than the skin are currently limited. However, the Illinois group plans to apply their system in mice to further study necroptosis and immune responses in cancer and other inflammatory diseases. They will also further investigate the potential of the in vitro platform to train T cells for immune therapies.

“Understanding the cell signaling pathways for necroptosis is particularly important because it is thought to be associated with diseases such as neurodegenerative disease and inflammatory bowel disease. It's important to know how necroptosis affects progression in these diseases. And if you don't know the molecular mechanisms, you won't really know what to target to slow down progression,” Oh said.

The National Institute of General Medical Sciences and the National Institute of Mental Health of the National Institutes of Health, the National Science Foundation, and the Illinois Cancer Center supported this work. Zhang is also affiliated with the Beckman Institute for Advanced Science and Technology at Illinois.

Source:

University of Illinois at Urbana-Champaign

Journal Reference:

Oh, T.-J., and others(2024). Spatial control of inflammatory lytic cell death through optogenetic induction of RIPK3 oligomerization. Journal of Molecular Biology.doi.org/10.1016/j.jmb.2024.168628.

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