CRISPR screens are a workhorse of cancer research, silencing genes across pools of hundreds of tumour cell variants to see which drive growth or metastasis. But the group of Nicola Aceto, professor of molecular oncology at ETH Zurich, found a hidden flaw: because CRISPR components are largely bacterial in origin, they provoke an immune response in mice that distorts results, causing tumour cells to be rejected more often, lose genetic diversity and form fewer metastases. The study appears in Cell.
The team's answer is StealTHY, a stealth version of the screening method developed with ETH Pioneer Fellow Massimo Saini as first author. The Cas9 protein is applied to tumour cells only temporarily, cells are isolated once a gene has been successfully silenced and no longer carry immune-triggering elements, and the usual bacterial reporter genes are replaced with one whose product differs only minimally from a natural mouse protein. The approach also works in humanised mice carrying a human immune system.
Put to work, the method delivered immediately: silencing the genes AMH and AMHR2 sharply reduced metastases in a mouse model of breast cancer, and patient data link high AMH protein levels in tumours to more frequent relapses and higher mortality. Beyond nominating a new target pathway, screens run in animals with intact immune systems should give the field a far more faithful picture of how cancers actually behave.