CCBIO Seminar – Andrew Leask

Speaker: Andrew Leask, School of Dentistry, University of Saskatchewan, Saskatoon, SK, Canada

Title: "Microenvironmental control of fibrosis: a central role for the CCN family of matricellular proteins"

Place: digital event as webinar in Zoom. Audience link: https://uib.zoom.us/j/64950174177?pwd=dVR6L2ViNWozLzYwYi9JbmdLM09zZz09

If asked for a passcode, use: a8AiC2ue

Time: June 10, 2021 at 14:30 (Norwegian time zone)

Chair: Donald Gullberg

Short bio: Dr. Leask has a BSc from the University of British Columbia and a PhD from the University of Chicago. After a CIHR Postdoctoral fellowship at Stanford, he was recruited to FibroGen as a Staff Scientist. He then went to the Royal Free Hospital in London, UK, before becoming Professor at the University of Western Ontario. Since 2019 he has been Professor at the University of Saskatchewan. According to Google Scholar, he has published >175 peer-reviewed papers (out of ~220 total), have an h index of 63, and have been cited over 17800 times.  His group has made substantial progress in the understanding of the molecular mechanisms underlying fibrosis, prinicipally using scleroderma as a model system. He is also currently Editor-in-Chief of Journal of Cell Communication and Signaling (IF=3.8), the official journal, published by Springer Nature, of the International CCN Society. He is also on several scientific boards including the American Society of Matrix Biology, the Canadian Skin Research and the International CCN Society. 

Abstract:

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, is a 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. 

Open to all!

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