Posted November 16, 2016
Dingcheng Gao, Ph.D., Weill Cornell Medicine, New York, NY
Dingcheng Gao, Ph.D., Weill Cornell Medicine, New York, NY. Courtesy of Weill Cornell Medicine>>
Metastasis has long been a concern of cancer researchers, since the spread of cancer throughout the body generally results in a number of challenges when it comes to treatment. In spite of the intense focus on the role of metastasis in cancer, it has been difficult to identify the exact mechanisms by which cancer cells spread. Dr. Gao has developed a successful animal model which allows scientists to visualize the epithelial to mesenchymal transition, allowing him to determine that epithelial cells are responsible for many metastases (contrary to previous hypotheses), but cells that have undergone EMT confer therapy resistance and make up most metastatic tumors post-chemotherapy.
The issue of metastasis, or the movement of cancer cells from the primary tumor site to more remote locations in the body, is a major concern when considering cancer treatments and prevention. Metastases are indicative of a more advanced cancer stage and are often difficult to treat since localized therapies are no longer as effective and metastases do not always retain the same features as the original tumor. To address this challenge, scientists are focusing on the mechanism by which cells mobilize from the original tumor, as well as differences in the phenotypes of metastatic cells. Until recently, scientists believed that epithelial cells in the original tumor underwent a transition to a more fluid, stem-cell-like state (mesenchymal cells), known as the epithelial-to-mesenchymal transition (EMT), before mobilizing from the original site of cancer and forming metastases. Unfortunately, identifying exactly when cells undergo EMT is difficult, and therefore researchers have not yet been able to confirm or refute this hypothesis.
Dr. Dingcheng Gao of Weill Cornell Medicine has developed an animal model of EMT in which epithelial cells initially express red fluorescent protein (RFP), whereas cells that have undergone EMT permanently switch to expressing green fluorescent protein (GFP). Even though these "EMT cells" may reverse back to epithelial phenotype at later stage of metastasis, they continue to express GFP. Using this model and funding from an LCRP Concept Award, Dr. Gao investigated cells as they metastasized and compared the differences in primary tumor and metastasis composition before and after chemotherapy.
Dr. Gao found that when breast cancer cells from primarily epithelial tumors first metastasized to the lungs, they did not undergo EMT and that metastases consisted primarily of unconverted epithelial cells. In addition, blocking the EMT pathway did not prevent metastasis. This suggests that the above-described hypothesis—that epithelial cells must undergo a transition to break free from the original tumor—is not the case, and that blocking EMT may not be the best approach to preventing the advance of cancer. In fact, when cancer cells (including lung cancer cells) with consistent EMT activation were injected into mice, Dr. Gao found that the resulting tumors were smaller than when control cancer cells were injected. This suggests that consistent activation of the EMT pathway in tumor cells inhibits the growth of lung cancer.
When Dr. Gao's group investigated the makeup of tumors and metastases after chemotherapy, they discovered that cells that had undergone EMT were more resistant to chemotherapy and contributed significantly to cancer proliferation and metastasis after treatment. While chemotherapy was effective in killing epithelial cancer cells, the more transient mesenchymal cells that had undergone EMT were not multiplying as rapidly and were therefore more resistant to the cell death mechanisms triggered by the tested chemotherapy drug. Post-chemotherapy, these EMT cells made up the bulk of metastases.
Dr. Gao's work shows that while EMT does not play the role previously believed in the initiation and progression of cancer metastasis, it is a key player in therapeutic resistance. These new findings demonstrate that therapies that target both EMT cells and original epithelial cancer cells should be developed to more effectively treat cancer patients and prevent recurrence.
Fischer KR, Durrans A, Lee S, Sheng J, Li F, Wong ST, Choi H, El Rayes T, Ryu S, Troeger J, Schwabe RF, Vahdat LT, Altorki NK, Mittal V, Gao D. 2015. Epithelial-to-mesenchymal transition is not required for lung metastasis but contributes to chemoresistance. Nature 527(7579):472-476.