Biological processes are often dynamic, thus researchers must monitor their activity at multiple time points. The most abundant source of information regarding such dynamic activity is time-series gene expression data. These data are used to identify the complete set of activated genes in a biological process, to infer their rates of change, their order and their causal effects and to model dynamic systems in the cell. In this Review we discuss the basic patterns that have been observed in time-series experiments, how these patterns are combined to form expression programs, and the computational analysis, visualization and integration of these data to infer models of dynamic biological systems.

Studying and modelling dynamic biological processes using time-series gene expression data

Wnt5a is a representative ligand that activates the β-catenin-independent pathways. Because the β-catenin-independent pathway includes multiple signalling cascades in addition to the planar cell polarity and Ca(2+) pathway, Wnt5a regulates a variety of cellular functions, such as proliferation, differentiation, migration, adhesion and polarity. Consistent with the multiple functions of Wnt5a signalling, Wnt5a knockout mice show various phenotypes, including an inability to extend the embryonic anterior-posterior and proximal-distal axes in outgrowth tissues. Thus, many important roles of Wnt5a in developmental processes have been demonstrated. Moreover, recent reports suggest that the postnatal abnormalities in the Wnt5a signalling are involved in various diseases, such as cancer, inflammatory diseases and metabolic disorders. Therefore, Wnt5a and its signalling pathways could be important targets for the diagnosis and therapy for human diseases.

Wnt5a: its signalling, functions and implication in diseases

The immunogenicity of cancer cells is an emerging determinant of anti-cancer immunotherapy. Beyond developing immunostimulatory regimens like dendritic cell-based vaccines, immune-checkpoint blockers, and adoptive T-cell transfer, investigators are beginning to focus on the immunobiology of dying cancer cells and its relevance for the success of anticancer immunotherapies. It is currently accepted that cancer cells may die in response to anti-cancer therapies through regulated cell death programs, which may either repress or increase their immunogenic potential. In particular, the induction of immunogenic cancer cell death (ICD), which is hallmarked by the emission of damage-associated molecular patterns (DAMPs); molecules analogous to pathogen-associated molecular patterns (PAMPs) acting as danger signals/alarmins, is of great relevance in cancer therapy. These ICD-associated danger signals favor immunomodulatory responses that lead to tumor-associated antigens (TAAs)-directed T-cell immunity, which paves way for the removal of residual, treatment-resistant cancer cells. It is also emerging that cancer cells succumbing to ICD can orchestrate "altered-self mimicry" i.e. mimicry of pathogen defense responses, on the levels of nucleic acids and/or chemokines (resulting in type I interferon/IFN responses or pathogen response-like neutrophil activity). In this review, we exhaustively describe the main molecular, immunological, preclinical, and clinical aspects of immunosuppressive cell death or ICD (with respect to apoptosis, necrosis and necroptosis). We also provide an extensive historical background of these fields, with special attention to the self/non-self and danger models, which have shaped the field of cell death immunology.

Cell death and immunity in cancer: From danger signals to mimicry of pathogen defense responses.

Malignant melanoma is notorious for its inter- and intratumour heterogeneity, based on transcriptionally distinct melanoma cell phenotypes. It is thought that these distinct phenotypes are plastic in nature and that their transcriptional reprogramming enables heterogeneous tumours both to undergo different stages of melanoma progression and to adjust to drug exposure during treatment. Recent advances in genomic technologies and the rapidly expanding availability of large gene expression datasets have allowed for a refined definition of the gene signatures that characterize these phenotypes and have revealed that phenotype plasticity plays a major role in the resistance to both targeted therapy and immunotherapy. In this Review we discuss the definition of melanoma phenotypes through particular transcriptional states and reveal the prognostic relevance of the related gene expression signatures. We review how the establishment of phenotypes is controlled and which roles phenotype plasticity plays in melanoma development and therapy. Because phenotype plasticity in melanoma bears a great resemblance to epithelial-mesenchymal transition, the lessons learned from melanoma will also benefit our understanding of other cancer types.

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Phenotype plasticity as enabler of melanoma progression and therapy resistance.

Wnt proteins are important for developmental processes and certain diseases. WNT5A is a non-canonical Wnt protein that previously has been shown to play a role in the progression of malignant melanoma. High expression of WNT5A in melanoma tumors correlates to formation of distant metastasis and poor prognosis. This has partly been described by the findings that WNT5A expression in melanoma cell lines increases migration and invasion.

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WNT5A induces release of exosomes containing pro-angiogenic and immunosuppressive factors from malignant melanoma cells

There are currently no effective therapies for metastatic melanoma and targeted immunotherapy results in the remission of only a very small percentage of tumors. In this study, we show that the noncanonical Wnt ligand, Wnt5A, can increase melanoma metastasis in vivo while down-regulating the expression of tumor-associated antigens important in eliciting CTL responses (e.g., MART-1, GP100, and tyrosinase). Melanosomal antigen expression is governed by MITF, PAX3, and SOX10 and is inhibited upon signal transducers and activators of transcription 3 (STAT3) activation, via decreases in PAX3 and subsequently MITF expression. Increasing Wnt5A in Wnt5A-low cells activated STAT3, and STAT3 was decreased upon Wnt5A knockdown. Downstream targets such as PAX3, MITF, and MART-1 were also affected by Wnt5A treatment or knockdown. Staining of a melanoma tissue array also highlighted the inverse relationship between MART-1 and Wnt5A expression. PKC activation by phorbol ester mimicked Wnt5A effects, and Wnt5A treatment in the presence of STAT3 or PKC inhibitors did not lower MART-1 levels. CTL activation studies showed that increases in Wnt5A correspond to decreased CTL activation and vice versa, suggesting that targeting Wnt5A before immunotherapy may lead to the enhancement of current targeted immunotherapy for patients with metastatic melanoma.

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Wnt5A regulates expression of tumor-associated antigens in melanoma via changes in signal transducers and activators of transcription 3 phosphorylation.

Activation of Wnt5A signaling is required for CXC chemokine ligand 12–mediated T-cell migration

Viral and bacterial infections of the lower respiratory tract are major causes of morbidity and mortality worldwide. Alveolar macrophages line the alveolar spaces and are the first cells of the immune system to respond to invading pathogens. To determine the similarities and differences between the responses of mice and macaques to invading pathogens we profiled alveolar macrophages from these species following infection with two viral (PR8 and Fuj/02 influenza A) and two bacterial (Mycobacterium tuberculosis and Francisella tularensis Schu S4) pathogens. Cells were collected at 6 time points following each infection and expression profiles were compared across and between species. Our analyses identified a core set of genes, activated in both species and across all pathogens that were predominantly part of the interferon response pathway. In addition, we identified similarities across species in the way innate immune cells respond to lethal versus non-lethal pathogens. On the other hand we also found several species and pathogen specific response patterns. These results provide new insights into mechanisms by which the innate immune system responds to, and interacts with, invading pathogens.

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Chineye D. Emeche

Papers

Wnt5A regulates expression of tumor-associated antigens in melanoma via changes in signal transducers and activators of transcription 3 phosphorylation.

Activation of Wnt5A signaling is required for CXC chemokine ligand 12–mediated T-cell migration

Large scale comparison of innate responses to viral and bacterial pathogens in mouse and macaque.