Key step in lung cancer evolution identified

Blocking a major switch that occurs as lung adenomas transition to more aggressive adenocarcinomas prevents this potentially lethal transition. Drugs that interfere with this switch could be useful in treating early-stage lung cancers.

MIT biologists, amongst them postdoc Tuomas Tammela, a University of Helsinki alumnus, have now identified a major switch that occurs as benign tumours, called adenomas, transition to adenocarcinomas in a mouse model of lung cancer. They’ve also discovered that blocking this switch prevents the tumours from becoming more aggressive.

The switch occurs when a small percentage of cells in the tumour begin acting like stem cells, allowing them to give rise to unlimited numbers of new cancer cells. “It seems that the stem-like cancer cells are the engine of tumour growth. They’re endowed with very robust proliferative potential, and they give rise to other cancer cells and also to more stem-like cells,” says Tuomas Tammela.

The researchers focused on the role of a cell signaling pathway known as Wnt. This pathway is usually turned on only during embryonic development, but it is also active in small populations of adult stem cells that can regenerate specific tissues such as the lining of the intestine.

In mice that are genetically programmed to develop lung adenomas that usually progress to adenocarcinoma, they found that Wnt signaling is not active in adenomas, but during the transition, about 5 to 10 percent of the tumour cells turn on the Wnt pathway. These cells then act as an endless pool of new cancer cells.

In addition, about 30 to 40 percent of the tumour cells begin to produce the Wnt signals that create a “niche,” a local environment that is necessary to maintain cells in a stem-cell-like state.

"It is remarkable how elegantly tumours utilize cellular cooperation and renewal capacity found in healthy tissues, and produce a tumour that is both fast growing and long-lasting" says Pekka Katajisto, a group leader at the Institute of biotechnology and Helsinki Institute of Life Science HiLIFE at the University of Helsinki, and one of the authors of the now published work. "In the ongoing collaborative work, we are now addressing the potential of such mechanisms in cancer treatment, but also whether they can be used to promote healthy recovery from tissue damage."

While Wnt has been found to drive tumour formation in some other cancers, including colon cancer, this study points to a new kind of role for it in lung cancer and possibly other cancers such as pancreatic cancer. The findings suggest that drugs that interfere with this switch could be useful in treating early-stage lung cancers.

Tuomas Tammela, Francisco J. Sanchez-Rivera, Naniye Malli Cetinbas, Katherine Wu, Nikhil S. Joshi, Katja Helenius, Yoona Park, Roxana Azimi, Natanya R. Kerper, R. Alexander Wesselhoeft, Xin Gu, Leah Schmidt, Milton Cornwall-Brady, Ömer H. Yilmaz, Wen Xue, Pekka Katajisto, Arjun Bhutkar & Tyler Jacks. A Wnt-producing niche drives proliferative potential and progression in lung adenocarcinoma. Nature (2017). doi:10.1038/nature22334