Resolving cancer–stroma interfacial signalling and interventions with micropatterned tumour–stromal assays

Abstract

Tumor-stromal interactions are a determining factor in cancer progression. In vivo, the interaction interface is associated with spatially-resolved distributions of cancer and stromal phenotypes. Here, we establish a micropatterned tumor-stromal assay (μTSA) with laser capture microdissection to control the location of co-cultured cells and analyze bulk and interfacial tumor-stromal signaling in driving cancer progression. μTSA reveals a spatial distribution of phenotypes in concordance with human estrogen receptor-positive (ER+) breast cancer samples, and heterogeneous drug activity relative to the tumor-stroma interface. Specifically, an unknown mechanism of reversine is shown in targeting tumor-stromal interfacial interactions using ER+ MCF-7 breast cancer and bone marrow-derived stromal cells. Reversine suppresses MCF-7 tumor growth and bone metastasis in vivo by reducing tumor stromalization including collagen deposition and recruitment of activated stromal cells. This study advocates μTSA as a platform for studying tumor microenvironmental interactions and cancer field effects with applications in drug discovery and development.

MARCKS contributes to stromal cancer-associated fibroblast activation and facilitates ovarian cancer metastasis

“…These data were analyzed as a continuum and differences between groups were compared with a semiquantitative method. Masson's trichrome (Sigma, HT15) staining was performed as described previously [57] on paraffin embedded sections of xenograft tumors.…”

Micropatterning Strategies to Engineer Controlled Cell and Tissue Architecture in Vitro

“…Since this approach provides control over the intimate juxtaposition of different cell types within the sheet, it enables the generation of architectures reminiscent of tissue structures observed in vivo, thus facilitating the investigation of key physiological processes over time using traditional or high-content microscopy. Recently, this approach has been used to probe signaling mechanisms at the tumor-stromal interface (43), and examine the establishment of tissue boundaries (S Javaherian et al, manuscript in preparation). Importantly, the stability of patterns generated using this method depends on the characteristics of the cell populations being patterned and their interactions, and pattern remodeling and degradation over time, due to cell re-organization within the sheet, is possible (44).…”

A simple engineered platform reveals different modes of tumor-microenvironmental cell interaction

“…Microfabricated stencils and stamps allow researchers to deposit different types of cells and extracellular matrices (ECMs) according to pre-defined patterns and can thus establish cell–cell interactions to a resolution of 100 μ m. For example, Dickinson et al created a series of finely controlled cancer-endothelial interactions with microcontact printing, taking advantage of preferential adhesion of endothelial colony-forming cells to fibronectin and of breast cancer cells to hyaluronic acid [13]. More recently, Shen et al used high resolution analysis of similar micropatterned tumor-microenvironmental co-culture experiments to demonstrate that the proximity of microenvironmental cells can have a strong influence on the growth rate, gene expression profile, and drug response of a given cancer cell [14]. …”