New approach could treat cancer by rearranging tumor cell structures

Biomedical research typically follows a familiar path: developing treatments that block, enhance or mutate certain signaling pathways, genes or proteins to change the function of different cells in the body.

University of Cincinnati researchers are pioneering a new biomedical technique: rearranging and altering the physical structure and location of subcellular organelles themselves.

UC’s Jiajie Diao, PhD, and colleagues have published new research showing a proof of concept that rearranging the location of lipid droplets within cells can increase the effectiveness of cell starvation, making it a potential cancer treatment. The research was published as the November cover story in the journal Trends in Biotechnology.

Study background

Lipid droplets act as a storage facility for fatty acids within cells and play a role in metabolism and signaling. When cells are deprived of food, lipid droplets move toward and make contact with mitochondria and supply cellular energy by transferring fatty acids.

Diao said lipid droplets can be thought of as emergency gas cans that move toward the car (mitochondria) whenever they run out of gas.

“This was important to look at, particularly for certain cancer cells, because the way the cancer cells or tumors will be targeted for treatment is to try to starve the cell to kill it,” said Diao, associate professor in the Department of Cancer Biology in UC’s College of Medicine. “However, cancer cells also have these lipid droplets, so they will use lipid droplets to supply food and energy. We’re trying to find a way to better cause starvation of tumor cells.”

Study details

Lipid droplets are naturally evenly distributed in cells. The researchers looked for a way to group the lipid droplets together and keep them from moving toward the mitochondria during cell starvation. To accomplish this, they engineered a sequence of proteins that includes one peptide linked to cancer cell lipid droplets and another peptide designed to be activated under blue light stimulation.

“When activated by light, the peptides will eventually bring all the lipid (droplets) together and lock them up,” Diao said. “It’s like a light-active glue, and they form a big chunk inside the cell.”

“We’ve locked all of the gas in the city in one place, far from the car. And the car is out of gas, so it can’t move to get to where the gas is,” Diao said.

Researchers found this approach of locking up lipid droplets away from mitochondria led to more complete cell starvation because the cancer cells had no energy reserves. In practice, this led to a slowing of tumor progression in cell lines and animal models.

Next steps

Diao said it is not practical to use blue light activation in patient settings due to the skin’s barrier. Instead, he is working with experts in UC’s Department of Chemistry to develop a new drug that would similarly lock lipid droplets together either as an oral medication or as an injection directly into tumors.

“The relationship between lipid droplets and mitochondria needs to be fine-tuned, so we are trying to develop processes to either make them link together or be very far apart,” Diao said.

Looking at the bigger picture, Diao said there are many different possibilities for new treatments when taking an approach that alters the physical structures within cells.

“It actually opens a completely new avenue for cancer treatment,” he said. “That’s the unique part of this. It’s the first method to treat cancer through subcellular physical distribution.”

Other study coauthors include Qingjie Bai, Xintian Shao, Qinghua Xia, Shuo Yang, Yanan Gao, Kai Sun, Jian Li, Xiuxiu Wang, Zhiqi Tian, Xiaoyuan Chen, Jing Zhao and Qixin Chen. The authors declare no competing financial interests.