ABSTRACT
Cancer screening is based upon a linear model of growth and invasion. Yet, early dissemination during the lengthy pre-diagnostic phase suggests that nonlinearity in growth can also occur. Therefore, we quantitatively traced the invisible and visible phases of tumorigenesis in the mammary gland for more than two-thousand tumors. Dynamic mathematical models of the invisible phase revealed an occult checkpoint resulting in nonlinear progression of transformed field cells. We found that expansile fields have increased dwell time at the occult checkpoint resulting in a large reservoir of image detectable precursors prior to invasion. In contrast, slowly proliferating lesions disseminate early and then transition rapidly through an occult checkpoint in a process we term nascent lethality. Our data illustrate how nonlinear growth across an occult checkpoint can account for a paradoxical increase in early-stage cancer detection without a dramatic reduction in metastatic burden. Highlights: Growth during the invisible phase of tumorigenesis is a nonlinear processField size and field growth rate are uncoupled from metastatic potentialOccult transition rates vary by genotypeNascent lethal lesions are currently undetectable.
