Blocking “Super-highways” Could Prevent the Spread of Cancer

Researchers reveal a key mechanism that controls tissue structure, which could help identify therapeutic strategies to stop the spread of cancer.

Two new studies, published in Nature Materials and PLOS Computational Biology, describe in detail the mechanism that causes tissues to undergo structural changes. The research indicates that, via the collision of cells, different tissue structures can be formed – this remodeling can in some cases create “super-highways” used by cancer cells to escape to other sites within the body.

The extracellular matrix

The extracellular matrix or “ECM” acts as a scaffold within the body, providing support to tissues, helping them to maintain their structure. The ECM can be organized in many ways depending on the specialized function of the tissue it is supporting, creating distinct ECM patterns.

The ECM is generated by several different cell types; however, fibroblasts play a particularly key role as they produce numerous “major” components of the ECM and can control its deposition and maintenance.

In 1953, Abercrombie, et al. published a study describing the ability of fibroblasts to interact with and influence neighboring cells – a process called “contact inhibition of locomotion”. This process involves repolarization and the changing of direction upon contact, with this behavior dependent upon actomyosin contractility at the point of cell–cell contact.

The extracellular matrix and cancer

The organization of the ECM often becomes dysregulated in disease – including in cancer. Cancer cells can “corrupt” the scaffold arrangement to create an advantageous tissue structure with clear routes that lead away from the primary tumor and into the neighboring tissue. Via these “super-highways”, cancer cells can travel to and invade new areas within the body.

Whilst these “super-highways” and their role in cancer progression is clear, until now, there has been limited understanding about the mechanisms that control the formation of these pathways.

“These super-highways provide roads for cancer cells to travel out of tumors and spread more widely in the tissue, having potentially disastrous consequences for the patient,” says Danielle Park, first author of the Nature Materials study, in a recent press release. “By understanding more about how this type of structure is formed, we can then look at finding ways to stop it and impose a roadblock on the spread of cancer cells.”

Can we “roadblock” cancer?

Wershof, et al. devised a novel computational model to determine exactly how ECM patterns emerge and more specifically how the interplay between fibroblasts, which produce the matrix fibers, and the fibers themselves influences emergent organization.

“Our computer model draws inspiration from how birds and fish, the fibroblasts in our case, move closely together in flocks or schools, despite being in very large groups,” explains first author Esther Wershof, in a recent press release.

“With this model, it’s much easier to study the relationship between cells and the scaffold than if we could only watch it in real-life.”

In parallel, Park, et al. combined numerous approaches, including long-term imaging, computational modeling, transcriptomic analysis, short interfering RNA (siRNA) and informatics-based pharmacological screening to uncover molecular regulators of fibroblast and ECM arrangement. The team found that reorientation of cells relative to each other, following collision, plays a role in creating ECM anisotropy. The researchers named this behavior “cell collision guidance”.

They then discovered a key regulator of this behavior – a transcription factor called TFAP2C. TFAP2C regulates these cellular collisions by controlling the expression of RND3. RND3 localizes to cell–cellcollision zones where it downregulates actomyosin activity. Now, knowing that TFAP2C plays role in these collisions, it may be possible to therapeutically target it.

By inhibiting TFAP2C, you could disrupt ECM remodeling and prevent the creation of these super-highways – forming a “roadblock” and consequently preventing cancer cells from spreading.

In fact, the researchers identified five drugs that altered the formation of super-highways.

“This work is a great example of insights that can be uncovered when experimental and computer biologists collaborate.,” says Paul Bates, senior author of the PLOS Computational Biology paper.

“By working together, using a range of techniques and bringing different expertise to the table, we can reach new understandings about how the body works and how we can better treat disease.”

References

Park, et al. (2019) Extracellular matrix anisotropy is determined by TFAP2C-dependent regulation of cell collisions. Nature Materials. DOI: https://doi.org/10.1038/s41563-019-0504-3

Wershof, et al. (2019) Matrix feedback enables diverse higher-order patterning of the extracellular matrix. PLoS Comput Biol. DOI: https://doi.org/10.1371/journal.pcbi.1007251