Descripción del proyecto
Ingeniería genómica para modelizar la aparición de neoplasias malignas
A pesar de la célula de origen, las neoplasias malignas siguen los mismos principios en cuanto a su desarrollo. Acumulan cambios genéticos que incluyen mutaciones, amplificaciones o deleciones de partes del ADN denominadas alteraciones del número de copias (CNA, por sus siglas en inglés). El objetivo del proyecto MACHETE, financiado por el Consejo Europeo de Investigación, es examinar el impacto funcional de las CNA. Sus investigadores utilizarán un novedoso conjunto de herramientas de ingeniería genómica para introducir CNA en el genoma de células pancreáticas con el fin de modelizar el desarrollo de neoplasias malignas de páncreas. Además, el trabajo desvelará información importante sobre el papel de las aberraciones genéticas en la metástasis y la respuesta al tratamiento, y podría desvelar nuevas dianas de valor terapéutico.
Objetivo
Cancers arise through genetic and epigenetic alterations that drive the transformation of single cells into malignant tumors. Among genetic changes, copy number alterations (CNAs) are recurrent chromosomal events that increase or decrease the dosage of specific regions of DNA, can affect up to 30% of a cancer cell genome, and are associated with poor clinical outcomes. Despite their pervasiveness, the functional effects of specific CNAs on cancer phenotypes remain largely unknown, as current approaches cannot faithfully recapitulate the unique properties of these chromosomal alterations. Indeed, CNAs can uniquely affect the expression of hundreds of linked genes and change DNA topology, which in turn can promote intra-tumor heterogeneity as illustrated by random segregation of oncogenes in extra chromosomal DNA (ecDNA). In order to study the functional role of CNAs in cancer, this proposal employs MACHETE, a novel genome engineering toolkit that enables the generation of megabase-sized deletions, gains, and oncogene amplification in ecDNA. Using pancreatic ductal adenocarcinoma (PDAC) as a disease model, we will engineer the major CNAs in this lethal tumor to dissect their role in immune evasion, metastasis, and response to therapy. Additionally, through sequential engineering we will study whether the order of CNA acquisition leads to divergent or convergent phenotypes, a highly relevant yet unexplored aspect of cancer biology. Overall, by combining the MACHETE genome engineering platform with in vivo cancer models and molecular approaches, this proposal will begin to systematically dissect the function of recurrent CNAs in PDAC, with direct implications for therapy. Importantly, the methods and conceptual framework of this proposal are broadly applicable to other cancers and diseases characterized by similar chromosomal alterations, where understanding their underlying biology may lead to a new class of CNA-based clinical targets.
Ámbito científico
Programa(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Régimen de financiación
ERC - Support for frontier research (ERC)Institución de acogida
08035 Barcelona
España