Edge effects in game theoretic dynamics of spatially structured tumours

TL;DR

This paper investigates how spatial edge effects influence tumor invasion dynamics by applying an evolutionary game theory model with spatial structure, revealing that tumor boundaries can harbor invasive cells even when the bulk does not.

Contribution

It introduces the use of the Ohtsuki-Nowak transform to incorporate spatial heterogeneity into tumor evolution models, highlighting the significance of boundary effects on invasion.

Findings

Spatial structure promotes invasive strategies in tumors.

Tumor boundaries can harbor invasive cells despite non-invasive bulk.

Edge effects can lead to underestimation of invasive cell populations.

Abstract

Background: Analysing tumour architecture for metastatic potential usually focuses on phenotypic differences due to cellular morphology or specific genetic mutations, but often ignore the cell's position within the heterogeneous substructure. Similar disregard for local neighborhood structure is common in mathematical models. Methods: We view the dynamics of disease progression as an evolutionary game between cellular phenotypes. A typical assumption in this modeling paradigm is that the probability of a given phenotypic strategy interacting with another depends exclusively on the abundance of those strategies without regard local heterogeneities. We address this limitation by using the Ohtsuki-Nowak transform to introduce spatial structure to the go vs. grow game. Results: We show that spatial structure can promote the invasive (go) strategy. By considering the change in neighbourhood size at a static boundary -- such as a blood-vessel, organ capsule, or basement membrane -- we show an edge effect that allows a tumour without invasive phenotypes in the bulk to have a polyclonal boundary with invasive cells. We present an example of this promotion of invasive (EMT positive) cells in a metastatic colony of prostate adenocarcinoma in bone marrow. Interpretation: Pathologic analyses that do not distinguish between cells in the bulk and cells at a static edge of a tumour can underestimate the number of invasive cells. We expect our approach to extend to other evolutionary game models where interaction neighborhoods change at fixed system boundaries.