Grafting Cancer Cells into Mice Alters Tumour Evolution
The analysis of more than 1,000 mouse models of cancer has challenged their ability to predict patient’ response to therapy.
The study published in Nature Genetics, catalogues the genetic changes that occur in human tumours after they have been grafted into mouse hosts. The models, known as 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.
New 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.
Todd Golub, lead author on the study, explained, “The assumption is that what grows out in the PDX is reflective of the bulk of the tumour in the patient. But there’s quite dramatic resulting of the tumour genome.”
Researchers have acknowledged for a long while that PDX’s have their limitations. Therefore, 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 particular interest given the success of cancer therapies that unleash the immune system.
However, previous research has suggested that the PDXs were reasonably faithful reproductions of the human tumours they are meant to model, in turn 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 have launched EurOPDX, a consortium that has developed more than 1,500 models for more than 30 tumour types.
During the study, the team examined how PDXs changed over time. The researchers studied data from tumour cells that were implanted into a mouse, allowed to grow into a tumour, and then harvested and re-implanted into a fresh mouse- sometimes for multiple cycles.
They looked for alterations in the number of copies of a given gene in the cell. They did this ffor more than 1,000 PDX samples representing 24 cancer types, often extrapolating gene copy number from data on gene expression.
As a result, the analysis revealed that tumours implanted in mice changes in ways that are not commonly seen in the human body. Some of the genetic changes were also associated with differences in how the PDX’s responded to cancers.