Project description
Novel imaging analysis to establish early events leading to melanoma metastases
Melanoma is aggressive cancer where lesions just over one millimetre in depth can lead to metastases. How melanoma cells acquire this invasive potential is unclear. The EU-funded METALERT-STOP project will perform a comprehensive spatio-temporal and functional analysis of pre-metastatic niches, addressing new risk factors for this disease and validating potential targets for therapeutic intervention. A main innovative feature of this study is the use of 'MetAlert' mice created for whole-body imaging of the aberrant expansion of the lymphatic vasculature as an early pre-metastatic event. This model will be combined with other reporter models, as well as with computational and histopathological analyses of human melanoma biopsies to define how melanoma cells remodel their microenvironment at proximal and distal sites, and how to use this information for gene discovery and pharmacological testing in vivo.
Objective
Melanomas are the only tumors where lesions barely over one millimeter in depth can be at risk for metastasis. An increasing number of (epi)genetic alterations and mechanisms of immune evasion have been identified in this disease. Nevertheless, no molecular biomarker has been approved as a bona fide prognostic indicator. Progress in this field has been hampered by the paucity of models to visualize premetastatic niches in vivo, and monitor relapse after surgery. We have overcome these limitations by generating reporter mouse strains to “illuminate” premetastatic niches. Specifically, our “MetAlert” mice were designed for whole-body imaging of the aberrant expansion of the lymphatic vasculature, an early event that precedes metastasis. MetAlert, together with functional studies in human cells and histopathological validation in clinical biopsies, revealed the growth factor MIDKINE as a new melanoma-secreted prometastatic driver. We have now discovered roles of MDK as an immune suppressor, and identified a MDK-associated transcriptional profile that separates patients with a distinct expression of alarmins and bacterial response factors. Proteomic analyses revealed a set of additional factors secreted by aggressive melanoma cells, but their specific contribution to premetastatic niches is unclear.
Here we will exploit our MetAlert and novel imaging reporters we have generated for a comprehensive spatio-temporal and functional analysis of premetastatic niches in vivo (including and beyond MDK). We will define how melanomas act “at a distance” before metastasis (Aim 1), and evade the immune system at different anatomical sites (Aim 2). Aim 3 will dissect the impact of the microenvironment, particularly via alarmins. Aim 4 will pursue the therapeutic targeting of metastatic niches (pre and post-surgery) with immunomodulators we discovered (and have led to clinical trials), and by targeting vulnerabilities that we found distinguish melanoma from other diseases.
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Funding Scheme
ERC-ADG - Advanced GrantHost institution
28029 Madrid
Spain