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Microenvironment Arrays for Tissue-Specific Functional Screening of Compounds

IB-3237

APPLICATIONS OF TECHNOLOGY:

ADVANTAGES:

ABSTRACT:

Berkeley Lab scientists have developed a platform for high-throughput analysis of the effect of tissue-specific microenvironments on the activity of drugs and other chemicals on a vast assortment of cells, their supporting structures, and signaling proteins that naturally interact within living tissues.

Using available microarray printing equipment, the team, led by researchers Mina Bissell and Mark LaBarge, built a system that mimics, within parallel arrays of printed microscopic pads, the reactivity of various combinations of cells and cellular components. Each pad represents a controlled microenvironment, the nature of which, under specified conditions, might determine whether a stem cell will differentiate; whether a cancer cell might grow, enter quiescence or apoptosis; or whether a drug might eradicate a tumor or unintentionally set the stage for a recurrence.

The team has printed slides of over 2,300 pads representing multiple replicates of 192 unique microenvironments, each one a combination of at least two different molecular components. The pads are printed on a substrate of silicone or polyacrylamide, which enables better biological mimicry of tissue stiffness compared to glass or tissue culture plastic. After cells of interest have attached to the printed arrays of microenvironments, the functional impact of those microenvironments can be measured in the cells with conventional fluorescent and colorimetric biomarkers and tags, and they can be read by commercially available microarray screening equipment for rapid, high-throughput analysis of each slide. The arrays are laid out such that each printed pad, while unique, has a chemical component shared by its neighbor. As such, the arrays depict a grid of chemical relationships. When analyzed, this grid not only shows how two particular components interact in one microenvironment, but serves as a map displaying visually the subtle functional differences imposed by closely related microenvironments.

Berkeley Lab experiments using these microenvironment microarrays (MEArrays) have demonstrated that distinct combinations of constituents within a tissue’s microenvironment impose different cell fate decisions in human mammary progenitor cells. Unique combinations of known mammary gland proteins can be formulated and observed to identify previously unrecognized stem cell activities that result from those combinations. The Berkeley Lab technology therefore can serve as a platform for a constellation of experiments that could shed light on the role of tissue microenvironments in determining stem cell fate. It can be used as a high-throughput screening device to evaluate the effects of drugs in different microenvironments (e.g., primary tumor site versus a metastatic site), and may reveal the role these milieus play in guiding the behavior of stem cells and progenitor cells in either promoting or suppressing disease.

DEVELOPMENT STAGE:  Bench-scale prototype

STATUS: Patent pending.  Available for licensing or collaborative research.

FOR MORE INFORMATION:

LaBarge, M.A., Nelson, C.M., Villadsen, R., Fridriksdottir, A., Ruth, J.R., Stampfer, M.R., Petersen, O.W., Bissell, M.J., “Human Mammary Progenitor Cell Fate Decisions are Products of Interactions with Combinatorial Microenvironments,” Integrative Biology, Vol. 1, pp. 70-79, 2009.

Lin, C.H., Lee, J.K., LaBarge, M.A., “Fabrication and use of MicroEnvironment microArrays (MEArrays)”. Journal of Visualized Experimentation (68), e4152, October 2012.

SEE THESE OTHER BERKELEY LAB TECHNOLOGIES IN THIS FIELD:

Tracking and Quantifying Organization of Epithelial Cells, IB-2903

REFERENCE NUMBER: IB-3237

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Last updated: 12/17/2012