Metastasis as a breakdown of the multicellular social contract

Laurine Lagache, Michel Salzet

Cancer Metastasis Reviews

https://doi.org/10.1007/s10555-026-10352-z

Abstract

Multicellular organisms are not just collections of cells; they are evolutionary compromises in which cell-level fitness is subordinated to organism-level integrity. Cancer begins when that compromise is locally subverted, but metastasis is the decisive escalation: malignant cells must cross tissue boundaries, survive a hostile systemic phase, condition remote organs, enter or escape dormancy and construct a new permissive ecology. This Perspective uses the social-contract metaphor as a disciplined heuristic, not as a claim of intention or moral agency, to integrate metastasis biology with eco-evolutionary thinking. We argue that the metastatic cascade can be read as serial failure of multicellular governance: local architecture loses territorial control; vascular and immune systems fail to exclude or destroy emigrant cells; distant tissues become preconditioned by tumour-derived signals; dormant disseminated cells persist as residual insurgencies and colonisation emerges when organ-specific restraint is converted into support. The framework becomes most useful when it also explains the paradox that cells which defect from host-level cooperation may cooperate locally with each other and with recruited stroma. Public goods, collective dissemination, metabolic exchange and premetastatic niche construction create dependencies that may be exploitable therapeutically. We give the Black Queen Hypothesis a precise but bounded role: it is a testable model for dependency-generating loss or outsourcing of costly shared functions, not a universal law of cancer evolution. Finally, we outline translational implications for metastasis: rearming immune enforcement, blocking niche education, maintaining or eradicating dormant disease, disrupting shared dependencies and using adaptive schedules to manage evolutionary escape. The social-contract lens is valuable only when it remains evidence-led and mechanistically anchored; used this way, it makes metastatic dormancy and colonisation a sharper target for ecological cancer therapy.