Descripción del proyecto
Modificaciones epigenéticas en la resistencia a los fármacos anticancerosos
La farmacorresistencia en el cáncer representa un reto importante en el tratamiento y es el resultado de mutaciones genéticas, el microambiente tumoral y cambios epigenéticos. Comprender estos mecanismos es crucial para elaborar estrategias eficaces para superar la resistencia y mejorar los resultados del tratamiento del cáncer. El equipo del proyecto EpiResist, financiado por el Consejo Europeo de Investigación, se centra en el papel de las modificaciones del ARN en la resistencia a los fármacos anticancerosos. El objetivo es crear un método para cartografiar las modificaciones de la N6-metiladenosina (m6A) a nivel unicelular y aplicarlo a células de cáncer de mama triple negativo para identificar dianas de resistencia. A través de un análisis sin precedentes, el equipo del proyecto prevé desvelar nuevas características epigenéticas y posibles intervenciones terapéuticas dentro del creciente campo de investigación de la epitranscriptómica.
Objetivo
Drug resistance is one of the biggest challenges in the clinical management of breast cancer (BC), but the underlying mechanisms are still not fully understood. What we do know is that epigenetic mechanisms play a key role in the adaptation of cancer cells to therapy, which is why they have become a prime field of investigation. Single-cell profiling of epigenetic DNA and histone modifications have already revealed intriguing and actionable insights into tumor heterogeneity. For the most recently discovered epigenetic layer however, which consists of RNA modifications, we have not yet reached single-cell resolution. The exciting potential of RNA modifications to fine-tune the processing and expression of mRNAs is currently an area of intense research termed ‘Epitranscriptomics’ and the most prevalent and best studied of these mRNA modifications, N6-methyladenosine (m6A), has recently been linked to drug resistance in cancer. Our lab has uncovered a new m6A-based layer of dysregulation of a major cancer pathway driving therapy resistance in BC. The ability to study m6A in single cells holds great promise as it would enable us to further delineate tumor heterogeneity and to find novel drug resistance targets that have eluded us so far. I propose to develop a method for streamlined m6A mapping at single-cell resolution (Aim 1), to apply it to triple-negative BC (TNBC) cells driven to chemoresistance in cell culture, mice, and human samples so as to determine uncharted targets of drug resistance (Aim 2), and to disrupt m6A-regulated chemoresistance targets in order to prevent therapy failure (Aim 3). These aims are aligned with my knowledge and skills related to both m6A and drug resistance. This unique and comprehensive analysis of the single-cell m6A methylome will provide invaluable new insights into the unknown epigenetic characteristics of chemoresistance and will pave the way for new therapeutic interventions.
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
1050 Bruxelles / Brussel
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