Researchers led by Ludwig Chicago Co-director Ralph Weichselbaum and Ronald Rock of the University of Chicago have identified in preclinical studies a potential drug target for curtailing cancer metastasis.
Their study, published in the Proceedings of the National Academy of Sciences, describes how a compound named 4-hydroxyacetophenone (4-HAP) activates a specific protein motor in cells and so monkey-wrenches biomechanical processes essential to cell motility. It also demonstrates in a mouse model that targeting this protein motor undermines the metastasis of colon cancer cells.
“Metastasis is a major problem in cancer and accounts for about 90% of cancer deaths,” said Weichselbaum. “The overall goal here was to find something that reduces the metastatic burden to improve outcomes of cancer therapy.”
For a cancer cell to establish a metastatic growth, it must first break out of the tumor in which it resides, slip into a blood or lymph vessel, drift to a new region of the body, climb out of the vessel, creep into another organ and plant itself firmly in the new tissue. To do all that, it has to squeeze, wriggle and crawl through the molecular stuffing between the cellular layers of various tissues. Each step of metastasis thus requires a good deal of shape shifting, which is accomplished by molecular motors that reorganize the dynamic protein skeleton of the cell and drive the cellular protrusions—or lamellipodia—that enable its crawl.
Researchers have long sought to block metastasis by targeting the biochemical signaling pathways that switch on these processes. Such efforts have, however, been met with limited success because multiple signaling pathways control cell motility, and cancer cells invariably find ways around the blockade of any one pathway.
The researchers thus turned their attention to the recipients of all those signals—the protein motors that dynamically remodel the protein skeleton of the migrating cell. Among these are a set of protein motors known as non-muscle myosins, which are critical to establishing the shape of a cell, anchoring it in place and forming and stretching its lamellipodia as it crawls.
In the current study, the researchers first established in cell culture experiments that 4-HAP disrupts the ability of colon cancer cells to invade, migrate and plant themselves at new sites.
Co-authors on the paper at Johns Hopkins University had previously shown that the molecule inhibits the motility of pancreatic cancer cells by targeting nonmuscle myosins. In an elegant series of subcellular molecular tracking experiments, Rock’s lab demonstrated that 4-HAP specifically exerts its effects through the activation of non-muscle myosin 2 (NM2C).
NM2C helps control the stiffness of cells and organizes components of the cellular skeleton known as actin filaments. Weichselbaum, Rock and colleagues hypothesize that NM2C’s abnormal activation essentially freezes it on certain types of actin filaments, gumming up the machinery of cellular motility.
The researchers also show that when colon cancer cells are injected into the spleen in a mouse model for liver metastasis, dosing the animals with 4-HAP significantly reduces the burden of tumors in the liver compared to untreated counterparts.
“Our next step is going to be to combine NM2C activation in animals with radiotherapy or chemotherapy,” says Weichselbaum. “We’re excited because, although 4-HAP is not suited to human use, we have shown that NM2C is likely to be a druggable target for the control of metastasis.”
The researchers also plan to evaluate other non-muscle myosins as potential drug targets and pin down the precise mechanisms by which NM2C activation disrupts cellular motility.
Reference: Bryan D, Stack M, Krysztofiak K et al. 4-Hydroxyacetophenone modulates the actomyosin cytoskeleton to reduce metastasis. PNAS. 2020. doi:www.pnas.org/cgi/doi/10.1073/pnas.2014639117
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