Abstract
ABSTRACTA complex network of inflammatory genes is closely linked to somatic cell transformation and malignant disease. Immune cells and their associated molecules are responsible for detecting and eliminating cancer cells as they establish themselves as the precursors of a tumour. By the time a patient has a detectable solid tumour, cancer cells have escaped the initial immune response mechanisms. Here, we describe the development of a double binary zebrafish model that enables regulatory programming of the myeloid cells as they respond to oncogene-activated melanocytes to be explored, focussing on the initial phase when cells become the precursors of cancer. A hormone-inducible binary system allows for temporal control of expression of different Ras oncogenes (NRasQ61K, HRasG12V and KRasG12V) in melanocytes, leading to proliferation and changes in morphology of the melanocytes. This model was coupled to binary cell-specific biotagging models allowing in vivo biotinylation and subsequent isolation of macrophage or neutrophil nuclei for regulatory profiling of their active transcriptomes. Nuclear transcriptional profiling of neutrophils, performed as they respond to the earliest precursors of melanoma in vivo, revealed an intricate landscape of regulatory factors that may promote progression to melanoma, including Serpinb1l4, Fgf1, Fgf6, Cathepsin H, Galectin 1 and Galectin 3. The model presented here provides a powerful platform to study the myeloid response to the earliest precursors of melanoma.
Highlights
Immune cells and their associated molecules are responsible for detecting and eliminating cancer cells and their precursors at early stages of cancer development (Williams et al, 2016; de Visser et al, 2006)
In the presence of the progesterone agonist, mifepristone, which binds within the LexPR transactivator, LexPR activates the transcription of the target reporter gene by binding to the LexA-binding sites within the LexA operon (LexOP) positioned upstream (Fig. 1A)
We report an inducible model to study the molecular mechanisms following oncogene activation in melanocytes that allows for the spatiotemporal control of oncogene expression in zebrafish melanocytes and the potential to study the earliest precursors of melanoma
Summary
Immune cells and their associated molecules are responsible for detecting and eliminating cancer cells and their precursors at early stages of cancer development (Williams et al, 2016; de Visser et al, 2006). A complex network of inflammatory genes is closely linked to somatic cell transformation and malignant disease. Analysis of the initial response of immune cells to cancer might lead. Transformed cells are able to shape the nature of the myeloid cells and evoke an immunosuppressive response, enabling progression of the disease (Engblom et al, 2016). Further studies are needed to understand the different inflammatory signalling pathways in tumour initiation and progression, and how they may be modulated for immunotherapy. Because we cannot predict when and where transformed cells may arise in the human host, little is known about the sterile inflammatory signalling pathways that closely follow somatic cell transformation (Feng et al, 2012)
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