Organ-On-Chip: A Potential Biophysical Modelling Tool To Modulate Breast Cancer Metastasis

Introduction: Breast cancer is the most prevalent cancer affecting women worldwide, with metastasis accounting for 90% of mortality. As breast cancer progresses, collagen is deposited to increase the surrounding extracellular matrix(ECM) stiffness, triggering breast cancer metastasis. However, existing in vitro models to study matrix rigidity in breast cancer are less physiologically relevant to investigate the underlying mechanisms, as they are typically conducted in conventional 2-dimensional (2D) monolayer models. Therefore, we aim to develop an organ-on chip system using a microfluidic device consisting of two compartments, including a spheroids compartment and a chemoattractant compartment, interconnected by invasion channels.

Materials and Methods: We first embedded 3D breast tumor spheroids derived from MDA-MB-231 cell line into the alginate/matrigel composite matrix with both stiff (50 kPa) and soft (25 kPa) properties, before seeding them into our organ-on-chip platform. Subsequently, 20% fetal bovine serum (FBS) as a chemoattractant is introduced to initiate the first step of cancer metastasis, which involves cell morphological changes prior to invasion. The changes in spheroids are observed using an inverted microscope.

Results: By measuring the morphology and circularity changes of our 3D breast tumor spheroids on-chip, we observed that the spheroids in the stiffer ECM exhibited a more spread-out morphology(circularity index: 0.22) compared to those in the softer ECM, which maintained a more circular shape with a circularity index of 0.35 by Day 2.

Discussion: This result suggests that the stiffer ECM triggers the cancer metastasis initiation on Day2. Conclusion: Given its ability to observe and perform real-time imaging on the breast tumor spheroids’ morphological change and migration in different ECM stiffness, our organ-on-chip system holds great potential as a biophysical modelling tool for studying breast cancer metastasis.