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

ABSTRACT: How metastatic cancer lesions survive and grow in secondary locations is not fully understood. There is a growing appreciation for the importance of tumor components, i.e. microenvironmental cells, in this process. Here, we used a simple microfabricated dual cell culture platform with a 500 ?m gap to assess interactions between two different metastatic melanoma cell lines (1205Lu isolated from a lung lesion established through a mouse xenograft; and WM852 derived from a stage III metastatic lesion of skin) and microenvironmental cells derived from either skin (fibroblasts), lung (epithelial cells) or liver (hepatocytes). We observed differential bi-directional migration between microenvironmental cells and melanoma, depending on the melanoma cell line. Lung epithelial cells and skin fibroblasts, but not hepatocytes, stimulated higher 1205Lu migration than without microenvironmental cells; in the opposite direction, 1205Lu cells induced hepatocytes to migrate, but had no effect on skin fibroblasts and slightly inhibited lung epithelial cells. In contrast, none of the microenvironments had a significant effect on WM852; in this case, skin fibroblasts and hepatocytes--but not lung epithelial cells--exhibited directed migration toward WM852. These observations reveal significant effects a given microenvironmental cell line has on the two different melanoma lines, as well as how melanoma effects different microenvironmental cell lines. Our simple platform thus has potential to provide complex insights into different strategies used by cancerous cells to survive in and colonize metastatic sites.

SUBMITTER: Zhang C

PROVIDER: S-EPMC4854650 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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

Zhang Chentian C Shenk Elizabeth M EM Blaha Laura C LC Ryu Byungwoo B Alani Rhoda M RM Cabodi Mario M Wong Joyce Y JY

Biofabrication 20151230 1

How metastatic cancer lesions survive and grow in secondary locations is not fully understood. There is a growing appreciation for the importance of tumor components, i.e. microenvironmental cells, in this process. Here, we used a simple microfabricated dual cell culture platform with a 500 μm gap to assess interactions between two different metastatic melanoma cell lines (1205Lu isolated from a lung lesion established through a mouse xenograft; and WM852 derived from a stage III metastatic lesi ...[more]

PMID: 26716792

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Project description:?-Catenin phosphorylation plays important roles in modulating its functions, but the effects of different phosphorylated forms of ?-catenin in response to heterocellular interaction are unclear. Here we investigated whether distinct modes of phosphorylation on ?-catenin could be triggered through heterocellular interactions between endothelial cells (ECs) and smooth muscle cells (SMCs), and the consequent modulation of EC functions. ECs were cocultured with SMCs to initiate direct contact and paracrine interaction. EC-SMC coculture induced EC ?-catenin phosphorylations simultaneously at tyrosine 142 (Tyr142) and serine 45/threonine 41 (Ser45/Thr41) at the cytoplasm/nuclei and the membrane, respectively. Treating ECs with SMC-conditional medium induced ?-catenin phosphorylation only at Ser45/Thr41. These findings indicate that different phosphorylation effects of EC-SMC coculture were induced through heterocellular direct contact and paracrine effects, respectively. Using specific blocking peptides, antagonists, and siRNAs, we found that the ?-catenin Tyr142-phosphorylation was mediated by connexin 43/Fer and that the ?-catenin Ser45/Thr41-phosphorylation was mediated by SMC-released bone morphogenetic proteins through VE-cadherin and bone morphogenetic protein receptor-II/Smad5. Transfecting ECs with ?-catenin-Tyr142 or -Ser45 mutants showed that these two phosphorylated forms of ?-catenin modulate differential EC function: The Tyr142-phosphorylated ?-catenin stimulates vascular cell-adhesion molecule-1 expression to increase EC-monocytic adhesion, but the Ser45/Thr41-phosphorylated ?-catenin attenuates VE-cadherin-dependent junction structures to increase EC permeability. Our findings provide new insights into the understanding of regulatory complexities of distinct modes of ?-catenin phosphorylations under EC-SMC interactions and suggest that different phosphorylated forms of ?-catenin play important roles in modulating vascular pathophysiology through different heterocellular interactions.

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

Publications

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

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