Researchers from UNSW Sydney and the University of Technology Sydney (UTS) have discovered that cancer cells can activate a force-generating rescue mechanism to stabilize a cell structure responsible for cell division and evade the effects of chemotherapy.

The findings are published in Current Biology in an article titled, “Cortical tension drug screen links mitotic spindle integrity to Rho pathway.”

“Mechanical force generation plays an essential role in many cellular functions, including mitosis,” the researchers wrote. “Actomyosin contractile forces mediate changes in cell shape in mitosis and are implicated in mitotic spindle integrity via cortical tension. An unbiased screen of 150 small molecules that impact actin organization and 32 anti-mitotic drugs identified two molecular targets, Rho kinase (ROCK) and tropomyosin 3.1/2 (Tpm3.1/2), whose inhibition has the greatest impact on mitotic cortical tension. The converse was found for compounds that depolymerize microtubules.”

“We discovered that cancer cells use the mechanical force supplied by the edge of the cell called the cell cortex, to overcome the impact of commonly used chemotherapy that blocks the ability of the cell to separate the chromosomes during cell division,” explained Peter Gunning, PhD, senior author of the study and a professor from the School of Biomedical Sciences, UNSW Medicine & Health.

“Now that we understand this exact pathway cancer cells use to avoid the toxic effects of the chemotherapy, it opens the door to improving cancer treatments.”

Gunning said we now know that this mechanism arises because the cancer cells activate a signal that recognizes microtubule fragmentation and causes the arms to reach toward the edge of the cell and pull on the cortex to bring the fragments back together.

The researchers initially suspected the mechanism existed after noticing a specific drug combination that targeted the microtubules enhanced chemotherapy for neuroblastoma. But to understand exactly how it worked, the researchers used advanced imaging to observe the mechanism in action.

“We needed good imaging of the cancer cells as they go through cell division to visualize what’s happening to the chromosomes, the microtubules, and the architecture of the cell in real-time,” Gunning said. “It was quite surprising to us because we did not expect this mechanism of the cancer cell to be used in this way to overcome the cancer therapy, but we could see it happening before our eyes.”

The researchers said the mechanism is likely to be a fundamental component of cell biology.

“We think it’s a fallback mechanism that evolved to allow any cell to overcome a small amount of microtubule disruption and ensure it can survive,” Gunning added. “It just so happens cancer cells use it to sidestep the anti-microtubule chemotherapy.”

The researchers are now looking to develop drugs that work in combination with current chemotherapy agents to overcome the cancer cell resistance mechanism. They first need to improve the activity of the drugs in animal models in the next few years before advancing into preclinical studies and eventually into patients.

“By attacking the force-generating machinery built by the cancer cells we expect that we will be able to allow the cancer therapy to do its job much more effectively,” Gunning said. “In practical terms, we have established a company that will allow us to develop the drugs needed to attack this rescue mechanism, enabling the anti-microtubule chemotherapy to act more effectively, and hopefully improve patient outcomes.”

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