Abstract
The progression of cancer in the breast involves multiple reciprocal interactions between malignantly transformed epithelia, surrounding untransformed but affected stromal cells, and the extracellular matrix (ECM) that is remodeled during the process. A quantitative understanding of the relative contribution of such interactions to phenotypes associated with cancer cells can be arrived at through the construction of increasingly complex experimental and computational models. Herein, we introduce a multiscale three-dimensional (3D) organo- and pathotypic experimental assay that approximates, to an unprecedented extent, the histopathological complexity of a tumor disseminating into its surrounding stromal milieu via both bulk and solitary motility dynamics. End point and time-lapse microscopic observations of this assay allow us to study the earliest steps of cancer invasion as well as the dynamical interactions between the epithelial and stromal compartments. We then simulate our experimental observations using the modeling environment Compucell3D that is based on the Glazier–Graner–Hogeweg model. The computational model, which comprises adhesion between cancer cells and the matrices, cell proliferation and apoptosis, and matrix remodeling through reaction–diffusion–based morphogen dynamics, is first trained to phenocopy controls run with the experimental model, wherein one or the other matrices have been removed. The trained computational model successfully predicts phenotypes of the experimental counterparts that are subjected to pharmacological treatments (inhibition of N-linked glycosylation and matrix metalloproteinase activity) and scaffold modulation (alteration of collagen density). Further parametric exploration-based simulations suggest that specific permissive regimes of cell–cell and cell–matrix adhesions, operating in the context of a reaction–diffusion–regulated ECM dynamics, promote multiscale invasion of breast cancer cells and determine the extent to which the latter migrate through their surrounding stroma.
Highlights
Within physiologically functioning tissues and organs, cells constantly interact with their surrounding extracellular matrix (ECM)
Such mammary epithelial architectures are surrounded by stromal ECM that is rich in fibrillar matrix proteins such as collagen I (Figure 1A) and connective tissue cells such as fibroblasts, macrophages, and adipocytes
We present a unified experimental– computational framework to investigate the interactions between cancer epithelia and spatially compartmentalized ECM microenvironments
Summary
Within physiologically functioning tissues and organs, cells constantly interact with their surrounding extracellular matrix (ECM). In normal mammary glands and breasts, luminal epithelial cells are surrounded by a layer of myoepithelial cells that secrete basement membrane (BM): a sheet-like ECM rich in laminin and nonfibrillar collagens. Such mammary epithelial architectures are surrounded by stromal ECM that is rich in fibrillar matrix proteins such as collagen I (Figure 1A) and connective tissue cells such as fibroblasts, macrophages, and adipocytes. In breast cancer, this architecture is lost: the lumen is filled with proliferating apolar transformed epithelia, myoepithelia are absent, and the BM is breached by invading cells (Polyak and Kalluri, 2010). More complicated versions comprise efforts to mimic the perivascular and endothelial metastatic niches (Ghajar et al, 2013; Carlson et al, 2019) as well as efforts to engineer platforms consisting of multiple organs-on-a-chip reviewed by Zhao et al (2019)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
