Descrizione del progetto
Imitazione della nicchia nel tumore del colon-retto
Secondo quanto indicato da prove emergenti, il tumore sviluppa un microambiente complesso e dinamico che si configura come un ecosistema circostante in grado di alimentare le cellule cancerose, influenzandone la crescita e la metastasi. Definire l’interazione tra le cellule cancerose e il loro microambiente è fondamentale per la progettazione di terapie mirate. Il progetto NIMICRY, finanziato dal Consiglio europeo della ricerca, si propone di approfondire la nuova ipotesi secondo cui le cellule cancerose imitano la nicchia tumorale nel cancro del colon-retto, promuovendone una crescita indipendente. I ricercatori studieranno i meccanismi di segnalazione delle cellule cancerose che risultano responsabili di questa imitazione, oltre alle dinamiche di clonazione associate. I risultati forniranno nuove informazioni su un concetto unico relazionato con la biologia dei tumori e la loro metastasi.
Obiettivo
Colorectal cancer (CRC) is a heterogeneous disease with widely variable clinical outcomes. I previously contributed to a unifying molecular classification of CRC, the consensus molecular subtypes (CMSs). The mesenchymal subtype (CMS4), representing ~25% of all CRC patients, is characterised by early metastatic dissemination and poor response to therapy. This is often attributed to activated and rich stroma and therefore much attention in the field goes to dissecting the interaction of the mesenchyme with the cancer cells in these tumours. However, in this research program I will investigate a radically different hypothesis: Mesenchymal CRCs display self-sustained growth by niche-mimicry (nimicry). I define nimicry as the adoption of niche features by cancer cells, thereby rendering the cancers independent of micro-environmental signals for their expansion. This hypothesis is directly based on preliminary experiments from my laboratory, which demonstrated that mesenchymal CRCs are not dependent on external growth factors for expansion in vitro and display autocrine and paracrine loops that drive self-sustained growth. The abundant stroma in mesenchymal CRCs is secondary to the growth factors and cytokines produced by the tumour cells.
To study this concept, I will employ primary human CRC models in combination with molecular and functional characterisation, to delineate the self-supporting signalling loops in a patient specific fashion. These studies are paralleled by the investigation of clonal dynamics within established human CRCs by means of a novel genetic lineage tracing strategy in combination with quantitative analysis. Dedicated analyses will resolve the impact of nimicry on metastasis formation, therapy resistance and tumour evolution.
These studies into nimicry as a critical concept in tumour biology, will importantly advance our understanding of the signals that drive CRC growth and progression, and will pave the way to new treatment strategies.
Campo scientifico
Parole chiave
Programma(i)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Argomento(i)
Meccanismo di finanziamento
HORIZON-ERC - HORIZON ERC GrantsIstituzione ospitante
1081 HV Amsterdam
Paesi Bassi