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.

Most strains of rhinovirus (RV), the common cold virus, replicate better at cool temperatures found in the nasal cavity (33-35°C) than at lung temperature (37°C). Recent studies found that although 37°C temperature suppressed RV growth largely by engaging the type 1 IFN response in infected epithelial cells, a significant temperature dependence to viral replication remained in cells devoid of IFN induction or signaling. To gain insight into IFN-independent mechanisms limiting RV replication at 37°C, we studied RV infection in human bronchial epithelial cells and H1-HeLa cells. During the single replication cycle, RV exhibited temperature-dependent replication in both cell types in the absence of IFN induction. At 37°C, earlier signs of apoptosis in RV-infected cells were accompanied by reduced virus production. Furthermore, apoptosis of epithelial cells was enhanced at 37°C in response to diverse stimuli. Dynamic mathematical modeling and B cell lymphoma 2 (BCL2) overexpression revealed that temperature-dependent host cell death could partially account for the temperature-dependent growth observed during RV amplification, but also suggested additional mechanisms of virus control. In search of a redundant antiviral pathway, we identified a role for the RNA-degrading enzyme RNAseL. Simultaneous antagonism of apoptosis and RNAseL increased viral replication and dramatically reduced temperature dependence. These findings reveal two IFN-independent mechanisms active in innate defense against RV, and demonstrate that even in the absence of IFNs, temperature-dependent RV amplification is largely a result of host cell antiviral restriction mechanisms operating more effectively at 37°C than at 33°C. apoptosis | RNaseL | innate immunity | rhinovirus | respiratory immunity I n the 1960s, rhinoviruses (RVs) were first cultured from patient samples and shown to cause acute upper respiratory infections (a.k.a. common colds). Early work showed that RV isolates replicated best in culture when incubated at temperatures slightly cooler than core body temperature (33-35°C) (1, 2). This observation fit with the role of RV as a cause of disease in the nasal cavity, but not the lungs, as the nasal cavity is cooled by inhalation of environmental air, but the lungs are generally considered to be at core body temperature (37°C). The primary target cells of RV infection are the airway epithelial cells that line the respiratory tract. Similar to all cells of the body, airway epithelial cells are equipped with a cell-intrinsic innate immune system that can sense the presence of a viral infection, using pattern recognition receptors such as toll-like receptors (TLRs) and RIG-I like receptors (RLRs), and can respond to the infection by inducing antiviral effector mechanisms (3). Recently, we used mouse primary airway cells and a mouse-adapted RV to show that replicating RV is recognized by the RLRs within airway epithelial cells, leading to two innate immune signaling events that occur more robustly at warm temperature than at cool temperatu...

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