From the discovery of malignant tumors in a dinosaur fossil to finding metastases in a 2,000-year-old skull from Peru, it is clear that cancer has been around for longer than mankind itself.
A key feature that makes a tumor malignant is its ability to degrade the extracellular matrix (ECM), a dense network of collagen fibers in solid tissues. This is an important factor in metastasis and many therapeutic strategies are designed to stop tumors from spreading via ECM degradation.
“For the past three to four decades, it was assumed that only cell-associated proteases are required for degrading collagen fibers, and efforts were focused on matrix metalloproteinases,” said Frederic Bard, a Senior Principal Investigator at A*STAR’s Institute of Molecular and Cell Biology (IMCB) and corresponding author on a study that reveals a novel pathway involved in ECM degradation.
In addition to matrix metalloproteinases that target peptide bonds, Bard and his international colleagues showed evidence of an oxidoreductase pathway that targeted disulfide bonds. “It is as if cells, in addition to sewing scissors, also require a pen knife to efficiently cut through the fabric of tissues,” Bard said.
This serendipitous discovery occurred when Bard and colleagues were hunting for glycosylation targets of the polypeptide N-acetylgalactosaminyltransferase activation pathway, also known as GALA. This led them to investigate one of GALA’s known targets—a chaperone protein called calnexin (Cnx).
An unusual observation that Cnx could be found in invadosomes piqued their attention. Given that invadosomes are sites where highly crosslinked ECM is degraded, could Cnx have a role to play in ECM degradation?
Bit by bit, they collected evidence proving Cnx’s role in ECM degradation. First, it turned out that there was indeed a link between GALA and Cnx—Cnx glycosylation increased by 6- to 12-fold in human and mouse liver tumors.
They also identified a binding partner for glycosylated Cnx. Using proximity ligation studies, they showed that ERp57, an oxidoreductase, formed a complex with Cnx and translocated to invadosomes. Crucially, they found that the complex was essential for degrading the ECM by reducing disulfide bonds.
Importantly, the potential of Crx as a therapeutic target was revealed in a mouse lung tumor model of metastasis: mice treated twice a week with an anti-Cnx antibody displayed smaller tumors, while metastases were barely detectable. “Perhaps more importantly, our data indicate that matrix degradation is required for tumor growth in general, not only for metastasis,” Bard noted.
Besides a patent pending on their research, the researchers have also launched biotech startup Albatroz Therapeutics to commercialize anti-Cnx treatments for primary and metastatic tumors. They are also exploring the use of glycosylated Cnx as a biomarker for early cancer detection.
The A*STAR-affiliated researchers contributing to this research are from the Institute of Molecular and Cell Biology (IMCB).
