Divergent and convergent evolution in metastases suggest treatment strategies based on specific metastatic sites

By Jessica J. Cunningham, Joel S. Brown, Thomas L. Vincent, and Robert A. Gatenby

In Evol Med Public Health published 20 March 2015, 10.1093/emph/eov006   (open access)

Abstract: Cancer cells, although maximally fit at their primary site, typically have lower fitness on the adaptive landscapes offered by the metastatic sites due to organ-specific variations in mesenchymal properties and signaling pathways. Clinically evident metastases will exhibit time-dependent divergence from the phenotypic mean of the primary population as the tumor cells evolve and adapt to their new circumstances. In contrast, tumors from different primary sites evolving on identical metastatic adaptive landscapes exhibit phenotypic convergence so that, for example, metastases in the liver from different primary tumors will evolve toward similar adaptive phenotypes. The combination of evolutionary divergence from the primary cancer phenotype and convergence towards similar adaptive strategies in the same tissue cause significant variations in treatment responses particularly for highly targeted therapies. This suggest that optimal therapies for disseminated cancer must take into account the site(s) of metastatic growth as well as the primary organ.