Exploring tumorigenesis as a process of phenotypic state-space exploration and selective funneling

Abstract

Tumorigenesis is widely studied within evolutionary frameworks, yet integrating genetic, non-genetic, spatial, and collective tumor-level dynamics into a unified description remains challenging. Here, we propose that tumorigenesis can be analyzed as a process in which tumors generate, explore, and filter phenotypic and organizational configurations over time. We use the concepts of phenotypic state-space exploration, selective funneling, and selection for function as an operational framework to describe how tumor systems diversify, become constrained, and stabilize or lose functional organization during cancer progression. In this view, tumors are not only populations of competing clones, but also dynamic systems whose persistence depends on plasticity, tissue constraints, spatial organization, and collective functional states. This perspective helps account for phenotypic plasticity, recurrent tumor architectures, and the emergence of collective properties such as group phenotypic composition. It also generates testable predictions, including convergence toward recurrent functional states, therapy-induced reorganization of accessible phenotypic space, and the disproportionate effect of disrupting key collective functions. By mapping these concepts onto tumor biology, we position cancer as a tractable system for studying constraint-driven tumor evolution and for informing therapeutic strategies that target tumor organization in addition to individual cancer cells.