Abstract 24: A genetic model of metastatic evolution: Driver and passenger mutations affect metastatic fitness

Abstract

Abstract Background: The metastatic process requires that cells accomplish two feats: 1) migrate from the primary tumor into the blood stream and arrest in foreign stroma, and 2) grow from a colony of only a few cells into a metastasis of macroscopic size. This second step is highly inefficient for reasons not well understood. Our previous research in tumorigenesis found that many mildly deleterious passenger mutations accumulate in cancer and can influence neoplastic progression, yet the effect of these mutations in metastatic evolution has not been studied. Methods: We developed a model of somatic evolution of neoplastic progressions and metastatic growth. Using a modified Gillespie algorithm, individual cells in our model stochastically divide and die, occasionally acquiring advantageous driver mutations or mildly deleterious (for cancer) passenger mutations. The rate of cell division and death depend on the collective effect of accumulated passenger and driver mutations. Evolutionary pressures lead to clonal expansion and occasionally carcinogenesis. In our in silico experiments, aliquots of cells were taken from successful primary tumors and “injected” into a new micro-environment with new stromal interactions, where they were assayed for metastatic success. This allowed us to track the entire evolutionary history of metastatic cells and genomic determinants of their success. Results: Accumulation of passengers during tumorigenesis as well as metastatic progression frequently prevents initial colonies and micrometastases from developing into metastatic tumors. The population bottleneck experienced during colony formation accelerates the accumulation of deleterious passenger mutations in cancerous populations. We find that in the model, metastatic efficiency depends heavily on primary tumor size, age, and genetic diversity in a manner consistent with clinical observations. A favorable stromal environment was also critical for metastatic success. Surprisingly, we found that as the total number of mutations in neoplastic cells increased, metastatic efficiency, on average, decreased as many of these additional mutations were deleterious passengers. Conclusions: Accumulation of deleterious passenger mutations helps explain metastatic inefficiency after extravasation, as well as many other features of metastasis. Our model makes several novel predictions testable in vivo_most notably that increased mutational load may prevent or impede metastasis. Cancer treatments exploiting the deleterious effects of passenger mutations may prevent metastatic disease. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 24. doi:10.1158/1538-7445.AM2011-24