Researchers Learning More About Extracellular Matrix, Its Effects on Cancer

University of Illinois Cancer Center members Alexandra Naba and Yu (Tom) Gao have been awarded two new multi-year federal grants to learn more about how alterations in the extracellular matrix (ECM) lead to cancer progression and how ECM proteins can be used to better predict cancer outcomes.

The extracellular matrix is a complex assembly of hundreds of proteins that form the scaffold that organizes cells and tissues, as well as control organ functions. It has been known for some time that cancers contain more ECM than healthy tissue, yet the ECM has remained largely understudied, mainly due to challenges posed by the intrinsic chemical properties of ECM proteins, said Naba, PhD, assistant professor of physiology at the UIC College of Medicine and a member of the Cancer Biology program.

During her postdoctoral training at the Massachusetts Institute of Technology (MIT), Naba pioneered the use of proteomics to profile the composition of the ECM of cancers, founding the field of “matrisomics.” With the assistance of Gao’s laboratory, Naba’s team is developing novel cutting-edge approaches to profile the composition of the ECM of tissues and tumors with a depth never before attained.

Naba and Gao’s latest research, funded by the National Cancer Institute (R21CA261642-01A1), proposes to further develop ECM proteomics methods by using computational modeling.

“Standard proteomic protocols rely on protein denaturation prior to protein digestion,” said Gao, PhD, assistant professor of pharmaceutical sciences at the UIC College of Pharmacy and member of the Cancer Center’s Translational Oncology program. “But we know that ECM functions are directed by its construction. With support from the NCI we will develop advanced methods to gain structural information on individual ECM proteins and on the ECM meshwork as a whole.”

Naba and Gao also received a second grant, funded by the Office of the Director of the National Institutes of Health (U01HB012680-01), where they will utilize resources generated by the Human Biomolecular Atlas Program (HuBMAP) consortium to build spatially-resolved maps of the ECM of each tissue of the human body. This, Naba said, is a first step toward understanding ECM functions in health and disease.

“The secretion and post-translational modifications that accumulate in the ECM over time are critical for proper ECM functions and cannot be fully studied solely by RNA-level observations,” Naba said. “Thus, protein-level evidence is key to understanding the function and dynamics of the ECM.”  

“We also do not fully understand which cell types produce which ECM proteins, nor do we know how the composition of the ECM changes over time and during diseases,” Gao said. “These gaps in knowledge are mainly due to the lack of adequate methods to study the ECM.”

Naba and Gao are also planning to develop tools for non-specialists to accelerate EMC research. One such tool is a database – called MatrisomeDB – that compiles ECM proteomic datasets generated by labs throughout the world. With newly received grants, the two researchers and their laboratories will enhance the contents and functionalities of this database to include new tools to visualize sequence coverage on 3D models of ECM proteins predicted by AlphaFold, a highly accurate artificial intelligence program.

Naba and Gao’s early studies were supported through a Cancer Center pilot program. Their latest project, “Thinking outside the cell: Leveraging HuBMAP date to build the human ECM atlas,” is funded for four years at $1.86 million. The second project, “Enhanced mass-spectrometry-based approaches for in-depth profiling of the cancer extracellular matrix,” will be funded by the NCI for three years at nearly $600,000.

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