Simulated Ablation for Detection of Cells Impacting Paracrine Signalling in Histology Analysis

TL;DR

This paper introduces a PDE-based mathematical model to analyze how individual tumor cells influence and respond to paracrine signaling in histology, aiding understanding of cellular heterogeneity and microenvironment interactions.

Contribution

The study develops a novel PDE model combined with FEM to separate phenotypic responses from physical contact and genetic factors in tumor microenvironments.

Findings

Model successfully quantifies cell contributions to diffusible factors.

Application to breast cancer tissue reveals correlations between gene amplification and signaling.

Method enables partial deconvolution of complex cellular signaling inputs.

Abstract

Intra-tumour phenotypic heterogeneity limits accuracy of clinical diagnostics and hampers the efficiency of anti-cancer therapies. Dealing with this cellular heterogeneity requires adequate understanding of its sources, which is extremely difficult, as phenotypes of tumour cells integrate hardwired (epi)mutational differences with the dynamic responses to microenvironmental cues. The later come in form of both direct physical interactions, as well as inputs from gradients of secreted signalling molecules. Furthermore, tumour cells can not only receive microenvironmental cues, but also produce them. Despite high biological and clinical importance of understanding spatial aspects of paracrine signaling, adequate research tools are largely lacking. Here, a partial differential equation (PDE) based mathematical model is developed that mimics the process of cell ablation. This model suggests how each cell might contribute to the microenvironment by either absorbing or secreting diffusible factors, and quantifies the extent to which observed intensities can be explained via diffusion mediated signalling. The model allows for the separation of phenotypic responses to signalling gradients within tumour microenvironments from the combined influence of responses mediated by direct physical contact and hardwired (epi)genetic differences. The differential equation is solved around cell membrane outlines using a finite element method (FEM). The method is applied to a multi-channel immunofluorescence in situ hybridization (iFISH) stained breast cancer histological specimen and correlations are investigated between: HER2 gene amplification; HER2 protein expression; and cell interaction with the diffusible microenvironment. This approach allows partial deconvolution of the complex inputs...