Study reveals critical role of the extracellular matrix in neuroblastoma progression

A groundbreaking study led by Children's Hospital Los Angeles has found a novel mechanism behind neuroblastoma progression: the shape and structure of the extracellular matrix.

The study, led by JinSeok Park, PhD, and published in Advanced Materials is the first to show that a fibrous extracellular matrix structure-the network of proteins surrounding and supporting tumors-triggers neuroblastoma cells to become more aggressive and resistant to treatment.

In addition, the team developed an innovative, first-of-its-kind nanoscale model to study this phenomenon.

"Our findings shed new light on the critical role of the extracellular matrix in neuroblastoma," says Dr. Park, an investigator in the Cancer and Blood Disease Institute at CHLA-a world leader in neuroblastoma care and research and the largest pediatric cancer program in the Western U.S. "This opens up a new way to investigate and potentially treat high-risk forms of this childhood cancer."

Why do cells become more aggressive?

The second-most common solid tumor in children (after brain tumors), neuroblastoma arises from immature nerve cells and typically affects children between the ages of 2 and 4. Nearly half of patients are diagnosed with high-risk, metastatic disease, which has a 50% mortality rate.

Neuroblastoma cells have two main types: adrenergic, which resemble nerve cells, and mesenchymal, which behave more like stem cells and tend to spread more easily.

Prior research has found that adrenergic cells can transition into mesenchymal cells, which may be why some patients respond poorly to treatment.

Dr. Park and his team investigated how and why this transition takes place, specifically looking at the physical structure of the extracellular matrix-an understudied aspect of the tumor microenvironment.

Key findings

To do this, the team created a special lab model with tiny, nanoscale grooves that match the size and shape of the actual extracellular matrix. Researchers then coated the surface with collagen III, a protein which forms the highly aligned fibers in the matrix. This novel model allowed the team to more closely study how the matrix works.

The researchers found that:

• High-risk and relapsed neuroblastoma tumors have an extracellular matrix or "scaffolding" with more aligned and structured fibers than low-risk tumors.
• The stiffer, more fibrous scaffolding exerts physical pressure on the tumor cells, triggering them to shift from adrenergic into mesenchymal.
• This shift occurs through two signaling pathways-rho-kinase (ROCK) and yes-associated protein (YAP). The fibrous structure first activates ROCK. ROCK then activates YAP, which turns off adrenergic-related genes and pushes cells to transform into the more aggressive type.

Importantly, when the team blocked the ROCK pathway, it stopped this transition from occurring.

We've shown for the first time that a biophysical factor-the shape and structure of the extracellular matrix-is driving this change and may play a major role in worsening neuroblastoma outcomes."

Dr. JinSeok Park, PhD, investigator, Cancer and Blood Disease Institute at CHLA

Dr. Park's lab is now using its new model to better understand the mechanisms causing these tumors to be resistant to current therapies. The team is also exploring exactly what causes the extracellular matrix to become so fibrous in the first place.

What this means for patients

One promising aspect of the team's discoveries is that drugs that block the ROCK pathway are already FDA-approved for other conditions and have been shown to slow tumor growth. In addition, an FDA-approved drug called verteporfin is known to block YAP function.

"More study is needed, but our findings suggest that inhibiting YAP may be a novel therapeutic strategy that could suppress the transition to more aggressive disease," Dr. Park says. "This is an exciting step toward improving outcomes for children with high-risk neuroblastoma."

This research was supported by funding from Children's Hospital Los Angeles, the CHLA Core Pilot Program, The Margaret Early Medical Research Trust, and the National Cancer Institute.