Decoding Cancer Cell Pathway to Unlock Effective Therapies

What if, like disabling a bomb by cutting the relevant wire, we could prevent cancer cells from spreading by ‘terminating’ the appropriate switch in their machinery? A team of researchers from the Mechanobiology Institute and the Department of Biological Sciences at the National University of Singapore, along with local and international collaborators, believe they have found that critical component—a scaffold protein known as BPGAP1—and how it functions. Their findings were published in the journal Molecular Biology of the Cell as part of 'Forces on and Within Cells’ (1^✔ ✔Trusted Source
The scaffold RhoGAP protein ARHGAP8/BPGAP1 synchronizes Rac and Rho signaling to facilitate cell migration

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The research was led by Dr. Darren Wong and guided by Assoc. Prof. Low Boon Chuan revealed how BPGAP1 synchronizes two critical proteins involved in cell migration, GTPases Rac1 and RhoA, which Dr. Wong described as "the two hands that work hand-in-hand to move the cell."

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The Migratory Ability of Metastatic Cells

The cell's migratory ability is what allows metastasis, which is when cancer cells leave their initial place, move via our bloodstreams, and invade distant organs; it is also what makes cancer so lethal.

Because metastasis is a sophisticated and multi-step process, effective therapy choices for advanced stages are limited and focus on symptom management rather than root cause elimination.

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Unraveling the BPGAP1 Molecule

Unraveling the underlying molecular activity of BPGAP1 may be the key to understanding cancer cell traversal and paving the path for more targeted cancer treatments.

A cell's mobility is accelerated by changes in its cytoskeletal architecture, which are mediated by a group of proteins known as GTPases. GTPase is a molecular switch that activates (or deactivates) particular pathways to perform cellular activities.

Rac1 and RhoA GTPases collaborate to remodel the cytoskeleton by mediating different pathways—Rac1 allows the cell to sense, grip onto its surroundings, and crawl by forming sheet-like membrane protrusions (known as lamellipodia), whereas RhoA generates adhesion sites and contractile force to propel the cell forward.

These two processes often oppose each other and do not occur at the same time or place, yet they are required for successful cell migration. As a result, it is necessary to orchestrate the proteins so that their actions are in sync.

They discovered that BPGAP1 attaches to an inactive Rac1 and that the two of them move to the lamellipodia. BPGAP1 must recruit another protein known as Vav1 to activate Rac1 while the cell is physically stimulated by epidermal growth factors.

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Cell Migration Behavior Observed

When all of these elements are present, the team observed improved cell migration behaviors, such as the cell flattening out and spreading growing longer protrusions, increasing motility, and having a better ability to extrude itself from blood vessels.

While scientists are aware of Rac1 and RhoA's roles in cell migration, Dr. Wong and his colleagues discovered that another protein, BPGAP1, not only interacts with both of them but is also highly expressed in cancer cells and promotes cell migration extensively.

They later discovered that BPGAP1 serves as a scaffold and coordinator between the two GTPases, acting as a critical regulator of their activity.

They worked with clinical scientists both locally and internationally to validate this. They discovered and pieced together the working mechanism of BPGAP1 by employing diverse models, assays, and biomaterials, particularly on metastatic breast cancer cells.

But where does RhoA come into all of this? In contrast to Rac1, BPGAP1 inhibits RhoA by binding to one of its domains. Thus, by "switching off" RhoA and "switching on" Rac1, BPGAP1 controls the actions of the two GTPases. The cell's mobility is ultimately reinforced by these repeated cycles of on/off switches.

It is also critical in terms of timing since it acts as a pacemaker to coordinate Rac1 activation with RhoA inactivation. Such close dynamics allow for a quick response to any shocks to the cell. Unsurprisingly, the researchers discovered that if BPGAP1 loses its function and is unable to regulate the two GTPases, the cell's ability to migrate is impaired.

By identifying BPGAP1's role in directing cell movement and its higher presence in metastatic cells, it is obvious that BPGAP1 is at the center of cell migration and metastasis.

Furthermore, the fact that it is increased in all stages of breast cancer, as well as malignancies of the lungs, pancreas, cervix, colon, ovary, and stomach, suggests that it plays a role in all types and stages of cancer.

As a result, the identification of BPGAP1 has enormous potential for cancer prediction and treatment. "We can use BPGAP1 as both a marker for cancer prognosis and a target for cancer intervention across different cancer types," Dr. Wong explained. "We hope that with this breakthrough, we can inspire new approaches for therapeutic designs about cancer and metastasis."

Reference

1. The scaffold RhoGAP protein ARHGAP8/BPGAP1 synchronizes Rac and Rho signaling to facilitate cell migration - (https://www.molbiolcell.org/doi/10.1091/mbc.E21-03-0099)

Source-Medindia