Innovating Works

INCANTAR

Financiado
TARGETING INHERITED CANCER SYNDROMES
Transcription factors EB and E3 (TFEB and TFE3), members of the MiT-TFE family, are master controllers of lysosomal biogenesis and autophagy. The activity of TFEB and TFE3 is regulated by mechanistic Target Of Rapamycin Complex 1... Transcription factors EB and E3 (TFEB and TFE3), members of the MiT-TFE family, are master controllers of lysosomal biogenesis and autophagy. The activity of TFEB and TFE3 is regulated by mechanistic Target Of Rapamycin Complex 1 (mTORC1), a central hub of cell metabolism, which inhibits their cytoplasm-to-nucleus translocation. We recently discovered that mTORC1 phosphorylates TFEB and TFE3 via a non-canonical TORC1 (NC-mTORC1) signaling mechanism, providing the first evidence that mTORC1 can produce specific responses to different environmental cues by differential substrate phosphorylation. We and others recently discovered that dysregulation of NC-mTORC1, leading to constitutive activation of TFEB/TFE3, is the main driver of the renal cystic and tumorigenic phenotype of inherited cancer syndromes Birt-Hogg-Dube' (BHD) and Tuberous Sclerosis Complex (TSC). Remarkably, deletion of TFEB completely rescued renal cystogenesis and tumorigenesis in BHD and TSC mouse models. Furthermore, additional types of cancer have been associated to induction of TFEB/TFE3, suggesting that this may be an emerging mechanism of tumorigenesis. In INCANTAR (INherited CANcer TARgeting) we aim to identify novel regulators of TFEB/TFE3 factors by CRISPR screening and protein interactome analyses, which may reveal new therapeutic targets. We also plan to thoroughly characterize the pathogenic role of TFEB and TFE3 in TSC and BHD using transgenic mice and kidney and brain organoids. Finally, we will explore novel therapeutic strategies for TFEB/TFE3 driven diseases, such as selective ablation of cells expressing GPNMB, a sensitive transcriptional target of MiT-TFE factors, and drug screening for MiT-TFE inhibitors using a newly developed MiT-TFE transcriptional reporter. These studies will shed new light on the mechanisms underlying the pathogenic role of MiT-TFE factors and are likely to generate novel therapeutic tools for several cancer-associated conditions. ver más
31/08/2028
2M€
Duración del proyecto: 62 meses Fecha Inicio: 2023-06-12
Fecha Fin: 2028-08-31

Línea de financiación: concedida

El organismo HORIZON EUROPE notifico la concesión del proyecto el día 2023-06-12
Línea de financiación objetivo El proyecto se financió a través de la siguiente ayuda:
ERC-2022-ADG: ERC ADVANCED GRANTS
Cerrada hace 2 años
Presupuesto El presupuesto total del proyecto asciende a 2M€
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FONDAZIONE TELETHON ETS No se ha especificado una descripción o un objeto social para esta compañía.
Perfil tecnológico TRL 4-5