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Undermining Malignancy The next step in understanding Plk4-mediated cancer cell metastasis and invasion

March 20, 2017

 

Plk4 Promotes Cancer Invasion and Metastasis through Arp2/3 Complex Regulation of the Actin Cytoskeleton

By Meghan Krizus

  Authors Dr. Kazazian (left) and Dr. Swallow (right)
  Authors Dr. Kazazian (left) and Dr. Swallow (right)
What makes a tumour malignant (and therefore cancerous), and not merely benign? This is a crucial question, given that while benign growths can pose health risks, the malignancy of cancerous growths makes them far more dangerous than their benign counterparts.

Malignancy itself is comprised of two primary features: the ability of a tumour’s cells to metastasize (to move through the circulatory system from their initial site of growth to form a new tumour elsewhere in the body) and to invade (to extend into and infiltrate neighbouring tissues).

Therefore, understanding what controls cell invasion and metastasis will help scientists not only understand how cancer progresses, but also how to interrupt these processes and, accordingly, treat cancer. For this reason, the study of malignancy is a crucial part of research conducted at the LTRI, and the focus of a recent publication from the institute. In the paper published in Cancer Research, researchers examined the functions of a regulatory protein called Plk4, studying specifically how this protein may be involved in the processes of cancer cell metastasis and invasion.

The study, spearheaded by Dr. Karineh Kazazian, revealed that in some human breast cancer cells, invasion and metastasis rely on the presence of Plk4. By eliminating (“knocking out”) the gene for Plk4, researchers found that these processes were slower and less severe, adding to other research investigating whether a drug that inhibits Plk4 function could be a promising cancer therapy in humans.

This publication also delves deeper into understanding the mechanism by which Plk4 controls cell migration that, in turn, leads to invasion and metastasis. The team of researchers discovered, for instance, that Plk4 regulates classical components of the cell migration pathway (and thus of key importance in studying metastasis and invasion) such as the proteins Cdc42 and Rac1.

Moreover, this work provides evidence that Plk4’s involvement in cell migration goes beyond its regulation Cdc42 or Rac1, showing that Plk4 may also regulate the Arp2/3 complex’s role in cytoskeleton restructuring via phosphorylation of Arp2. Just as the human skeleton supports the structure of the human body, a cell’s cytoskeleton supports and gives structure to the cell. The cytoskeleton is also crucial in determining various capabilities, including a cell’s ability to move. Thus, the cytoskeleton is an important focus in the study of cancerous processes that involve cell movement, such as metastasis and invasion.

Finally, this work also makes a key discovery in separating the various functions of Plk4 in cancer progression. Elsewhere, research has shown that misregulation of Plk4 leads to supernumerary centrioles, which, in turn, have a tumorigenic effect by interfering with efficient segregation of chromosomes between daughter cells. However, Dr. Kazazian and her colleagues have demonstrated in their new study that Arp2 does not regulate centriole number, leading to the conclusion that the cancer-promoting effects of Plk4 misregulation stem not only from its role in centrosomal defects but via it’s activity on other processes as well.

This research represents not only a noteworthy step toward understanding what controls the malignant processes of cell migration and invasion, but also to how discoveries in fundamental research are key to developing clinical treatments. In such research, senior author Dr. Carol Swallow stresses the importance of the fundamental approach. “In cases such as this,” she says, “fundamental investigation often reveals unexpected mechanisms that allow us to see clinical implications.” With its combined focuses on both the fundamental and the clinical, and its collaboration between teams headed both by a clinician-scientist (Dr. Swallow) and more fundamental research-focused senior investigators (Drs. Anne-Claude Gingras and Jim Dennis), this study represents the compelling discoveries made possible by the LTRI’s collaborative research environment.

Reference:

Want to know more?

What is the difference between malignant and benign growths? Here are two very simple definitions:

This publication addressed several cellular structures. Want to learn about them, or about organelles in general? Here are some handy resources:

Learn more about our wonderful team of researchers!

 

 

 

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