Descrizione del progetto
Indagare le basi molecolari delle metastasi del cancro al pancreas
Il progetto PACA-MET, finanziato dall’UE, studierà le basi genetiche e molecolari delle metastasi nell’adenocarcinoma duttale pancreatico. Gli scienziati utilizzeranno il sequenziamento e gli schermi genomici per studiare i geni e i percorsi che conducono alle metastasi in modelli murini della malattia. Il progetto convaliderà i geni appena scoperti usando coorti di pazienti umani affetti da adenocarcinoma duttale, mentre la caratterizzazione funzionale di questi geni a livello di organismo aiuterà a sezionare la complessità della cascata metastatica. PACA-MET dovrebbe individuare le reti molecolari chiave implicate nelle metastasi dell’adenocarcinoma duttale e svelare nuovi obiettivi terapeutici contro questa aggressiva neoplasia.
Obiettivo
Metastasis is the major cause of death in pancreatic ductal adenocarcinoma (PDAC). International sequencing efforts on >800 human primaries gave comprehensive insights into PDAC genetics. In contrast, equivalent studies for “metastasis genetics” were not possible, largely because of a lack of metastatic tissue resources, particularly of treatment-naive ones. Another bottleneck is the scarcity of adequate experimental models recapitulating the multi-step nature of metastasis. As a consequence, the molecular basis of metastasis remains poorly understood.
We developed unique resources and tools for metastasis research and propose to use them at three levels to systematically interrogate the molecular underpinnings of PDAC metastasis.
We will first perform complementary genome-scale surveys for genes and pathways driving metastasis and metastatic organotropism. We will (i) sequence our unique, largely unpublished resource of 1200 metastatic mouse PDAC, (ii) will perform genome-wide in vivo metastasis screens using transposon tools and approaches, which we pioneered in mice, and (iii) will perturb the human metastasis transcriptome and epigenome.
Second, we will validate newly discovered genes using human PDAC cohorts, and through functional studies in mice. We will deploy next-generation metastasis models based on advanced somatic genome engineering. They allow rapid functional studies at an organismal level, thus capturing the complexity of the metastatic cascade.
Third, building on our recent discovery of two prototype PDAC metastasis drivers, we will perform in depth mechanistic studies to identify underlying molecular networks and vulnerabilities.
This work will unravel - for the first time - comprehensive genetic and functional landscapes of PDAC metastasis. PACA-MET thus promises to uncover fundamental novel biological principles and identify therapeutic targets for one of biggest challenges in medicine.
Campo scientifico
Parole chiave
Programma(i)
Argomento(i)
Meccanismo di finanziamento
ERC-COG - Consolidator GrantIstituzione ospitante
81675 Muenchen
Germania