Ovarian Cancer Cells Use Fructose to Promote Metastasis 

More than a decade ago, Katherine Aird, at the time a staff scientist at The Wistar Institute, attended a seminar that blew her mind. The talk was about how metabolites could act as signaling molecules that influence an organism’s functions. After the talk, Aird, who had been studying cancer, knew that researching metabolism in the context of cancer was the path she wanted to pursue in her own laboratory. When Aird started her own group in 2016, she focused on non-dividing but metabolically active cells, called senescent cells, and the factors that they secrete, or the senescence-associated secretory phenotype (SASP), that can remodel the microenvironment.^1,2

In a recent study, Aird, today a cancer biologist at The Wistar Institute, and her team described how senescent, chemotherapy-resistant cancer cells secrete fructose to reprogram other cancer cells that leads to tumor metastasis in a mouse model.³ The findings, published in Nature Aging, demonstrate for the first time that cancer cells use a metabolite to fuel their dissemination and hint at potential new avenues for the development of cancer treatments.

“It's one of the first papers that shows that these metabolites, in this case fructose, have a role in the bioactivities of the SASP,” said Gregory David, a cell and molecular biologist at New York University Langone who was not involved in the study. “It really opens [a] whole field of what we are doing when we study the SASP, and [it] really proves to us that we have to expand our studies.”

Cancer treatments, including chemotherapy, induce senescence in cancerous cells, and for years researchers considered this phenotype beneficial, explained Aird. “But it turns out that because [senescent cancer cells] are so active and release all these factors into the tumor area, they are likely bad,” she added. “It's this unique paradox in biology where the lack of growth and proliferation in a cancer is actually a bad thing.”

According to Aird, SASP research has focused on proteins such as inflammatory cytokines and chemokines for years, leaving other components unexplored. This lack of knowledge motivated Aird and her team to investigate them and uncover their potential roles in cancer.

To accomplish this, the team exposed ovarian cancer cells to cisplatin—a standard drug given to patients with an aggressive form of ovarian cancer—and collected the media in which the cells grew. They then injected the media into mice that previously received a tumor implantation and examined the animals’ peritoneal cavities to assess tumor dissemination. Exposure to SASP-rich media caused cancer cells to spread more in the animals’ bodies than exposure to non-senescent media, suggesting that secreted factors from malignant cells fuel tumor metastasis.

Using a CRISPR screen, the team next pinpointed the genes that drive ovarian cancer dissemination. They found that downregulation of genes involved in the production of cholesterol, a key component of the plasma membrane, caused cells to detach from one another by reducing their membrane adhesion properties. “It certainly was quite interesting from a point of view of thinking about how one metabolite from another cell can get into this cell and do all these things to make cholesterol different,” Aird said.

To identify the SASP signal driving the cholesterol-mediated cancer spread, the researchers performed a mass spectrometry analysis and found that the cisplatin-induced senescent cell media had high fructose levels. Injecting mice with physiological doses of fructose promoted tumor spread, a phenotype that was prevented when the team knocked down key enzymes involved in fructose metabolism. “We’ve been focused on proteins being responsible for [cancer dissemination] that the fact that proteins don't seem to be, at least in this context, the main driver of the SASP activity was really a shocking discovery for me,” David added.

Moving forward, Aird plans to test ways to inhibit fructose production to see if this limits tumor spread—a next step that David agreed is key to better understand how this metabolite leads to these effects. Since the composition of SASP changes over time, David noted that investigating the kinetics of fructose synthesis and its potential interactions with other SASP components would also be an interesting direction for future work.

Even though the experiments provided compelling evidence of the effects of fructose on ovarian cancer metastasis in preclinical models, both Aird and David noted that it is still unclear whether fructose would have the same effect on humans. Still, David emphasized that the findings revealed an undescribed role of metabolites in cancer metastasis, expanding what researchers understand about the secretome of chemotherapy-induced senescent cells and potentially paving the way for new treatment options. “It’s a great paper. It will change the way we think about the SASP, which is a good thing,” he added.