Thinking (Metastasis) outside the (Primary Tumor) Box

Abstract

The metastasis of tumor cells into vital organs is a major cause of death from diverse types of malignancies [...].

Figure 1

Primary tumor cells (left) evolve via a Darwinian process that selects tumor cell clones (e.g., yellow cells) with the ability to rapidly proliferate, survive, and dominate the primary tumor population locally. However, these cells may lack the plasticity required for metastasis. In contrast, other tumor cells (green), driven by shared oncogenic alterations that promote both primary and metastatic growth with the necessary cell plasticity, are capable of metastatic dissemination. Additional metastasis-enriched or metastatic-specific alterations potentiate tumor cells with a complete (elongated clusters of blue cells) or partial (elongated single purple cells) ability to form macro-metastasis. a—primary tumor cells driven by primary-only oncogenic drivers (yellow epithelial cells) dominate the primary tumor landscape but fail to metastasize; b—primary tumor cells driven by shared oncogenic drivers (green epithelial cells); c—disseminating tumor cells driven by shared oncogenic drivers plus metastasis-enriched or specific drivers with incomplete metastatic potential (elongated purple cells); d—disseminating tumor cells driven by shared plus metastasis-enriched/-specific tumor cells that undergo group migration with complete metastatic potential (elongated blue cells); e—aborted circulating tumor cells (purple) that fail to survive or form macro-metastases; f—circulating tumor cells (purple) that acquired additional mutations or signals from the TME that endowed them with full metastatic potential (elongated purple to blue conversion); g—mesenchymal-to-epithelial transition (MET) and the colonization of a distal site (blue epithelial cells). Targeted therapies against 2–3 shared oncogenic drivers or against shared plus metastasis-enriched/-specific drivers but not primary-only drivers offer a rational, neo-adjuvant approach to prevent metastatic cancer upon diagnosis.