Periodic Reporting for period 1 - NutFLirsFA (NUTRIENT FLUCTUATIONS AND THE INTEGRATIVE STRESS RESPONSE AS METABOLIC CELL FATE DETERMINANTS IN B CELL LYMPHOMA)
Berichtszeitraum: 2024-09-01 bis 2026-08-31
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 to regulate 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 a dedifferentiated phenotype 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 changes in 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, we will establish if and how MITF and FA composition, along with the ISR, control B-cell transitions (Objective 1) and impact lymphomagenesis (Objective 2). I propose that an abnormal ISR and MITF/SCD1 deregulation corrupt the B-cell differentiation process, contributing to lymphomagenesis.
This proposal, by means of using cutting edge technology combining in vivo and in vitro approaches, 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.
As in melanoma, B-cell differentiation depends on changes in 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, we will establish if and how MITF and FA composition, along with the ISR, control B-cell transitions (Objective 1) and impact lymphomagenesis (Objective 2). I propose that an abnormal ISR and MITF/SCD1 deregulation corrupt the B-cell differentiation process, contributing to lymphomagenesis.
This proposal, by means of using cutting edge technology combining in vivo and in vitro approaches, 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.
Early at the beginning of the project, I found that MITF is barely expressed in normal primary B cells, so as a sensible alternative, and according to the risks assessment foreseen, I focused on other relevant MiT family member, TFEB, unveiling that this transcription factor modulates b-cell fate downstream the RagC-nutrient signalling axis, having both, the lack of TFEB and the excess of TFEB activity a direct, but different, impact on B-cell differentiation and activation. While B cells with enhanced antigen-driven activation and increased capacity to undergo to GC reaction display suppression of TFEB activity, the constant activation of TFEB impairs the formation of GC upon immunization but originates spontaneous autoreactive B cells which formation may be related with an abnormal ISR activation.
Therefore, Objective 1 is just partly achieved, since due to the lack of time, I have not been able to dissect the precise crosstalk between TFEB activity and ISR either in the impairment of the GC formation or in B-cell spontaneous activation. Moreover, I have done very little progress to clarify how TFEB activation affects b-cell fatty acid metabolism. This question must be addressed in the next future.
As aforementioned, it has been impossible to assess the role of MITF and its interplay with ISR and fatty acid metabolism in B-cells, and the same is true for lymphomagenesis, but with the help of my supervisor, I have redirected my research to investigate the role of TFEB in lymphomagenesis. The preliminary data, mainly generated along these months, includes signatures of suppressed TFEB activity in Follicular Lymphomas with increased nutrient signalling, and increased cytoplasmic retention of TFEB in human Follicular Lymphomas samples with mutations in components of the nutrient signalling pathway (RagC), strongly suggest that, despite TFEB being reported as an oncogenic pathway in several epithelial tumours, this MiT transcription factor downstream of nutrient signalling may be a tumour suppressive for Follicular lymphoma.
Beyond the scientific goals, in this proposal I included specific training objectives addressed to foster my scientific development, aiming to promote my scientific independency in short-term, so, together, my supervisor and I, we designed a tailored career development plan to reinforce my competences at different levels.
Therefore, Objective 1 is just partly achieved, since due to the lack of time, I have not been able to dissect the precise crosstalk between TFEB activity and ISR either in the impairment of the GC formation or in B-cell spontaneous activation. Moreover, I have done very little progress to clarify how TFEB activation affects b-cell fatty acid metabolism. This question must be addressed in the next future.
As aforementioned, it has been impossible to assess the role of MITF and its interplay with ISR and fatty acid metabolism in B-cells, and the same is true for lymphomagenesis, but with the help of my supervisor, I have redirected my research to investigate the role of TFEB in lymphomagenesis. The preliminary data, mainly generated along these months, includes signatures of suppressed TFEB activity in Follicular Lymphomas with increased nutrient signalling, and increased cytoplasmic retention of TFEB in human Follicular Lymphomas samples with mutations in components of the nutrient signalling pathway (RagC), strongly suggest that, despite TFEB being reported as an oncogenic pathway in several epithelial tumours, this MiT transcription factor downstream of nutrient signalling may be a tumour suppressive for Follicular lymphoma.
Beyond the scientific goals, in this proposal I included specific training objectives addressed to foster my scientific development, aiming to promote my scientific independency in short-term, so, together, my supervisor and I, we designed a tailored career development plan to reinforce my competences at different levels.
The preliminary data generated during these months, strongly suggest that TFEB is the main MiT family member involved in modulating b-cell fate, having both, the lack of TFEB and the excess of TFEB activity a direct but different impact on B-cell differentiation and activation. Thus, I have found that he suppression of TFEB downstream the activation of the RagC-nutrient signalling axis underpins the exacerbation of the b cells functions, (as I originally hypothesized for MITF), while TFEB constant reactivation, impairs germinal centre (GC) formation in response to stimulation but, paradoxically, also leads to the generation of autoreactive B-cells. Moreover, my data new data in human in Follicular Lymphomas with increased nutrient signalling support that the MiT transcription factor TFEB, a efector downstream of nutrient signalling is a potential tumour suppressive for Follicular lymphoma.
Although more reserchar is required to better understan the precise mechanims underlying our main observaions, these are very promissing results that once confirmed, will open a new landscape regarding to the molecular efectors underpining lymphomagenesis.
Although more reserchar is required to better understan the precise mechanims underlying our main observaions, these are very promissing results that once confirmed, will open a new landscape regarding to the molecular efectors underpining lymphomagenesis.