Development of a Scoring Function for Comparing Simulated and Experimental Tumor Spheroids

Abstract

AbstractEnormous progress continues in the field of cancer biology, yet much remains to be unveiled regarding the mechanisms of cancer invasion. In particular, complex biophysical mechanisms enable a tumor to remodel the surrounding extracellular matrix (ECM), thus allowing cells to escape and invade alone or as multicellular collectives. Tumor spheroids cultured in collagen represent a simplified, reproducible 3D model system, which is sufficiently complex to recapitulate the evolving internal organization of cells and external interaction with the ECM that occur during invasion. Recent experimental approaches enable high resolution imaging and quantification of the internal structure of invading tumor spheroids. Concurrently, computational modeling enables simulations of complex multicellular aggregates based on first principles. The comparison between real and simulated spheroids represents a way to fully exploit both data sources, but remains a challenging task. We hypothesize that comparing any two spheroids requires first the extraction of basic features from the raw data, and second the definition of key metrics to match such features. Here, we present a novel data-agnostic method to compare spatial features of spheroids in 3D. To do so, we define and extract features from spheroid point cloud data, which we simulated using Cells in Silico (CiS), a high-performance framework for large-scale tissue modeling previously developed by our group. We then define metrics to compare features between individual spheroids, and combine all metrics into an overall deviation score. Finally, we use our features to compare experimental data on invading spheroids in increasing collagen densities. We propose that our approach represents the basis for defining improved metrics to compare large 3D data sets. Moving forward, this approach will enable informing in silico spheroids based on their in vitro counterparts, and vice versa, thus enabling both basic and applied researchers to close the loop between modeling and experiments in cancer research.Author summaryCells within a tumor use various methods to escape and thereby invade into healthy parts of the body. These methods are studied experimentally by examining tumor spheroids, spherical aggregates of hundreds to thousands of individual cells. Such spheroids can also be simulated, and the comparison of simulation and experiment is desirable. Here, we present an analysis strategy for the comparison of tumor spheroids, a widely used workhorse of cancer research. Using this strategy, we aim to improve the collaborative potential between experimentalists and theorists.