A fatty acid found in palm oil may promote metastasis in mouth and skin cancers, found a study in mice, published in Nature.
“There is something very special about palmitic acid that makes it an extremely potent promoter of metastasis,” said Prof Salvador Aznar-Benitah, of the Institute for Research in Biomedicine (IRB), Barcelona. “I think it is too early to determine which type of diet could be consumed by patients with metastatic cancer that would slow down the metastatic process.”
The study adds to emerging evidence that diet can be used to enhance existing cancer treatments, because certain nutrients are disproportionately relied on by tumour cells, or are required at critical stages such as metastasis.
The study built on previous work by the same team showing that, within a tumour, just a small subset of cells have the capacity to spread by travelling out of the tumour, reaching other organs and colonising them. These specialised cancer cells appeared to rely particularly heavily on fatty acids and the latest work narrowed this down to palmitic acid, which is found in palm oil – but also in a wide variety of foods such as butter and olive oil.
The study found that when palmitic acid was supplemented into the diet of mice, mouth and skin cancers were more likely to spread. Other fatty acids called oleic acid and linoleic acid – omega-9 and omega-6 fats found in foods such as olive oil and flaxseeds – did not show the same effect. Neither of the fatty acids tested increased the risk of developing cancer in the first place.
The research, write The Guardian, suggested that exposure to palmitic acid caused changes to the function of genes in cancer cells that allowed them to sense fatty acids and consume them more efficiently. The presence of palmitic acid also appeared to send cancer cells into a “regenerative state” allowing them to form signalling networks beyond the tumour, which is known to be a crucial step towards spreading.
Metastasis of cancer remains the main cause of death in cancer patients and the vast majority of people with metastatic cancer can only be treated, but not cured.
By understanding what cancer cells need to make this leap, the scientists also identified ways to block the process and are planning a clinical trial of proteins that interfere with the tumour response to palmitic acid.
Helen Rippon, chief executive at Worldwide Cancer Research, said: “This discovery is a huge breakthrough in understanding how diet and cancer are linked and, perhaps more importantly, how we can use this knowledge to start new cures for cancer. Metastasis is estimated to be responsible for 90% of all cancer deaths (around 9m deaths globally). Learning more about what makes cancer spread and, importantly, how to stop it, is the way forward to reduce these numbers.”
Dietary palmitic acid promotes a prometastatic memory via Schwann cells
Gloria Pascual, Diana Domínguez, Marc Elosúa-Bayes, Felipe Beckedorff, Carmelo Laudanna, Claudia Bigas, Delphine Douillet, Carolina Greco, Aikaterini Symeonidi, Inmaculada Hernández, Sara Ruiz Gil, Neus Prats, Coro Bescós, Ramin Shiekhattar, Moran Amit, Holger Heyn, Ali Shilatifard & Salvador Aznar Benitah
Published in Nature Journal on 10 November 2021
Fatty acid uptake and altered metabolism constitute hallmarks of metastasis, yet evidence of the underlying biology, as well as whether all dietary fatty acids are prometastatic, is lacking. Here we show that dietary palmitic acid (PA), but not oleic acid or linoleic acid, promotes metastasis in oral carcinomas and melanoma in mice. Tumours from mice that were fed a short-term palm-oil-rich diet (PA), or tumour cells that were briefly exposed to PA in vitro, remained highly metastatic even after being serially transplanted (without further exposure to high levels of PA). This PA-induced prometastatic memory requires the fatty acid transporter CD36 and is associated with the stable deposition of histone H3 lysine 4 trimethylation by the methyltransferase Set1A (as part of the COMPASS complex (Set1A/COMPASS)).
Bulk, single-cell and positional RNA-sequencing analyses indicate that genes with this prometastatic memory predominantly relate to a neural signature that stimulates intratumoural Schwann cells and innervation, two parameters that are strongly correlated with metastasis but are aetiologically poorly understood. Mechanistically, tumour-associated Schwann cells secrete a specialised proregenerative extracellular matrix, the ablation of which inhibits metastasis initiation.
Both the PA-induced memory of this proneural signature and its long-term boost in metastasis require the transcription factor EGR2 and the glial-cell-stimulating peptide galanin. In summary, we provide evidence that a dietary metabolite induces stable transcriptional and chromatin changes that lead to a long-term stimulation of metastasis, and that this is related to a proregenerative state of tumour-activated Schwann cells.
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