Under a microscope, normal adipose cells – which make up the body’s fatty tissue – look a bit like densely packed raindrops on a windshield. Each cell is filled with fat and is highly biologically active, regulating both metabolism and immunity.
Liposarcoma, a cancer subtype that affects adipose tissue, perturbs these essential activities. In some cases, cancerous cells form hard sheets that get in the way of normal functions. Worse, they can spread and become metastatic cancer.
In recent research, Dana-Farber’s Erica Pimenta, MD, PhD, working in the lab of Eliezer Van Allen, MD, chief of the Division of Population Sciences, has uncovered molecular mechanisms that cause liposarcomas to become more aggressive. She has identified two dysregulated pathways and is investigating ways to target them with existing medicines. One pathway is the GLP-1 pathway, which is the target of popular weight loss drugs called GLP-1 agonists like semaglutide.
Currently, there are no targeted medicines for liposarcomas. Patients are treated with chemotherapy which might shrink the tumors in about 20 percent of patients.
“We don’t typically see complete tumor shrinkage or even major tumor regression,” says Pimenta, who published the research in Science Translational Medicine. “This really highlights our need to understand the biology so we can nominate new therapies that can improve outcomes for patients with these rare sarcomas.”
Secrets revealed in the nuclei
Pimenta focused her research on two subtypes of liposarcomas that share a common genetic root, an overamplification of an individual gene called MDM2 that causes adipose cells to malfunction.
In one subtype, tumors stay “well differentiated,” meaning they maintain some of their functionality but swell with lipids and create large soft tumors that can reach the size of a football. In the other subtype, they become de-differentiated, meaning they lose their normal shape and functionality entirely and begin to spread.
In 2019, Van Allen’s lab in collaboration with Dana-Farber’s Sarcoma Center team, tried to find a genetic mutation in the tumor DNA responsible for the switch from well differentiated liposarcoma to de-differentiated liposarcoma. They didn’t find one.
In this study, Pimenta knew she needed to look beyond the cell’s DNA. She needed to examine the epigenetics of these cells to determine if the problem was in the way genes are regulated rather than in the genes themselves.
One way to do this is to use single cell multi-omic profiling, technologies that enable scientists to learn which genes a cell can read, whether the cell is producing the factors needed to read them, and if so, at what levels. To use this technology, however, Pimenta needed to carefully separate and analyze each individual cell from a tumor sample.
“It is really hard to break up connective tissues like adipose tissue into whole cells,” she says. “It sticks together too well.”
Recently, however, a technique that enables analysis of each cell’s nucleus emerged. Pimenta was able to break open each tumor cell, remove the nuclei, and perform her analyses.
Homing in on therapeutic targets
Pimenta found two pathways of interest in the genetic programs of liposarcoma cells across many patients. One was the IGF-1 pathway. This pathway was present in well differentiated liposarcomas but completely missing in the de-differentiated form.
In normal cells, IGF-1 switches on the genes needed for a cell to become an adipose cell. Pimenta reasoned that turning IGF-1 back on in dedifferentiated cancer cells might restore their normal functions. It did not work.
“We were back to the drawing board,” she says.
The team did find that restoring a downstream signal, PPARG2, which is unique to adipose cells, did revive the cells’ functions. However, more research needs to be done to understand how this insight might be leveraged clinically.
Meanwhile, the team also found that the IGF-1 receptor is overexpressed in de-differentiated liposarcoma cells. Dana-Farber clinical trials had previously tested a monoclonal antibody that targeted the IGF-1 receptor – but it failed. However, new technology can link an anticancer drug to a monoclonal antibody to form an antibody-drug conjugate (ADC). Pimenta tested an IGF-1-receptor-targeting ADC across six liposarcoma cell lines and saw cells die in five of them.
“This is a strong rationale to try IGF-1 receptor targeted therapies in liposarcoma in early phase clinical trials,” says Pimenta.
An intriguing new cancer target: GLP-1
The other pathway Pimenta identified as important in de-differentiated liposarcomas is GLP-1. This pathway is targeted by weight loss drugs that are GLP-1 agonists, which encourage the creation of small adipose cells that are metabolically stable and not growing.
In de-differentiated liposarcomas, Pimenta found GLP-1 receptors in the cells, although her studies indicated that the GLP-1 pathway was not operating properly. She hypothesized that a GLP-1 agonist might stimulate the receptors and help the cells return to a more normal state. Tests in cell lines showed intriguing data that Pimenta wants to study further.
“There are some really good signs that there might be some promise there,” says Pimenta, who is collaborating with colleagues in the Sarcoma Center to test existing GLP-1 agonists in clinical trials in patients with liposarcomas. “We want to know if this approach works against this cancer in people.”