Pound for pound, fat contains more energy than any other nutrient. So it’s perhaps not surprising that certain cancer cells show a clear preference for growth in fatty tissues.
According to a new study by researchers at the Sloan Kettering Institute (SKI) at Memorial Sloan Kettering (MSK), melanomas prefer to grow near adipose (fat) tissue. The team, led by Richard White, a physician-scientist in the Cancer Biology and Genetics Program at SKI, showed that melanomas actively take in lipids if given the chance, and they tend to migrate toward tissues rich in fat cells.
“This is the seed-and-soil hypothesis,” White says. “Tumor cells like to go to places where there is fertile soil. Based on our results, we think that adipose tissue can be very fertile soil for melanoma.”
That the presence of fat cells could help some cancer cells grow and spread sheds new light on the deepening connection between obesity and cancer and could offer a new avenue for treatment. For certain cancers, cutting off the fat supply could be a means of fighting the disease.
Follow the Fat
White and his colleagues did not set out to implicate fat in cancer: they stumbled upon the connection.
His team uses zebrafish as a model system for studying skin cancer. The small freshwater fish grow melanomas very similar to those in humans. The fish are also transparent, which makes it easy to track cancer cells as tumors progress.
“We did a screen to look for what helped melanoma cells grow in certain locations,” White says. “When we looked at what was different in the melanoma cells growing at metastatic sites, we found a lot of changes in genes that regulate how cells use lipids.”
This finding led to more questions. Were cancer cells making their own fats? Or were they importing them from the nearby adipocytes (fat cells)?
To investigate, postdoctoral fellow Maomao Zhang labeled lipids in adipocytes with a fluorescent marker. She then put the adipocytes and melanoma cells together in a dish and followed where they went. The melanoma cells clearly consumed the lipids.
They did the same thing in fish. When Zhang injected melanoma cells next to adipocytes in the zebrafish, they also accumulated lipids. Moreover, as the melanoma cells metastasized to form tumors elsewhere, more than half migrated to locations near adipocytes.
To further test the hypothesis, the researchers in White’s lab examined tumor samples from people with melanoma who were treated at MSK. As in zebrafish, the human cancer cells also contained deposits of fat.
Rich Soil for Cancer Growth
In studying this connection, researchers found that consuming fat changed the cancer cells’ behavior. Fat-fueled melanoma cells showed an enhanced capability to chew through collagen and cross membranes, allowing them to spread more easily. They also changed their metabolism to burn fat for energy instead of sugar.
The results led the team to wonder if blocking a melanoma’s ability to take up fat would dampen its aggressiveness. To test the premise, they used a drug to block a protein, called the FATP transporter, that enables the cancer cells to take in fat. Cancer cells have much more of this protein than normal cells, so they are more sensitive to the drug. As predicted, reducing the cells’ ability to take up fat slowed their growth and spread.
White says the results could instruct a new treatment regime against melanoma. “Can we identify a subset of patients that are particularly lipid dependent? Those might be the ones who could benefit from an approach geared toward blocking fat uptake into the cells,” he says.
Obesity and Cancer
Researchers have found that obesity is a significant risk factor for cancer and they are still untangling the relationship. While White’s study doesn’t directly address the matter, he says it does show a concrete link between lipids and cancer growth. In that sense, it adds one piece to what is likely a very large puzzle.
Whether altering one’s diet to consume less fats might forestall melanoma progression is another open question, one the team is interested in exploring further.
The study shows the utility of model systems like zebrafish for studying cancer, and the advantage of a place like MSK, where basic scientists and clinicians can easily collaborate. MSK melanoma specialists Jedd Wolchok, Charlotte Ariyan, Travis Hollmann and Paul Chapman collaborated on the project.
“We started this in the zebrafish and were able to take it all the way through to human tissues,” White says. “It would have been tough to pull this off at another institution.”
This work was supported by the National Institutes of Health Director’s New Innovator Award (DP2CA186572), the Mentored Clinical Scientist Research Career Development Award (K08AR055368), the Melanoma Research Alliance, the Pershing Square Sohn Foundation, the Alan and Sandra Gerry Metastasis Research Initiative at Memorial Sloan Kettering, the Harry J. Lloyd Foundation and Consano, the Starr Cancer Consortium, the Memorial Sloan Kettering Translational Research Oncology Training Program fellowship, and National Cancer Institute F32 Postdoctoral Training Grant (CA210536-01A1).