MIT Research News' Journal

Gene-controlling mechanisms play key role in cancer progression

As cancer cells evolve, many of their genes become overactive while others are turned down. These genetic changes can help tumors grow out of control and become more aggressive, adapt to changing conditions, and eventually lead the tumor to metastasize and spread elsewhere in the body.

MIT and Harvard University researchers have now mapped out an additional layer of control that guides this evolution — an array of structural changes to “chromatin,” the mix of proteins, DNA, and RNA that makes up cells’ chromosomes. In a study of mouse lung tumors, the researchers identified 11 chromatin states, also called epigenomic states, that cancer cells can pass through as they become more aggressive.

“This work provides one of the first examples of using single-cell epigenomic data to comprehensively characterize genes that regulate tumor evolution in cancer,” says Lindsay LaFave, an MIT postdoc and the lead author of the study.

In addition, the researchers showed that a key molecule they found in the more aggressive tumor cell states is also linked to more advanced forms of lung cancer in humans, and could be used as a biomarker to predict patient outcomes.

Tyler Jacks, director of MIT’s Koch Institute for Integrative Cancer Research, and Jason Buenrostro, an assistant professor of stem cell and regenerative biology at Harvard University, are the senior authors of the study, which appears today in Cancer Cell.

Epigenomic control

While a cell’s genome contains all of its genetic material, the epigenome plays a critical role in determining which of these genes will be expressed. Every cell’s genome has epigenomic modifications — proteins and chemical compounds that attach to DNA but do not alter its sequence. These modifications, which vary by cell type, influence the accessibility of genes and help to make a lung cell different from a neuron, for example.

Epigenomic changes are also believed to influence cancer progression. In this study, the MIT/Harvard team set out to analyze the epigenomic changes that occur as lung tumors develop in mice. They studied a mouse model of lung adenocarcinoma, which results from two specific genetic mutations and closely recapitulates the development of human lung tumors.

Using a new technology for single-cell epigenome analysis that Buenrostro had previously developed, the researchers analyzed the epigenomic changes that occur as tumor cells evolve from early stages to later, more aggressive stages. They also examined tumor cells that had metastasized beyond the lungs.

This analysis revealed 11 different chromatin states, based on the locations of epigenomic alterations and density of the chromatin. Within a single tumor, there could be cells from all 11 of the states, suggesting that cancer cells can follow different evolutionary pathways.

For each state, the researchers also identified corresponding changes in where gene regulators called transcription factors bind to chromosomes. When transcription factors bind to the promoter region of a gene, they initiate the copying of that gene into messenger RNA, essentially controlling which genes are active. Chromatin modifications can make gene promoters more or less accessible to transcription factors.

“If the chromatin is open, a transcription factor can bind and activate a specific gene program,” LaFave says. “We were trying to understand those transcription factor networks and then what their downstream targets were.”

As the structure of tumor cells’ chromatin changed, transcription factors tended to target genes that would help the cells to lose their original identity as lung cells and become less differentiated. Eventually many of the cells also gained the ability to leave their original locations and seed new tumors.

Much of this process was controlled by a transcription factor called RUNX2. In more aggressive cancer cells, RUNX2 promotes the transcription of genes for proteins that are secreted by cells. These proteins help remodel the environment surrounding the tumor to make it easier for cancer cells to escape.

The researchers also found that these aggressive, premetastatic tumor cells were very similar to tumor cells that had already metastasized.

“That suggests that when these cells were in the primary tumor, they actually changed their chromatin state to look like a metastatic cell before they migrated out into the environment,” LaFave says. “We believe they undergo an epigenetic change in the primary tumor that allows them to become migratory and then seed in a distal location like the lymph nodes or the liver.”

A new biomarker

The researchers also compared the chromatin states they identified in mouse tumor cells to chromatin states seen in human lung tumors. They found that RUNX2 was also elevated in more aggressive human tumors, suggesting that it could serve as a biomarker for predicting patient outcomes.

“The RUNX positive state was very highly predictive of poor survival in human lung cancer patients,” LaFave says. “We’ve also shown the inverse, where we have signatures of early states, and they predict better prognosis for patients. This suggests that you can use these single-cell gene regulatory networks as predictive modules in patients.”

RUNX could also be a potential drug target, although it traditionally has been difficult to design drugs that target transcription factors because they usually lack well-defined structures that could act as drug docking sites. The researchers are also seeking other potential targets among the epigenomic changes that they identified in more aggressive tumor cell states. These targets could include proteins known as chromatin regulators, which are responsible for controlling the chemical modifications of chromatin.

“Chromatin regulators are more easily targeted because they tend to be enzymes,” LaFave says. “We’re using this framework to try to understand what are the important targets that are driving these state transitions, and then which ones are therapeutically targetable.”

The research was funded by a Damon Runyon Cancer Foundation postdoctoral fellowship, the Paul G. Allen Frontiers Group, the National Institutes of Health, and the Koch Institute Support (core) Grant from the National Cancer Institute.

Finch Therapeutics unleashes the power of the gut

As scients continue searching for treatments to some of the most complex diseases and conditions, they’re increasingly looking to our gut.

The human gut microbiome contains trillions of bacteria that play important roles for the proper functioning of our bodies. But those bacterial colonies went relatively unexplored until recently, when new computational tools made it possible to understand their makeup in more detail.

Finch Therapeutics is one of a number of companies trying to turn that new perspective into new treatments. The company is leveraging its deep connections and expertise in the field to reach a number of milestones in microbiome therapeutics — and it’s outpacing older, better-funded competitors in the process.

The company recently became the first to show a microbiome therapy could reach its primary goals in a Food and Drug Administration trial for patients with Clostridioides difficile infection (C. diff).

Now, as the research community continues to discover connections between gut health and metabolic, immune, and cognitive functions, Finch is developing a broad group of drugs aimed at conditions including chronic hepatitis B, Crohn’s disease, ulcerative colitis, and autism spectrum disorder.

“The biology [around gut bacteria’s influence on health] is fairly complex, and we’re still in the early days of unravelling it, but there have been a number of clinical studies that have reported benefits to restoring gut health, and that’s our north star: the clinical data,” Finch co-founder and Chief Executive Officer Mark Smith PhD ’14 says.

A path unplanned

Smith always thought he’d spend his career doing academic research. Then, while pursuing his PhD in microbiology at MIT, a family member contracted C. diff, a potentially life-threatening infection that can cause diarrhea, fever, and abdominal pain. Smith saw his relative gradually grow discouraged with conventional treatment options as he went through seven unsuccessful rounds of antibiotics over the course of one painful year.

Around that time, a clinical trial showed the promise of using stool transplants to restore gut bacteria in people struggling with C. diff, improving their symptoms. Still, there were very few places collecting stool samples or conducting the procedure at the time. Increasingly desperate, Smith’s relative ended up conducting the stool transplant himself with the help of a friend and an at-home enema kit. The procedure was successful, but risky, and is not rcommended by doctors.

Smith knew his relative was not alone — about a half million people contract C. diff each year — so he set out to expand access to medically certified stool transplants. The effort led to OpenBiome, a nonprofit stool bank that collects and screens stool samples, then ships the formulations to hospitals to conduct transplants. Along the way, Smith partnered with OpenBiome cofounders Andrew Noh and James Burgess, who were attending the MIT Sloan School of Management; Zain Kassam, a postdoc who had worked with Smith in the lab of MIT Professor Eric Alm; and Carolyn Edelstein, now the executive director of OpenBiome, who is also Smith’s wife.

Today OpenBiome works with around 1,300 health care providers across the country and has helped treat about 55,000 patients struggling with C. diff, making it the largest stool bank in the world. OpenBiome also facilitates research into the microbiome, uncovering surprising links between the bacteria in our guts and a range of complex conditions like depression, multiple sclerosis, diabetes, and autism.

The research was enough to convince Smith he needed a new way to help the microbiome field reach its full potential. He founded Finch Therapeutics in 2014 with many of his colleagues from MIT and OpenBiome, including Noh, Kassam, and Burgess.

Since then, the company has focused on developing drugs that mimic as closely as possible the bacterial makeup of the stool transplants used in some of the field’s most promising studies.

Finch’s drugs are made by collecting a stool sample from a vetted donor, screening that sample, processing it to extract the microbial strains, freeze drying the strains, then, following some additional testing, putting it into a pill capsule.

By closely following the methodologies of intervention studies, Finch hopes to safeguard against any major setbacks in clinical trials and become the first company to earn FDA approval for a microbiome-based treatment.

Last month, Finch achieved a major milestone in that direction when it announced preliminary phase 2 results for its oral C. diff drug. The company says it was the largest placebo-controlled trial for an oral microbiome drug to date, and the first to meet its primary efficacy targets in a pivotal trial.

“The first chapter in this field, and our history, has been validating this modality,” Smith says. “Until now, it’s been about the promise of the microbiome. Now I feel like we’ve delivered on the first promise. The next step is figuring out how big this gets.”

Realizing the potential of a promising field

Companies hoping to create treatments from our nascent understanding of the microbiome must navigate some uncertainty around the biological mechanisms that are behind the links between our guts and a range of diseases. Still, those connections are being reinforced in new studies all the time.

“There’s a wide range of indications that are potentially related to microbiome,” Smith says. “We’re just starting to figure out what some of those are. The ones where there’s more research, we understand [the underlying biological] mechanism, and there’s likely going to be this broadening ring of indications we discover as the field continues to mature.”

Finch is planning another, larger study to confirm its C. diff results before submitting the drug for FDA approval. In addition, by the middle of next year, the company will have data on the effects of another oral microbiome drug for children with autism and gastrointestinal issues. Next year it will also complete a trial using the same C. diff drug to help patients with chronic hepatitis B.

“Our view is there are 42 billion doses of antibiotics administered every year, and we think they’ve driven really profound changes to this microbial organ system. We’d be surprised if restoring that functionality doesn’t turn out to be important for a lot of different indications,” Smith says.

Smith notes there are 300 ongoing clinical trials exploring connections between the microbiome and diseases like Alzheimer’s, Crohn’s disease, and multiple forms of cancer.

“The next chapter for us at Finch and the broader field is figuring out what the breadth of this modality can be,” Smith says. “In the next couple of years, we should have visibility into whether this works in autism, chronic hepatitis B, ulceritive colitis, and Crohn’s disease. If we get a positive readout in any one of those, those are very large patient populations with significant unmet needs. So if it works in any one, it would really spur the field into the third chapter. The next step is testing this in an even wider range of indications.”