Cancer-genome study challenges mouse ‘avatars’

A brain tumour called glioblastoma, shown here as the circular region in a patient’s brain scan, is among the cancers that have been tested in mouse avatars.

An analysis of more than 1,000 mouse models of cancer has challenged their ability to predict patients’ response to therapy.

The study, published today in Nature Genetics1, catalogues the genetic changes that occur in human tumours after they have been grafted into mouse hosts. Such models, called patient-derived xenografts (PDXs), are used in basic research and as ‘avatars’ for individual patients. Researchers use these avatar mice to test a bevy of chemotherapies against a person’s tumour, in the hope of tailoring a treatment plan for the patient’s specific cancer.

But fresh data from geneticists at the Broad Institute of MIT and Harvard in Cambridge, Massachusetts, suggest that transplanting human cancer cells into a mouse alters the cells’ evolution, reshaping the tumour’s genome in ways that could affect responses to chemotherapy.

“The assumption is that what grows out in the PDX is reflective of the bulk of the tumour in the patient,” says cancer geneticist Todd Golub, a lead author on the study. “But there’s quite dramatic resculpting of the tumour genome.”

No animal model is perfect, and researchers have long acknowledged that PDXs have their limitations. To avoid an immune assault on the foreign tumour, for example, PDXs are typically grafted into mice that lack a functioning immune system. This compromises scientists’ ability to study how immune cells interact with the tumour — an area of increasing interest given the success of cancer therapies that unleash the immune system.

PDXs can also take months to generate, making them too slow to serve as avatars for those patients who need to make immediate decisions about their therapy.

Reasonable reproductions

But previous research had suggested that the PDXs were reasonably faithful reproductions of the human tumours they are meant to model, offering researchers a chance to explore the tumour’s interaction with its environment in ways that are not possible using cells grown in a Petri dish. The US National Cancer Institute has developed a library of more than 100 PDXs for distribution to researchers, and European scientists…