CAMBRIDGE, MA -- Most colon cancer deaths are caused by the spread of tumor cells beyond the colon, usually to the liver. In a new study, MIT biologists identified a cellular pathway necessary for colorectal cancer metastasis.
The pathway they identified, controlled by a protein known as YAP1, is normally involved in tissue repair. When activated in cancer cells, it promotes cell proliferation and migration. The researchers also found that a high-fat diet is more likely to turn on this pathway, through the production of fatty molecules called ceramides.
Drugs that block ceramide production could offer a new way to help prevent metastasis in patients diagnosed with colon cancer, the researchers say.
"We've found a pathway that we think is druggable. If we shut down the enzymes that make ceramides, tumor cells can't switch on this regenerative program, and they largely fail to seed metastases in the liver," says Omer Yilmaz, director of the MIT Stem Cell Initiative, a professor of biology at MIT and a member of MIT's Koch Institute for Integrative Cancer Research. He is also a gastrointestinal pathologist and director of translational research in pathology at Beth Israel Deaconess Medical Center.
Yilmaz, Nilay Sethi, an associate professor of medicine at Harvard Medical School and Dana Farber Cancer Institute, and Alpaslan Tasdogan, head of the Institute for Tumor Metabolism and a professor in the Department of Dermatology at University Hospital Essen and the German Cancer Consortium (DKTK), are the senior authors of the study, which appears today in Science. MIT postdocs Swagata Goswami, Qiming Zhang, and Abdullah Burak Yildiz are the paper's lead authors.
A hijacked pathway
In the United States, colon cancer is usually diagnosed at stage 2 or 3 — before the cancer has spread. However, even after successful surgery, up to a third of these patients will relapse with metastatic disease.
While scientists have identified many genetic mutations that drive the development of colon cancer, it's unknown exactly what prompts them to spread beyond the colon.
"Many studies have looked for a genetic driver of metastasis and come up empty," Yilmaz says. "There isn't a defining mutational signature that separates metastatic cells from the primary tumor, which points to metastasis being driven largely by changes in which genes are switched on and off, rather than by new mutations."
In this study, the researchers sought to identify epigenetic programs that enable colon cancer cells to metastasize. Using tumor organoids from mouse models of several types of colon cancer and from patients with colorectal cancer, they found that metastatic cells shared one key feature: activation of the YAP1 program.
YAP1 is a protein that works with partner factors to switch on genes related to development, stem cell maintenance, and regeneration. In normal tissue, it is active during fetal development, and after injury, to promote healing.
In the gut, that repair response runs through a rare, fetal-like cell type, which normally appears only briefly to rebuild the intestinal lining after damage. YAP1 has been linked to cancer for years, but the new work shows that diet-derived lipids push tumor cells into this specific regenerative state — and that the state itself is what licenses metastasis.
"The regenerative program that we described is generally observed in the gut when there is severe injury or infection and the gut needs to regenerate. We see the tumor cells hijack this program to drive metastatic progression," Goswami says.
Activation of this set of genes helps cancer cells to break free from the original tumor site and spread to other locations in the body. For colon cancer, the most common site of metastasis is the liver, followed by the lungs.
In mouse studies, the researchers also found that cancer cells in animals fed a high-fat diet turned on YAP1 to a greater extent than mice fed a healthy diet. A high-fat diet, the researchers found, triggers activation of enzymes that produce ceramides, a type of lipid. Ceramides then release the molecular brake that normally keeps YAP1 inactive, allowing it to move into the nucleus and switch on its target genes.
Preventing metastasis
The researchers showed that genetically targeting YAP1, or the genes involved in ceramide production, markedly reduced the spread of colon cancer to the liver in mice.
To determine if YAP1 is also involved in metastasis in humans, the researchers analyzed RNA sequencing data from patients with colorectal cancer. They found that YAP1 was more active in metastatic cancer cells, and that patients with higher body mass index (BMI) showed higher expression of the genes activated by YAP1 than normal-weight patients. Patients with higher levels of those genes also had lower survival rates.
"We don't think that the YAP1 program is specific to obesity. It's just that it becomes accentuated in obesity, and that may account for why obesity is known to drive the progression of colorectal cancer," Yilmaz says.
They now plan to develop drugs that inhibit two of the enzymes involved in ceramide production, DEGS1 and DEGS2, in hopes that such drugs could help prevent colon cancer metastasis.
The researchers caution that the findings do not yet translate into dietary advice for patients who have already been diagnosed, and that any drug targeting ceramide synthesis will have to clear a high bar for selectivity, since these lipids are also essential in healthy tissues.
