Capturing cancer : 3-D model of solid tumor cancer evolution

Though models have been developed that capture the spatial aspects of tumors, those models typically don't study genetic changes. Non- spatial models, meanwhile, more accurately portray tumors' evolution, but not their three-dimensional structure. A collaboration between Harvard, Edinburgh, and Johns Hopkins Universities including Martin Nowak, Director of theProgram for Evolutionary Dynamicsand Professor of Mathematics and of Biology at Harvard, hasnow developed thefirst model of solid tumors that reflects both their three-dimensional shape and genetic evolution. The new model explains why cancer cells have a surprising number of genetic mutations in common, how driver mutations spread through the whole tumor and how drugresistanceevolves. The study is described in an August 26paper in Nature. "Previously, we and others have mostly used non- spatial models tostudy cancer evolution," Nowak said. "But those models do not describe the spatial characteristics of solid tumors. Now, for the first time, we have a computational model that candothat." A key insight of the new model, Nowak said, is the ability for cells to migrate locally. "Cellular mobility makes cancers grow fast, and it makes cancers homogenous in the sense that cancer cells sharea common set of mutations. It is responsible for the rapid evolution of drug resistance," Nowak said. "I further believe that the ability to form metastases, which is what actually kills patients, is a consequenceof selection for local migration." Nowak and colleagues, includingBartek Waclaw of the University of Edinburgh, who is thefirst author of the study, Ivana Bozic of Harvard University and Bert Vogelstein of Johns HopkinsUniversity, set out to improve on past models, becausethey wereunableto answer critical questions about the spatial architecture of genetic evolution. "The majority of the mathematical models in the past counted thenumber of cells that have particular mutations, but not their spatial arrangement," Nowak said. Understanding that spatial structure is important, he said, because it plays a key role in how tumorsgrow andevolve. In a spatial model cells divideonly if they havethe space to do so. This results in slow growth unless cells can migratelocally. "By giving cells the ability to migrate locally," Nowak said, "individual cells can always find new space wherethey candivide. The result isn't just faster tumor growth, but a model that helps to explain why cancer cells share an unusually high number of genetic mutations, and how drug resistance can rapidly evolveintumors. As they divide, all cells -- both healthy and cancerous -- accumulate mutations, Nowak said,and most areso called "passenger" mutations that havelittleeffect on the cell. In cancer cells, however, approximately 5percent are what scientists call "driver" mutations -- changes that allow cells to divide faster or livelonger.In addition to rapid tumor growth, those mutations carry some previous passenger mutationsforward,andasa result cancer cells often haveasurprisingnumber of mutationsincommon. Similarly, drug resistance emerges when cells mutate to become resistant to a particular treatment. While targeted therapies wipeout nearly all other cells, the few resistant cells begin to quickly replicate, causing a relapseof thecancer. "This migration ability helps to explain how driver mutations are able to dominate a tumor, and also why targeted therapies fail within a few months as resistance evolves," Nowak said. "So what we have is a computer model for solid tumors, and it's this local migration that is of crucial importance." "Our approach does not provide a miraculous cure for cancer." said Bartek Waclaw, "However, it suggests possible ways of improving cancer therapy. One of them could be targeting cellular motility (that is local migration) and not just growth as standard therapiesdo."