Simon Wilkinson: Autophagy in Tissue Homeostasis and Cancer

Cancer cells from certain tissue types are sensitive to inhibition of autophagy, much more so than healthy cells. This means that there are therapeutic opportunities to be discovered if we can understand the molecular basis of autophagy dependence. We have used protein-protein interaction screens to determine the targets and regulatory molecules of autophagy, specifically in cancer cells. We address the function of these in cell signalling in vitro and in preclinical models of grafted human cancer cells and/or transgenic models of cancer. We have found a strong association of autophagy status with regulation of gene expression via NF-κB signalling. This links autophagy to regulation of transcription involved in processes such as cell proliferation, inflammation and epithelial-mesenchymal transition. The consequences of this for tumourigenesis are being actively pursued.

We are also interested in the mechanisms by which autophagy ‘remodels’ cells during metaplasia. Metaplasia involves the conversion of one cell type to another, sometimes via generation of a proliferative, stem-like intermediate. This occurs during both tissue renewal and tumourigenesis in certain organs, such as the exocrine pancreas (where acinar cells provide either facultative stem cells for tissue regeneration, or seeds for cancer). We have discovered that, in the absence of a new gene (Ccpg1) that we recently showed to drive ER-phagy (selective degradation of the endoplasmic reticulum by autophagy), oncogene-driven metaplasia is associated with increased inflammation and desmoplasia, driving tumorigenesis. We are dissecting this phenomenon mechanistically and are screening for therapeutic agents to modify it.

Last, it is known that autophagy suppresses innate immune reactions and inflammatory events emanating from a variety of cell types during infection paradigms. We have discovered novel molecular mechanisms by which autophagy also suppresses such responses in cancer cells treated with therapeutic agents. The significance of these autophagy-regulated responses to cancer therapy are currently being dissected in vivo.