Secondary breast cancer tumours program lung cells to feed them energy-rich fats. Could this dependency be their downfall?
Lung metastasis from a mammary gland tumour. Blue is cell nuclei, green is fatty acid synthase, red is surfactant protein C (a marker for AT2 cells). Yellow is an overlap between green and red, indicating more fatty acid synthase in AT2 cells surrounding a metastatic lesion (the blue mass at the top of the image). Credit: Mariia Yuneva.
Cancer cells grow rapidly, learn to survive in environments that work against them and spread to new areas of the body. To fuel these energy-intensive activities, they learn to hijack the body’s energy production or survive on different nutrients.
Cancer biologist Mariia Yuneva is interested in how cancer cells change their metabolism to boost their growth. She recently joined forces with Sarah-Maria Fendt’s team at the VIB-KU Leuven Center for Cancer Biology to understand how co-opting energy production allows cancer to spread.
“We’re keen to understand how the body allows cancer to spread to another organ – the process called metastasis,” she says. “We’re focusing on breast cancer, which becomes much harder to treat if it spreads to other organs, like the lungs.”
A critical aspect of metastasis is how a specialised environment develops in organs far away from the original tumour site. This environment essentially allows cancer cells to embed and grow in the new location. In a study published today in Cancer Discovery, Mariia and then Crick PhD student, Yulia Panina, along with Sarah’s team, set out to understand which cells in the lung support incoming breast cancer cells, and how.
At the Crick, Yulia and Mariia, with the help of physicists from the National Physical Laboratory, analysed samples with a technique called mass spectrometry imaging. Using this technology, molecules, in this case nutrients, were separated out spatially, allowing the team to visualise each type in specific tissue regions.
“Through comparing the nutrients in metastatic and healthy lung tissue, we found that there were more fat molecules, called lipids, surrounding the metastatic, or secondary, tumours than in the healthy tissue,” says Mariia. “It struck us that fat metabolism may be helping these secondary tumours survive in the new location.”
The team looked at where a key lipid-producing enzyme, fatty acid synthase, was present in metastatic lung tissue. They identified more fatty acid synthase in AT2 cells, lung cell progenitors that produce surfactant, the lubricating fluid in the lungs. Mariia reflects, “At this point, we joined forces with Sarah’s lab as we were both looking for the same thing: why was lipid metabolism boosted in the lung environment when breast cancer cells embedded there?”
Next, Mariia and Yulia monitored mice with metastatic lung tumours, observing that as the tumours grew, the number of nearby AT2 cells increased. The same was observed when tumours that had spread to the lung were transplanted into the mice, suggesting this process likely also occurs in humans. Indeed, Sarah’s group measured lung samples from breast cancer patients, and found they had more AT2 cells, lipids and fatty acid synthase accumulated around metastatic lesions. But how were metastatic tumours initiating this AT2 production line?
“By analysing which genetic instructions were boosted in AT2 cells next to metastatic tumours, we saw that a master gene for lipid metabolism was switched on,” says Mariia. “So, we suspected that signals from cancer cells were boosting AT2 production and activity.” Another experiment confirmed this: treating AT2 cells in a dish with factors secreted from metastatic tumours also expanded the AT2 cell population. Genes for surfactant production were also switched on.
“Cancer cells reprogram AT2 cells into ‘lipid feeders’,” concludes Mariia. “And further work from Sarah’s lab showed that these lipids were not just used for energy, but also as signals to modify proteins inside the cancer cells."
Finally, Yulia removed fatty acid synthase from AT2 cells of mice with secondary lung cancer to see if blocking this lipid factory could treat metastatic breast cancer. Tumour growth was indeed reduced, and, crucially, lung function was not affected. Healthy cells had adapted to the loss of fatty acid synthase, but the cancer hadn’t.
Drugs that inhibit lipid production are currently in clinical trials, and Mariia and Sarah are keen that this work helps to inform future drug development. “Treatments might work best in people with metastatic tumours that recruit large numbers of AT2 cells,” Mariia says. “It’s also possible that blocking lipid metabolism could help to treat primary lung cancer, as AT2 cells have been linked to lung tumours. I think we’re just scratching the surface of lipid metabolism as a way to target what tumours depend on.”
This research was part of the work of Cancer Grand Challenges team Rosetta. Mariia is now a senior principal investigator at Calico, researching how metabolism impacts ageing and cancer.
