The role of mechanical forces in vascular disease and cancer.

To date, we are beginning to understand the molecular pathways by which cells respond to force and how these can be exploited for therapeutics. We have previously reported the discovery of the Angiomotin protein family (Amot).

This family of scaffold proteins are implicated in relaying mechanical forces from the environment to the intracellular actin network. During the previous grant period we have made progress in how Amot proteins form a mechanotransductory complex. The Amot protein complex was identified using BioID technology together with state-of-the art mass spec analysis.

We have further used our in house transgenic models to show that inactivation of AmotL2 in aortic endothelial cells results i lack response to blood flow resulting in the formation of abdominal aortic aneurysms (AAA). AAA is major cause of sudden death of men above 60-years.

Interestingly, not only does our mice form AAA in the same location as in humans we also observe a preferential presentation of disease in the male lineage.

In the outlined proposal we aim to further analyze the interplay of endothelial cells, inflammatory cells and smooth muscle.

We also have shown that an isoform of AmotL2 acts as a dominant-negative promoting tumor cell migration and invasion in mouse and in vitro models. This isoform is also expressed in "budding" human cancer cells in patient material. In the proposal, we present a novel strategy to target these specific cells using a phenotypic drug screening approach.