Cancer metastasis is no longer viewed as a linear cascade of events but rather as a series of concurrent, partially overlapping processes, as successfully metastasizing cells assume new phenotypes while jettisoning older behaviors. The lack of a systemic understanding of this complex phenomenon has limited progress in developing treatments for metastatic disease. Because metastasis has traditionally been investigated in distinct physiological compartments, the integration of these complex and interlinked aspects remains a challenge for both systems-level experimental and computational modeling of metastasis. Here, we present some of the current perspectives on the complexity of cancer metastasis, the multiscale nature of its progression, and a systems-level view of the processes underlying the invasive spread of cancer cells. We also highlight the gaps in our current understanding of cancer metastasis as well as insights emerging from interdisciplinary systems biology approaches to understand this complex phenomenon.

Background: Regulation of hypoxia-inducible factor-1 (HIF-1) is focused on proteasomal degradation of the HIF-1␣ subunit. Results: Pharmacological and genetic approaches establish that HIF-1␣ binds to effectors of chaperone-mediated autophagy (CMA) and is targeted for lysosomal degradation. Conclusion: CMA targets HIF-1␣ for lysosomal degradation. Significance: Lysosomal degradation of HIF-1␣ represents a novel mechanism of HIF-1 regulation and a potential therapeutic target.