Spatial Ecology of Cancer Stem Cells in Structured Microenvironments

Abstract

Tumour progression is an emergent phenomenon driven by the interplay between cancer stem cells (CSCs) and the tumour microenvironment (TME). While homeostatic tissues use negative feedback to maintain stability, the regulatory capacity of purely cooperative, positive feedback in spatially constrained systems remains poorly defined. We developed a stochastic spatial agent-based model (ABM) to examine CSC dynamics regulated by juxtacrine (contact-mediated) signalling with stromal cells, utilizing a mean-field ordinary differential equation (ODE) system to isolate the effects of spatial structure. Our analysis reveals that spatial architecture fundamentally alters tumour fate. We identify a paradoxical ‘spatial crowding’ effect where maximal CSC-stroma cooperation actively self-limits growth by depleting local spatial availability. Furthermore, we show that spatial clustering acts as an evolutionary buffer, rescuing tumours from Allee-type extinction thresholds predicted by well-mixed models. Finally, by simulating cyclic targeted therapies that eradicate CSCs but spare the stroma, we demonstrate that persistent stromal architectures act as a structural memory. This surviving stroma aggressively reprograms differentiated cells, driving a ratchet-like, irreversible enrichment of the CSC compartment. Together, these results establish that spatial microenvironments are not passive backdrops, but primary causal drivers of tumour resilience and therapy resistance.