CCBIO webinar: Andrew Leask

Andrew Leask
College of Dentistry, University of Saskatchewan, Saskatoon, SK Canada

Inflammation is associated with chronic health conditions including the autoimmune connective tissue disease scleroderma (SSc), the metabolic disorder nonalcoholic steatohepatitis (NASH) and the skin cancer melanoma. Although the etiology of these diseases is likely to differ, in all three indications, inflammation triggers a fibrotic response, characterized by excessive production of extracellular matrix (ECM), that results in organ failure and, often, death. Similarly, activated cancer-associated fibroblasts (CAFs) in the tumor stroma generate a stiff ECM reminiscent of a fibrotic microenvironment that is essential for promoting metastasis. The cells responsible for generating a fibrotic microenvironment are myofibroblasts, highly adhesive/contractile connective tissue cells that arise from resident fibroblasts in response to pro-inflammatory signals.

We and others hypothesize that a shared feed-forward mechanism, namely an autocrine pro-adhesive/contractile signaling loop acting via integrins/focal adhesion kinase (FAK), leads to the activation and perpetuation of myofibroblasts and, hence, fibrosis. More specifically, we propose, downstream of FAK, that a persistently activated hippo/YAP/TAZ mechanotransduction pathway, initially activated in response to inflammation, is necessary to initiate and maintain the fibrotic phenotype. Moreover, we have shown that collagen-lineage fibroblasts are required for this process.

CCN1 and 2, members of the pro-adhesive CCN family of matricellular proteins, are prototypical hippo/YAP/TAZ targets that, in a context-dependent fashion, mediate fibrosis in a variety of models. Conversely, the related protein CCN3, which is reciprocally regulated to CCN2, is antifibrotic. Our idea is that this is a general pathway responsible for all fibrotic conditions, including scleroderma, cancer metastasis, NASH and idiopathic pulmonary fibrosis and thus strategies targeting CCN proteins will have wide therapeutic value. 

Chairperson: Donald Gullberg, CCBIO