Regulation of metastatic phenotypes by autophagy
- Author(s): Kenific, Candia Marie
- Advisor(s): Debnath, Jayanta
- Werb, Zena
- et al.
Metastasis, the process by which primary tumor cells disseminate throughout the body and colonize distant organs, continues to be the principal cause of cancer-associated death. Although our understanding of the biology underlying metastasis has advanced significantly in recent years, there is still a lack of effective therapies available for treating this disease. In light of this unmet clinical need, my thesis has focused on establishing whether autophagy, a cellular stress response pathway, may be a novel therapeutic target for treating cancer metastasis.
Autophagy is an evolutionarily conserved process that involves the formation of a double-membrane vesicle, the autophagosome, which consumes cellular constituents and delivers them to the lysosome for degradation. Autophagy is well-recognized to be a crucial regulator of tumorigenesis. Moreover, roles for autophagy in regulating metastatic phenotypes, such as adhesion-independent growth and survival and tumor cell invasion and migration have emerged. However, the mechanisms underlying regulation of these metastasis traits by autophagy are poorly understood, and it is not known precisely how autophagy regulates in vivo cancer metastasis.
Here, I investigate the cell biological mechanisms through which autophagy regulates cell migration. I find that autophagy is required for the efficient assembly and disassembly, or turnover, of integrin-based cell-matrix focal adhesions (FAs) in motile cells, and I uncover that the autophagy cargo receptor NBR1, which mediates targeting of autophagosomes to their substrates, acts as a key mediator of cell migration and autophagy-dependent FA disassembly. Collectively, these findings point to a molecular mechanism of NBR1-mediated selective autophagy in directly regulating FA turnover during migration.
I also explored the role of autophagy during in vivo cancer metastasis. Despite extensive data suggesting autophagy would function to promote metastasis, I find that autophagy functions as a metastasis suppressor. In addition, autophagy does not impact growth or viability of established metastatic tumors, suggesting it regulates stages of metastasis prior to overt secondary tumor growth. Finally, I identify the autophagy cargo receptor, NBR1, as a novel metastasis promoter. Because NBR1 is itself degraded by autophagy, overall, these results hint at an unexpected model in which NBR1 accumulation upon autophagy inhibition drives metastasis.