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Intercellular and Intracellular Communication in the Human Mammary Gland

Interaction network of 169 genes/proteins
Example of autocrine and reciprocal paracrine feedback between HMEC and SF: HMEC produce amphiregulin (AR) and platelet-derived growth factor (PDGF), which stimulate SF to produce hepatocyte growth factor (HGF), which can exert positive feedback on the HMEC. The pathway appears to be a central node in this regulatory loop.

The human mammary gland consists of one to two layers of human mammary epithelial cells (HMEC) surrounded by stromal fibroblasts (SF) embedded in a loose connective tissue containing adipose cells. Though much is known about HMEC and SF as independent cell types, little is known about the feedback loops and regulatory mechanisms that occur between them and with their extracellular environment. Systems biologists at Pacific Northwest National Laboratory are applying their functional modules approach to model how HMEC and SF interact.

Building this predictive model of multicellular interactions requires understanding the control hierarchy of autocrine and paracrine regulatory circuits. Autocrine signaling – signaling involving cells of the same type – is prevalent in multiple cell types and is relatively simple compared to paracrine signaling, which occurs when a factor from one cell type stimulates a neighboring cell. These circuits couple individual cells to their immediate environment and link different cell types to each other. Of the two circuits, paracrine signaling is more difficult to understand using cultured cells because it is so strongly influenced by cellular context. Importantly, paracrine signaling controls overall cell proliferation, migration and tissue structure.

As part of our modeling effort, we are particularly interested in predicting the conditions that create a sustainable positive (or negative) feedback loop between two cell types. To this end, we are using a combination of characterization tools, including proteomics, phosphoproteomics, inhibitor studies, and sophisticated live-cell imaging technologies. The initial step in our modeling work is to profile paracrine signaling between HMEC and SF. Additional tasks are to study the regulation of soluble factor production by HMEC, characterize information processing by SF, and image and model the multicellular response.

Systems Biology at PNNL

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