METALERT-STOP
Financiado
Imaging characterizing and targeting metastatic niches in melanoma
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....
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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Duración del proyecto: 65 meses
Fecha Inicio: 2020-06-05
Fecha Fin: 2025-11-30
Fecha Fin: 2025-11-30
Línea de financiación: concedida
El organismo H2020 notifico la concesión del proyecto el día 2020-06-05
Línea de financiación objetivo
El proyecto se financió a través de la siguiente ayuda:
ERC-2019-ADG:
ERC Advanced Grant
Cerrada
hace 5 años
Presupuesto
El presupuesto total del proyecto asciende a
2M€
Líder del proyecto
FUNDACION SECTOR PUBLICO ESTATAL CENTRO NACIO...
No se ha especificado una descripción o un objeto social para esta compañía.
Perfil tecnológico
TRL
4-5
18M
Perfil tecnológico
TRL
4-5
18M