Systems Biology of Cancer Metastasis

Abstract

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.

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Figure 1. Overview of the observed complex and concurrent routes of metastasis.

Metastasis is a complex, multiscale process which involves multiple sub-processes occurring in parallel through partially overlapping routes. Emerging evidence suggests that pre-malignant lesions are capable of giving rise to distant, latent metastasis and are thus not only associated with late stage primary tumors. However, it is still commonly thought that metastasis occurs mainly through dissemination from malignant lesions when microenvironmental stressors induce cellular reprogramming events that facilitate cellular migration and invasion towards more nutrient-rich niches. These stressors, associated with metabolic reprogramming, can trigger phenotypic changes in cancer cells to adopt more mesenchymal-like states that are not binary, but plastic, with the cells capable of sampling these dynamic states throughout the metastatic process. While this may advance a cell’s ability to metastasize, it is now appreciated that it is likely not the only mechanism by which metastasis occurs. Indeed, there are multiple parallel mechanism co-opted by cancer cells. Lymphatics and blood vasculature are the primary route of cell seeding into the common metastatic organs across cancer types (lymph nodes, liver, lung, bone marrow, and brain), though the tropism cancer exhibit for specific organs is still poorly understood. The combination of genetic and epigenetic changes, and interactions with the diverse milieu of cells in the host microenvironment, determines cancer cell survival and outgrowth.

Figure 2. Systems techniques to study disease progression at different steps in the metastatic cascade.

Tumor outgrowth from the primary node to a more metastatic phenotype entails different physiological environs which pose different experimental and analytical constraints for data acquisition, visualization, sample acquisition, requiring tailored approaches to explore metastasis. Similarly, analytical techniques to mechanistically understand cancer progression at different physiological stages also differ.

Figure 3. Integrated Models to Study Cancer Metastasis.

To understand and describe cancer metastasis at the multiple scales it exists in as a disease require integration of its characteristics at multiple scales. Technological developments in sequencing, imaging, immunological assays etc. have enabled integrated collection of data at multiple scales in which cancer metastasis manifests (molecular, cellular, tissue-level, organ-level, epidemiological, and clinical), as well as along the steps involved in the metastatic cascade. Our ability to describe events on those scales will need to be integrated to develop a more holistic and systems understanding of cancer metastasis.