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 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.