title: Divergent and convergent evolution in metastases suggest treatment strategies based on specific metastatic sites.
abstract: OBJECTIVE
  Systemic therapy for metastatic cancer is currently determined exclusively by the site of tumor origin. Yet, there is increasing evidence that the molecular characteristics of metastases significantly differ from the primary tumor. We define the evolutionary dynamics of metastases that govern this molecular divergence and examine their potential contribution to variations in response to targeted therapies.
  
  
  METHODS
  Darwinian interactions of transformed cells with the tissue microenvironments at primary and metastatic sites are analyzed using evolutionary game theory. Computational models simulate responses to targeted therapies in different organs within the same patient.
  
  
  RESULTS
  Tumor 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 usually 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. Thus, metastases in the liver from different primary tumors and even in different hosts 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.
  
  
  CONCLUSIONS
  The results suggest that optimal therapies for disseminated cancer must take into account the site(s) of metastatic growth as well as the primary organ.
authors: Cancer Biology and Evolution Program, Moffitt Cancer Center, Tampa, FL 33612; Department of Biological Sciences, University of Illinois at Chicago, Chicago, IL 60607; Aerospace and Mechanical Engineering, University of Arizona, Tucson, AZ, 85745, USA.
authors: Jessica J
authors: JJ
authors: Cunningham
authors: Cancer Biology and Evolution Program, Moffitt Cancer Center, Tampa, FL 33612; Department of Biological Sciences, University of Illinois at Chicago, Chicago, IL 60607; Aerospace and Mechanical Engineering, University of Arizona, Tucson, AZ, 85745, USA.
authors: Joel S
authors: JS
authors: Brown
authors: Cancer Biology and Evolution Program, Moffitt Cancer Center, Tampa, FL 33612; Department of Biological Sciences, University of Illinois at Chicago, Chicago, IL 60607; Aerospace and Mechanical Engineering, University of Arizona, Tucson, AZ, 85745, USA.
authors: Thomas L
authors: TL
authors: Vincent
authors: Cancer Biology and Evolution Program, Moffitt Cancer Center, Tampa, FL 33612; Department of Biological Sciences, University of Illinois at Chicago, Chicago, IL 60607; Aerospace and Mechanical Engineering, University of Arizona, Tucson, AZ, 85745, USA Cancer Biology and Evolution Program, Moffitt Cancer Center, Tampa, FL 33612; Department of Biological Sciences, University of Illinois at Chicago, Chicago, IL 60607; Aerospace and Mechanical Engineering, University of Arizona, Tucson, AZ, 85745, USA Robert.gatenby@moffitt.org.
authors: Robert A
authors: RA
authors: Gatenby
keywords: cancer therapy; evolution; evolutionary game theory; metastases