Research Area: Cell Biology

Biologists identify key step in lung cancer evolution

Blocking the transition to a more aggressive state could offer a new treatment strategy.

Anne Trafton | MIT News Office
May 10, 2017

Lung adenocarcinoma, an aggressive form of cancer that accounts for about 40 percent of U.S. lung cancer cases, is believed to arise from benign tumors known as adenomas.

MIT biologists have now identified a major switch that occurs as adenomas transition to adenocarcinomas in a mouse model of lung cancer. They’ve also discovered that blocking this switch prevents the tumors from becoming more aggressive. Drugs that interfere with this switch may thus be useful in treating early-stage lung cancers, the researchers say.

“Understanding the molecular pathways that get activated as a tumor transitions from a benign state to a malignant one has important implications for treatment. These findings also suggests methods to prevent or interfere with the onset of advanced disease,” says Tyler Jacks, director of MIT’s Koch Institute for Integrative Cancer Research and the study’s senior author.

The switch occurs when a small percentage of cells in the tumor begin acting like stem cells, allowing them to give rise to unlimited populations of new cancer cells.

“It seems that the stem cells are the engine of tumor 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, a postdoc at the Koch Institute and lead author of the paper, which appears in the May 10 online edition of Nature.

Tumor stem cells

In this study, 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.

One of the Wnt pathway’s major roles is maintaining cells in a stem-cell-like state, so the MIT team suspected that Wnt might be involved in the rapid proliferation that occurs when early-stage tumors become adenocarcinomas.

The researchers explored this question in mice that are genetically programmed to develop lung adenomas that usually progress to adenocarcinoma. In these mice, they found that Wnt signaling is not active in adenomas, but during the transition, about 5 to 10 percent of the tumor 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 tumor cells begin to produce chemical signals that create a “niche,” a local environment that is necessary to maintain cells in a stem-cell-like state.

“If you take a stem cell out of that microenvironment, it rapidly loses its properties of stem-ness,” Tammela says. “You have one cell type that forms the niche, and then you have another cell type that’s receiving the niche cues and behaves like a stem cell.”

While Wnt has been found to drive tumor 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.

“What’s new about this finding is that the pathway is not a driver, but it modifies the characteristics of the cancer cells. It qualitatively changes the way cancer cells behave,” Tammela says.

“It’s a very nice paper that points to the influence of the microenvironment in tumor growth and shows that the microenvironment includes factors secreted by a subset of tumor cells,” says Frederic de Sauvage, vice president for molecular oncology research at Genentech, who was not involved in the study.

Targeting Wnt

When the researchers gave the mice a drug that interferes with Wnt proteins, they found that the tumors stopped growing, and the mice lived 50 percent longer. Furthermore, when these treated tumor cells were implanted into another animal, they failed to generate new tumors.

The researchers also analyzed human lung adenocarcinoma samples and found that 70 percent of the tumors showed Wnt activation and 80 percent had niche cells that stimulate Wnt activity. These findings suggest it could be worthwhile to test Wnt inhibitors in early-stage lung cancer patients, the researchers say.

They are also working on ways to deliver Wnt inhibitors in a more targeted fashion, to avoid some of the side effects caused by the drugs. Another possible way to avoid side effects may be to develop more specific inhibitors that target only the Wnt proteins that are active in lung adenocarcinomas. The Wnt inhibitor that the researchers used in this study, which is now in clinical trials to treat other types of cancer, targets all 19 of the Wnt proteins.

The research was funded by the Janssen Pharmaceuticals-Koch Institute Transcend Program, the Lung Cancer Research Foundation, the Howard Hughes Medical Institute, and the Cancer Center Support grant from the National Cancer Institute.

From MSRP student to MIT professor
Justin Chen
March 13, 2017

The biology department welcomes Eliezer Calo back to MIT

By Justin Chen

 

As the newest faculty member of the MIT biology department, Eliezer Calo is working in Building 68, the same building where he was first inspired to become a scientist. Professor Calo’s relationship with MIT began eleven years ago when he was a chemistry major at the University of Puerto Rico with hazy career aspirations. Encouraged by his instructors to attend a Minority Access to Research Careers (MARC) conference, Calo came across a booth advertising the MIT Summer Research Program (MSRP). Even though Calo initially associated MIT with engineering and math, he applied for and received a summer internship position in Professor Stephen Bell’s lab studying DNA replication. “Experiencing the scope of MIT’s biological research and seeing how collaborative and enthusiastic people were about biology was eye opening,” Calo says. “That was the summer I decided to do a PhD.”

MSRP launched Calo’s scientific career and cemented his love for MIT. After graduating from the University of Puerto Rico, he returned to MIT’s biology department for graduate school and earned a PhD under the mentorship of Professor Jackie Lees. He then moved to Stanford University for postdoctoral training with Professor Joanna Wysocka. He began his faculty position at MIT in January and became an extramural member of the Koch Institute in March.

“We are thrilled to welcome Eliezer back to MIT as a faculty member,” says Biology Department head Alan Grossman. “He and the two other new faculty members, Professors Stefani Spranger and Sebastian Lourido, exemplify the energy and cutting edge research in the department. We eagerly anticipate many years of exciting discoveries from their labs.”

Now leading his own lab, Calo seeks to understand how cells assemble ribosomes and the roles they play in development and in disease. Ribosomes, intricate molecular machines, create building blocks of the body by translating the genome into proteins.  In order to sustain growth, human cells assemble millions of ribosomes. When defects in ribosome assembly occur during embryonic development, cells are unable to grow and divide, leading to developmental disorders.

One such disorder is Treacher Collins syndrome, which arises from a genetic alteration that impairs the expression of a gene named Treacle,whose protein product assists in ribosome assembly.  Surprisingly, although Treacle is expressed in most cells during early embryo development, the mutation affects only the nascent face: individuals have smaller facial bones making up their cheeks and jaws.

“Treacher Collins and other syndromes caused by abnormal ribosome assembly and function challenge our understanding of the ribosome,” Calo explains. “We think of ribosomes as constitutively expressed molecular machines required only for protein synthesis. These diseases, however, suggest that ribosomes might unexpectedly have very specific developmental roles as well.”

Describing how a single genetic mutation warps cell biology and triggers disease is a difficult task. In the case of Treacher Collins Syndrome, the precise mechanism remains unknown but scientists have identified two potential factors.  First, cells destined to become facial bones grow quickly during development and may be especially sensitive to reduced protein production. Second, new research suggests that Treacher Collins may also be caused by defective ribosomes activating cancer suppressor pathways, leading to slower cell division and cell death.

To design a simplified model of Treacher Collins syndrome, Calo has used CRISPR gene editing technology to introduce disease-relevant mutations into human embryonic stem cells in culture. The cells are then grown and differentiated into the specific facial tissues affected by Treacher Collins syndrome. These in vitro cell communities allow Calo to closely observe abnormalities as they arise during development and better understand how decreased protein levels, tumor suppressor pathways, or other factors yet to be discovered contribute to cell death.

To determine whether the results in cultured cells apply to whole organisms, Calo plans to validate his findings in zebrafish. Mutant zebrafish, like humans, have craniofacial defects and allow researchers to screen chemicals that may lessen facial anomalies. By working with human embryonic stem cells in culture and then testing the findings in zebrafish, Calo has created a powerful two-pronged approach to understand Treacher Collins and address fundamental questions of ribosome biology and disease.

As Calo establishes his new laboratory, he is also reprising a familiar role of instructor and mentor. While performing graduate research, he served as a teaching assistant for MIT’s introductory biology course (7.01) and as a program assistant for MSRP. Calo, who still runs into former students in New York, Boston, and Stanford, enjoys learning about their accomplishments and future goals. Now a professor, Calo will inspire the next generation of biologists by advising graduate students and MSRP researchers. “My MSRP experience shaped the course of my scientific career, so I look forward to having MSRP students working in my lab,” Calo says. “I want them to experience what it is like to do research at MIT.”

Posted: 12.5.17