Stopping cancer in its tracks, The University of Chicago Medical Center, May 12, 2016.
Spreading cancer can be halted by blocking a key mechanism that allows tumour cells to break free from their birthplace.
Researchers from the University of Chicago have shown that inhibiting autophagy, a self-devouring process used by cells to degrade large intra-cellular cargo, effectively blocks tumor cell migration and breast cancer metastasis in tumor models.
Autophagy Promotes Focal Adhesion Disassembly and Cell Motility of Metastatic Tumor Cells through the Direct Interaction of Paxillin with LC3, Cell Reports S2211-1247(16)30509-5, May 12, 2016.
Macro-autophagy (hereinafter termed autophagy) is a catabolic process important for the degradation of damaged organelles and protein aggregates, as well as the intracellular recycling of metabolites that are used by tumor cells to survive nutrient stress, hypoxia, and cytotoxic therapies .
Consequently, autophagy has emerged as a potential therapeutic target. However, such efforts are complicated by the growing realization that autophagy plays opposing roles in tumorigenesis, likely influenced by the stage of progression, driving oncogene and tissue type. Mouse models support a tumor-suppressive role for autophagy in the early stages of tumorigenesis by promoting genome stability and limiting necrosis and inflammation. Conversely, autophagy is required for malignant progression. Consistently, clinical studies have associated increased staining for the autophagy marker LC3 with melanoma metastases and with node positivity and decreased overall survival in human breast cancer, whereas overexpression of the key autophagy regulator Beclin1 is linked to reduced latency of melanoma metastasis.
Here, we report that autophagy is required for the motility and invasion of highly metastatic tumor cells due to a function for autophagy in promoting focal adhesion (FA) turnover. The key FA protein paxillin is degraded by autophagy, and paxillin is targeted to the autophagosome through the Src-regulated interaction of LC3 with a conserved LC3-interacting region (LIR) in paxillin. These results broaden our understanding of the multi-faceted role of autophagy in tumor progression and indicate that inhibiting autophagy may be an effective approach to blocking metastatic dissemination in the clinic.