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Diagnostics

Visualizing cross-linking in collagen

Probe targets process that is involved in cancer spread and wound healing

by Celia Henry Arnaud
July 13, 2021

 

Fluorescent images of tumor tissue showing areas of LOX activity and collagen cross-linking.
Credit: Nat. Chem. Biol.
In tumor tissue, a molecular sensor detects collagen crosslinking (blue) via activity of the LOX enzyme at the tumor edge (right) but not in the tumor middle (left). Cell nuclei are stained red and collagen is stained green.

The enzyme lysyl oxidase (LOX) initiates cross-linking in collagen, a structural protein that is the main component of the extracellular matrix in connective tissues, by converting lysyl amines to aldehydes. The cross-linking is part of normal tissue maturation, but the process goes into overdrive in cancer and wound healing. A new probe makes it easier to detect this process selectively and sensitively, which could improve the understanding of collagen remodeling and help clinicians monitor fibrotic diseases.

The probe, developed by Helma Wennemers, postdoc Matthew R. Aronoff, and coworkers at the Swiss Federal Institute of Technology (ETH) Zurich, for detecting collagen cross-linking has three parts: a small molecule LOX sensor, a collagen-mimicking peptide, and a reactive anchoring group (Nat. Chem. Biol. 2021, DOI: 10.1038/s41589-021-00830-6).

The peptide has repeating sequences like those in collagen, so it interacts with collagen in tissues . The reactive anchoring group then anchors the peptide to surrounding collagen by reacting with the aldehydes produced by LOX activity. Lastly, the LOX sensor is a coumarin dye with a masking propylamine group that shifts the dye’s fluorescence wavelength. When LOX is present, the enzyme oxidizes the propylamine on the dye to an aldehyde, shifting the dye’s fluorescence wavelength back. The researchers can selectively monitor the unmasked dye wavelength to measure the extent of LOX activity. All three pieces are needed for specificity. “If we don’t have the targeting peptide, the sensor–reactive group conjugate will diffuse away and go wherever there is an aldehyde,” Wennemers says.

Wennemers and her coworkers used the combination to image LOX activity in tumor tissue. “We stain the boundaries because collagen and thus LOX production is higher there than in the rest of the tissue,” Wennemers says. She envisions that with further development the probe could become a tool for determining tumor boundaries during surgery.

“At the moment, it is not possible to noninvasively detect collagen in vivo with high precision,” says Ruud A. Bank, who studies collagen and wound healing at the University of Groningen. That makes it hard to study processes such as the formation of scar tissue following severe burns. “Treating fibrosis—scarring—in the internal organs is even more difficult to tackle, first of all as we can’t visualize it. This probe will certainly help to visualize fibrotic processes.”

Wennemers has patented the probe but has not yet taken steps to commercialize it.

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