NUTRIENT FLUCTUATIONS AND THE INTEGRATIVE STRESS RESPONSE AS METABOLIC CELL FATE...
NUTRIENT FLUCTUATIONS AND THE INTEGRATIVE STRESS RESPONSE AS METABOLIC CELL FATE DETERMINANTS IN B CELL LYMPHOMA
Metabolic reprogramming enables cells to adopt different phenotypes, providing flexibility in response to environmental stress, of particular relevance during tumour development. I recently demonstrated that the transcription fact...
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Información proyecto NutFLirsFA
Duración del proyecto: 40 meses
Fecha Inicio: 2023-04-28
Fecha Fin: 2026-08-31
Fecha límite de participación
Sin fecha límite de participación.
Descripción del proyecto
Metabolic reprogramming enables cells to adopt different phenotypes, providing flexibility in response to environmental stress, of particular relevance during tumour development. I recently demonstrated that the transcription factor MITF, known regulator of cell transitions in melanoma, controls the expression of the fatty acid (FA) desaturase SCD1. The MITF/SCD1 axis maintains cell differentiation, while its suppression by starvation-induced Integrative Stress Response (ISR) originates dedifferentiation and melanoma progression. Our findings support that metabolic rewiring and phenotype switching are interconnected events that govern tumour progression.
As in melanoma, B-cell differentiation depends on MITF activity, FA metabolism and a dynamic modulation of ISR, but weather an interplay among these factors dictates B-cell fate is still unknown. Importantly, MITF is regulated by mTORC1/RagGTPase signalling, pathway frequently mutated in B-cell lymphomas. I hypothesize that the ISR/MITF axis and FA metabolism enable normal and pathological B cells to adapt to stress, and critically licenses switches in phenotypic identity and B-cell behaviour. Thus, I will establish if and how MITF and FA composition control B-cell transitions and impact lymphomagenesis, along with its regulation by the ISR. We propose that abnormal ISR and MITF/SCD1 deregulation corrupts B-cell differentiation process, contributing to lymphomagenesis.
This proposal aims at shedding light on the interplay between nutritional signals and stress-related cellular responses that precipitate cancer cell transitions through the regulation of specific transcriptional programs controlling metabolic rewiring.