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

Evolution, Medicine, and Public Health
Jessica J CunninghamRobert A Gatenby

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 ...Continue Reading

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Citations

Sep 6, 2017·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·Jasmine A McQuerryAndrea H Bild
Oct 3, 2017·Archives of Pathology & Laboratory Medicine·Reena Singh, Kathleen R Cho
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Mar 31, 2021·ELife·Jean-Pascal CappFrédéric Thomas
Aug 8, 2021·Cancers·Antoine M DujonFrédéric Thomas

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Methods Mentioned

BETA
imaging techniques
environmental stresses

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