When chromosomes are mis-segregated, some of the genome ends up outside the nucleus. Micronuclei and chromosome bridges form around the displaced material, and their envelopes rupture, spilling DNA into the cytoplasm. There it is read as a danger signal. The sensor cGAS binds it and triggers type I interferon, the same alarm a cell raises against a virus.
That poses a problem for a chromosomally unstable tumour. The instability that supplies its genetic variation also risks announcing it to the immune system.
We found that the exonuclease TREX1 resolves the conflict by degrading the exposed DNA and limiting cGAS activation at these sites, and that it must be anchored to the endoplasmic reticulum to do so. That requirement was puzzling, because the DNA in question lies open to the cytoplasm once the envelope has failed. The explanation is a protein barrier that assembles on the ruptured compartment and restricts which molecules can reach the DNA. ER anchoring lets TREX1 bypass it.
Tumours exploit this. Chromosomally unstable cancers induce TREX1, which digests the cytosolic DNA and damps the response, forming a feedback loop that keeps them out of sight. Removing TREX1 from a genomically unstable breast cancer model increased interferon secretion, slowed tumour growth, improved the response to checkpoint blockade and prolonged survival, and did so only in tumours still able to mount an interferon response.
Our long-term aim is to understand how unstable tumours silence their own immune signalling, and to turn that into a way of restoring immune detection of cancer.
Read more at maciejowskilab.org.
