It is becoming increasingly clear that cancer initiation and progression is actively regulated by signaling between neoplastic cells and their non-neoplastic neighbors. Yet current tools are not well suited to dissecting these multicell type conversations. While microfluidic-based tools have shown promise, typical embodiments present barriers to wide spread use. Here we propose to apply a microfluidic culture platform that utilizes surface tension effects to manipulate fluids allowing seamless integration with ubiquitous pipetting methods (manual and automated) eliminating the need for new infrastructure/equipment. Using this approach, we have developed a number of devices/ assays to probe cell-cell communication via soluble factors. Here we propose to rigorously validate the platform biologically and apply the technology to two important areas of inquiry in cancer biology - hormonal regulation and stromal-epithelial interactions. The long term goal of the hormonal regulation studies is to improve prediction of responsiveness to hormone therapies. Towards this goal we will first validate the microchannel assay using a panel of stress assays. This will be followed by determining the sensitivity of the assay, the use of a one way signaling system to explore ER? reciprocal signaling and finally a study of the ability of the assay to measure hormone resistance. Regarding stromal-epithelial interactions, altered and activated cancer-associated fibroblasts (CAF) promote breast cancer growth and progression, whereas normal fibroblasts (NF) may keep cancer growth in check. Currently, our understanding of the molecular pathways involved in heterotypic stromal-epithelial signaling is limited. The systematic examination of these signaling pathways is hindered by the lack of a suitable in vitro assay platform. We propose to apply a microchannel three dimensional co-culture assay to examine the heterotypic interactions between human mammary fibroblasts and breast carcinoma cells. Broadly, we will apply the technology to monolayer (2D) culture, culture in matrices (3D) and primary cell culture. By evaluating the technology across both experimental and biological models we aim to enhance researchers'ability to identify and characterize molecular factors that influence cancer risk and progression.

Public Health Relevance

The proposed work will apply new tools to elucidating the molecular basis of cancer. We predict that these innovative assays will become tools to improve our understanding and may result in better treatment approaches and predictive tests. Specifically, innovations that can identify patients that don't respond to hormonal therapy will be of significant benefit by eliminating the monetary, physical, and emotional expense associated with treatment. Moreover, the outcomes of this study will not only have relevance to breast cancer but to other important hormone-dependent cancers, such as prostate cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Exploratory/Developmental Grants Phase II (R33)
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Special Emphasis Panel (ZCA1-SRRB-4 (O1))
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Knowlton, John R
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University of Wisconsin Madison
Biomedical Engineering
Schools of Engineering
United States
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