Descripción del proyecto
Mimetismo de nicho en el cáncer colorrectal
Cada vez hay más pruebas de que los tumores desarrollan un microentorno complejo y dinámico, un ecosistema circundante que nutre a las células cancerosas e influye en su crecimiento y metástasis. Definir la interacción entre las células cancerosas y su microentorno es fundamental para diseñar tratamiento dirigidos. El proyecto NIMICRY, financiado por el Consejo Europeo de Investigación, se centra en el cáncer colorrectal y su objetivo es investigar la novedosa hipótesis de que las células cancerosas imitan el nicho tumoral para lograr un crecimiento autosostenido. Los investigadores estudiarán los mecanismos de señalización de las células cancerosas responsables de este mimetismo, junto con la dinámica clonal. Los resultados aportarán nueva información sobre un concepto singular relacionado con la biología tumoral y la metástasis.
Objetivo
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.
Ámbito científico
Palabras clave
Programa(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Régimen de financiación
HORIZON-ERC - HORIZON ERC GrantsInstitución de acogida
1081 HV Amsterdam
Países Bajos