Scientists at ETH Zurich have created a groundbreaking method for using CRISPR/Cas9 in cancer research without triggering immune responses, paving the way for more precise discoveries and effective treatments.
In a groundbreaking development, researchers at ETH Zurich have unveiled a pioneering method that significantly enhances the precision of CRISPR/Cas9 technology in cancer research. Their findings, published in the journal Cell, employs a molecular “cloak of invisibility” that allows CRISPR/Cas9 components to evade detection by the immune system in mouse models, thereby providing more accurate data for developing cancer therapies.
CRISPR/Cas9 technology has revolutionized genetic research, enabling scientists to swiftly edit genes. This has made it invaluable in identifying genetic factors that influence cancer development and metastasis.
However, because CRISPR/Cas9 components are primarily derived from bacteria, they are often recognized as foreign by the immune systems of mice, leading to a distorted response that can skew experimental results.
The research, spearheaded by Nicola Aceto, a professor of molecular oncology at ETH Zurich, has rigorously demonstrated this problem for the first time.
“We were surprised at how significantly this can distort the results of CRISPR screens,” first author Massimo Saini, an ETH Pioneer Fellow in Aceto’s group, said in a news release.
To counter this, the team devised a strategy to make CRISPR/Cas9 “invisible” to the immune system. This was achieved by temporarily exposing tumor cells to the CRISPR/Cas9 components and then isolating only those cells in which a gene had been successfully silenced. These modified cells no longer contained elements that could provoke an immune response.
Additionally, the team replaced traditional reporter genes with a new gene closely resembling a naturally produced protein in mice, ensuring it would go undetected by the immune system.
“We have developed a method for performing CRISPR screens in mice with intact immune systems, without incurring any undesirable side effects,” added Aceto. “This is as close to cancer patients as you can get.”
The innovative method holds particular promise for humanized mice — models that possess a human immune system — which makes the findings highly relevant for human cancer therapies.
“With this system, we are now achieving a new level of accuracy and – particularly significant for us – we are able to discover new targets for therapies,” Saini added.
The research team has already achieved a major breakthrough using this cloaked CRISPR system. By targeting the genes AMH and AMHR2 in a breast cancer mouse model, they observed a significant reduction in metastasis formation.
Clinically, high levels of AMH protein in tumors correlate with more frequent relapses and higher mortality rates, indicating that these genes play a critical role in cancer progression.
“The significance of this signalling pathway has been underestimated,” added Aceto. “Thanks to CRISPR in stealth mode, we are now able to uncover connections that were previously hidden.”
Source: ETH Zurich