Lauffenburger:Shannon Alford

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Shannon Alford (BE postdoctoral, Lauffenburger/Gertler Labs)

The role of Mena invasive isoforms in breast cancer metastasis

Pathological dissemination of malignant breast cancer involves specific alteration to underlying cell regulatory processes. Recent work from the Lauffenburger and Gertler labs identified Mena, a member of the Ena/VASP family, as being differentially regulated in metastatic carcinoma versus cells within the original primary tumor. The expression of a specific invasive Mena isoform (MenaINV) results in hypersensitivity to EGF stimulation in vitro and in vivo. In human mammary tumors, Mena overexpression is correlated with intravasation of carcinoma cells when associated with perivascular macrophages. The response is likely mediated by low level paracrine EGF signaling, reflecting the sensitivity of the cells to EGF stimulation. The intracellular mechanisms regulating EGF sensitivity in the Mena-overexpressing cells are not yet known.

We hypothesize that the aberrant expression of the Mena isoforms that confer hypersensitivity to EGF results in quantifiable changes in motility-related signaling network activities involving multiple pathway components, with respect to both spatial and temporal dynamics. Due to the complex multivariate nature of this problem, an integrative systems approach may be especially appropriate to its address. We are combining experiment and computation to develop a data-driven model capable of elucidating important signaling variables in the context of differential Mena isoform overexpression. In the long term, the multivariate model could be used to predict network responses to pharmacologic intervention and may lend important insight to the effects of drugs that target individual, and perhaps more importantly, multiple points within the motility pathway. Our approach provides the possibility of identifying non-trivial compensatory mechanisms that mediate drug resistance.