Proteogenomic Characterization of Uterine Cancer

Proteogenomic Characterization of Uterine Cancer


A study published in Cell provides an unprecedented look at the dozens of molecular steps that occur to bring about endometrial cancer, commonly known as uterine cancer. The study offers insights about how physicians might be able to better identify which patients will need aggressive treatment and which won't, and offers clues about why a common treatment is not effective with some patients.

The study, also suggests a potential new role for already-approved drugs that target proteins known as CDK12, SMARCA4 and PML in other types of cancer.

One could say that the work is a detailed molecular snapshot of endometrial cancer. However, the information is so vast, touching upon tens of thousands of molecular actors taking part in thousands of interactions at different times, that the work is more like a frame-by-frame video, documenting steps that play out over years in patients' bodies.

"This is like the Google Earth of endometrial cancer," said one of five corresponding authors of the paper. "It's a very comprehensive portrait of this particular cancer type. We tried to measure everything we possibly could. Then we searched for patterns."

The research builds on work by The Cancer Gene Atlas, or TCGA, which identified some of the genetic underpinnings of the disease in 2013.

But genes are only the start of the story when it comes to cancer. When and where are those genes turned on, turned off, or mutated? What do they produce and how do those products interact?

The team studied 95 uterine tumors and 49 normal uterine tissue samples. Scientists measured the abundance and modifications of a dizzying array of molecular players, including genes, messenger RNAs, circular RNAs, micro RNAs and proteins. The measurements of what scientists call "post-translational modifications," including phosphorylation and acetylation, are key to determining when and where proteins, the molecular workhorses of every cell, are active or inactive.

"This unique, rich resource of high-quality data about all these molecular players from the same set of samples provides cancer researchers with a precious view of protein activity and regulation," said another corresponding author.

Altogether the team took more than 12 million measurements. What did they learn from the painstaking process? Here are the top takeaways.

Scientists developed a promising new way to identify tumors that are not currently classified as aggressive but which turn out to be just as invasive as serous tumors, which grow quickly and are more likely than other tumors to kill patients.

Right now the aggressiveness of an endometrial tumor is determined largely by viewing the cells under a microscope. The team showed that activity levels of certain proteins clearly differentiate more-aggressive from less-aggressive tumors. For example, the team showed how the protein beta-catenin, a well-known actor in many types of cancer, interacts with a signaling pathway known as Wnt to evade detection, accumulate and spur cells to grow out of control.

Unexpectedly, the team also found that a process that involves packing and unpacking genes happens more often than expected in tumor cells. There's more than 7 feet of DNA squeezed into nearly every one of our cells, and it's packed super efficiently, but cells need to unspool the DNA so that other molecular machinery can access it. The team's measures indicate that a key part of the process, known as histone acetylation, is very active in endometrial cancer.

The team created a new way to determine which patients are most likely to benefit from a treatment known as checkpoint therapy, where drugs like pembrolizumab and nivolumab are used to dodge the barriers that some cancer cells use to evade the immune system. It's one of many ways that physicians are exploring the use of immunotherapy to spur the body's natural defenses to fight cancer.

Currently in endometrial cancer, physicians use a measurement known as tumor mutation burden to determine which patients are most likely to benefit. Based on the measurements of immune activity in this study, the scientists have proposed a new measure focused on a patient's antigen presentation machinery, known as the APM. The APM describes how well the body flags cancer cells and presents them to the body's immune system for destruction - a key function for checkpoint inhibitors to be effective.

Better insight into exactly who would benefit from the drugs would allow physicians to avoid their use in patients who are unlikely to benefit, sparing those patients severe and unnecessary side effects.

The team also discovered that small, oft-overlooked molecules known as circular RNAs seem to be involved in the transformation that cells undergo when they gain the ability to spread. The transition is called the endothelial-mesenchymal transition, or EMT; it's what makes endometrial cancer deadly.

https://www.pnnl.gov/news-media/new-detailed-molecular-roadmap-boosts-fight-against-endometrial-cancer

https://www.cell.com/cell/fulltext/S0092-8674(20)30107-0

Edited

Rating

Unrated
Rating: