Researchers at Tel Aviv University say that common fat cells under the skin help melanoma cells penetrate the body and become lethal metastatic cancer cells that can spread to vital organs.
“We have answered a major question that has preoccupied scientists for years,” said Prof. Carmit Levy of the Department of Human Genetics and Biochemistry at Tel Aviv University’s Sackler Medical School, who led the study.
Melanoma, when present on the epidermis, the skin’s outer layer, is very treatable; it is considered Stage 1, it has not penetrated the dermis to spread through blood vessels to other parts of the body, and it can simply be removed without further damage, she explained.
So, “what makes melanoma change form, turning aggressive and violent?” she asked, “Melanoma turns fatal when it ‘wakes up,’ sending cancer cells to the dermis layer of skin, below the epidermis, and metastasizing in vital organs.”
Blocking the transformation of melanoma is one of the primary targets of cancer research today, she said, “and we now know fat cells are involved in this change.”
The research was conducted with Dr. Tamar Golan, also of the Department of Human Genetics at TAU, and in collaboration with pathologists Dr. Hanan Vaknin of Wolfson Medical Center, Dr. Dov Hershkowitz, and Dr. Valentina Zemer of Tel Aviv Medical Center.
The study was published on Tuesday in Science Signaling and is featured on its cover.
In the study, the researchers examined dozens of biopsy samples taken from melanoma patients at Wolfson Medical Center and Tel Aviv Medical Center, and observed an unexpected phenomenon: the fat cells are generally organized in the shape of a beehive under the skin, but in the area close to the melanoma, these cells were disorganized. This raised their suspicions.
“We asked ourselves what these fat cells were doing there and began to investigate,” Levy said.
The researchers took the fat cells and, in a lab, placed them on a petri dish close to melanoma cells “and followed the interactions between them.”
This revealed that the fat cells transferred proteins called cytokines, which affect gene expression, to the melanoma cells.
The main effect of this transfer of cytokines was the reduction of the expression of a gene called miRNA211, whose role is to curb the number of melanoma receptors, called TGF beta, in the skin.
“Like a seesaw, when the amount of miRNA211 genes go down, the number of TGF beta melanoma receptors goes up,” Levy said in a phone interview.
The tumor, in turn, now manages to recognize the TGF beta melanoma receptors, and this stimulates the melanoma cells “and renders them aggressive,” she said.
“This is a cascade of events,” she said, “triggered by the fat cells.”
The researchers said they may have also found a way to block the transition to aggressive cancer.
“In the lab, we found the process can be reversed,” she said. “When we removed the fat cells from the melanoma, the cancer cells calmed down and stopped migrating.”
An additional study, this time on mouse models, yielded similar results: When miRNA211 was repressed, metastases were found in other organs. When the gene was re-expressed, and brought back to original levels, it managed to block the formation of metastasis.
In the search for a potential drug based on their discovery, the researchers experimented with therapies that are known to inhibit cytokines and TGF beta but have never been used to treat melanoma.
“We are talking about substances that are currently being studied as possible treatments for pancreatic cancer, and are also in clinical trials for prostate, breast, ovarian, and bladder cancers,” Golan said. “We saw that they restrained the metastatic process, and that the melanoma returned to its relatively ‘calm’ and dormant state.”
“Our findings can serve as a basis for the development of new drugs to halt the spread of melanoma – therapies that already exist, but were never used for this purpose,” Levy said. “In the future, we are seeking to collaborate with drug companies to enhance the development of the metastatic melanoma prevention approach.”
In addition, finding the disorganized clusters of fat under the skin could serve as a sort of a biomarker to flag a potentially dangerous melanoma, she said.
What still needs to be studied, she emphasized, is why the cells become lethal in some people but not in others, given that everyone has these fat cells beneath the skin.