Probing three-dimensional collective cancer invasion with DIGME

Amani A. Alobaidi,Bo Sun

doi:10.1186/s41236-017-0004-9

Abstract

BackgroundMulticellular pattern formation plays an important role in developmental biology, cancer metastasis and wound healing. While many physical factors have been shown to regulate these multicellular processes, the role of ECM micro-to-meso scale geometry has been poorly understood in 3D collective cancer invasion.ResultsWe have developed a mechanical-based strategy, Diskoid In Geometrically Micropatterned ECM (DIGME). DIGME allows easy engineering of the shape of 3D tissue organoid, the mesoscale ECM heterogeneity, and the fiber alignment of collagen-based ECM all at the same time. We have employed DIGME to study the 3D invasion of MDA-MB-231 diskoids in engineered collagen matrix. We find that the collective cancer invasion is closely regulated by the micro-to-meso scale geometry of the ECM.ConclusionsWe conclude that DIGME provides a simple yet powerful tool to probe 3D dynamics of tissue organoids in physically patterned microenvironments.

Highlights

Multicellular pattern formation plays an important role in developmental biology, cancer metastasis and wound healing
We extend the mold-based technique developed by Nelson et al (2006) into a low-cost, flexible strategy, Diskoid In Geometrically Micropatterned extracellular matrix (ECM) (DIGME)
To demonstrate the working principles and biocompatibility of DIGME, we first formed a cylindrical MDA-MB-231 tumor diskoid in 3D type-I collagen gel

Summary

Introduction

Multicellular pattern formation plays an important role in developmental biology, cancer metastasis and wound healing. It has been shown that cell-cell adhesion (Maruthamuthu et al 2011; Bi et al 2015; Bazelliéres et al 2015), exclusion volume (Angelini et al 2011), contact inhibition (Liu et al 2011; Zimmermann et al 2016), cell-secreted chemical factors (Theveneau et al 2013), and substrate-mediated mechanical forces (Ma et al 2013) coordinate the multicellular motility and pattern formation of multiple cells in 2D. These results, have limited applicability in 3D tumor progression. Chemical signaling in 3D suffers from rapid dispersive dilution, the diffusion-mediated 3D intercellular correlations are much weaker compared to the case in 2D (Sun et al 2012)

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Conclusion