Uncovering how cells reshape their surroundings

A novel chemoselective strategy explores one of biology’s most elusive processes, how cells rebuild the world around them. Developed by Carnegie Mellon University and University of Wisconsin–Madison researchers, the method introduces a new way to tag, enrich, and analyze cells’ newly synthesized extracellular matrix proteins with unprecedented precision. 

The extracellular matrix (ECM) is the intricate web of proteins surrounding nearly every cell in the body. It provides structure, transmits signals, and helps determine how tissues form and function. In both natural and engineered tissues, cells are constantly modifying this matrix by digesting old components and depositing new ones. 

Tracking this activity has been notoriously difficult. Conventional methods struggle to distinguish between the vast number of existing matrix proteins and the much rarer, newly made ones. 

“When you’re engineering tissues, you’re always combining cells and materials,” explained Xi (Charlie) Ren, associate professor of biomedical engineering at Carnegie Mellon. “We know materials influence how cells behave, but we can also ask the reverse: how do cells respond to and modify their materials? That interaction tells us how the cells are feeling and what they’re going to do, whether that’s repair tissue or, in this case, progress tumor growth.”

To demonstrate their approach, the Ren lab built two engineered tumor tissue models using the same lung tumor cells. In one setup, the cells grew freely as three-dimensional tumor spheroids (tumoroids). In the other, they grew atop a scaffold made from decellularized lung extracellular matrix (dECM), a material derived from natural tissue proteins.

The team directly observed how the presence of an external scaffold changed cellular behavior by comparing the two models. Results revealed that tumor cells supported by the dECM scaffold not only degraded more of the surrounding matrix, but also, deposited substantially more new ECM of their own.

“We developed this chemoselective strategy to specifically study how resident cells deposit new matrix proteins onto engineered biomaterials,” said Zihan Ling, first author of the Advanced Materials paper and biomedical engineering Ph.D. student. “With exposure to biomaterials, the tumor cells actually showed much stronger matrix remodeling activity compared to cells cultured alone.”

The findings suggest that tumor cells use their material environment as both a playground and a workshop, reshaping it to their own advantage.

The work also showcases a long-term collaboration with Dr. Brian Frey’s group at the University of Wisconsin–Madison, who co-led the analysis of all proteins in the sample, a technique called proteomics. Their expertise in high-sensitivity mass spectrometry was essential to identifying the newly synthesized proteins enriched by the labeling method.

“This is a powerful collaboration that pairs the Ren group’s impressive method of separating new proteins from existing proteins with my group’s capability to identify and quantify all of those proteins,” noted Brian Frey, senior scientist at University of Wisconsin–Madison.

Although the proof-of-concept focused on cancer, the Ren lab views this as a platform technology. The same chemoselective labeling strategy can be applied to nearly any engineered tissue to study how cells interact with their environment in real time.

These cells don’t just grow; they rebuild the world around them in their favor. This new technology finally lets us see that in action.

Xi (Charlie) Ren, Associate Professor, Biomedical

“What’s fascinating is how actively tumor cells modify their environment to promote their own survival,” added Ren. “These cells don’t just grow; they rebuild the world around them in their favor. This new technology finally lets us see that in action.”

Building on their expertise in lung bioengineering, Ren’s group is applying the method to studies of lung development, regeneration, and aging, as well as ex vivo organ perfusion models in collaboration with University of Chicago and Mayo Clinic.

This research was funded in part by the National Institute of Health and Elsa U. Pardee Foundation. Additional collaborators from University of Wisconsin–Madison on the paper include Burke Niego (co-first author) and Lloyd M. Smith, professor of chemistry.