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

J J Cunningham,J S Brown,T L Vincent,R A Gatenby

doi:10.1093/emph/eov006

Abstract

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. 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. 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. 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.

Highlights

Primary tumors can usually be controlled or eradicated leaving metastases as the cause of death in $90% of cancer patients [1,2,3,4,5,6]
We propose that the formation of metastases from circulating tumor cells (CTCs) is a Darwinian process involving evolution of the tumor cells’ phenotype along the new adaptive landscape provided by the novel tissue environment
We describe the interactions of tumor and normal cells with each other and with the microenvironment using evolutionary game theory [20,21,22]

Summary

Introduction

Primary tumors can usually be controlled or eradicated leaving metastases as the cause of death in $90% of cancer patients [1,2,3,4,5,6]. The metastatic cascade includes invasion of tumor cells into lymphatic or blood vessels at the primary site, circulation, arrest in a distant organ, extravasation into the adjacent tissue and proliferation to form a new invasive (metastatic) cancer [2, 3]. We define the evolutionary dynamics of metastases that govern this molecular divergence and examine their potential contribution to variations in response to targeted therapies. 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. Tumors from different primary sites evolving on identical metastatic adaptive landscapes exhibit phenotypic convergence. 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 for highly targeted therapies

Methods

Findings

Discussion

Conclusion