Decoding and targeting the PGE2-MEF2A axis in tumor-associated macrophages

Informations projet

MEFHISTO

N° de convention de subvention: 101088887

DOI

10.3030/101088887

Date de signature de la CE 30 Mai 2023

Date de début 1 Septembre 2023

Date de fin 31 Août 2028

Financé au titre de

• European Research Council (ERC)

Coût total

€ 2 000 000,00

Contribution de l’UE

€ 2 000 000,00

Coordonné par

UNIVERSITA VITA-SALUTE SAN RAFFAELE
Italy

Periodic Reporting for period 1 - MEFHISTO (Decoding and targeting the PGE2-MEF2A axis in tumor-associated macrophages)

Période du rapport: 2023-09-01 au 2026-02-28

Résumé du contexte et des objectifs généraux du projet

Cancer remains a major cause of death, and several malignancies—such as pancreatic ductal adenocarcinoma (PDAC)—remain highly resistant to immunotherapy due to a tumor microenvironment dominated by inflammation, fibrosis, and immune suppression. Among its key regulators are tumor-associated macrophages (TAMs), which can either sustain tissue repair or promote anti-tumor immunity. The ERC project MEFHISTO aims to uncover how macrophages balance these opposing functions by investigating a newly identified regulatory pathway, the PGE2-MEF2A axis, which acts as a molecular switch between cytotoxic and reparative inflammation. By combining advanced genomic, spatial, and functional analyses, the project will define how this axis is deregulated in cancer and how its modulation could restore immune control in resistant tumors like PDAC. Ultimately, MEFHISTO will provide a new conceptual framework for understanding and therapeutically harnessing inflammation, paving the way for next-generation immunotherapies.

Travail effectué depuis le début du projet jusqu’à la fin de la période considérée dans le rapport et principaux résultats atteints jusqu’à présent

During the reporting period, the project established experimental and analytical approaches to study how inflammatory signals influence macrophage behavior in cancer, with a focus on transcriptional regulation and tissue context. The work integrated molecular analyses, animal models, and the study of human tumor samples. At the molecular level, the project developed platforms to investigate how inflammatory signaling affects transcriptional programs that regulate macrophage identity and function. These approaches enable systematic analysis of gene regulation in macrophages under inflammatory conditions. Genetic mouse models allowing selective manipulation of transcriptional regulators in macrophages were generated and validated. These models were combined with established cancer systems and immune-profiling pipelines, providing a robust foundation for in vivo studies. Spatial transcriptomic methods were applied to human tumor samples to analyze the organization of macrophages within tissues. These analyses revealed that macrophages are spatially organized within tumors, highlighting structured immune landscapes rather than a random distribution of immune cells. Overall, work performed for this project delivered validated molecular tools, in vivo models, and spatial analysis workflows, and provided initial insights into how inflammatory cues and tissue organization shape macrophage states in cancer.

Progrès au-delà de l’état des connaissances et impact potentiel prévu (y compris l’impact socio-économique et les conséquences sociétales plus larges du projet jusqu’à présent)

Results reflect the activities carried out during this reporting period, which focused on establishing and integrating experimental platforms. These efforts extend current approaches by enabling the study of macrophage regulation across molecular, in vivo, and tissue contexts. The transcriptional and molecular tools developed allow inflammatory signaling to be investigated in relation to macrophage identity, moving beyond purely descriptive analyses. In parallel, the generation and validation of macrophage-specific genetic models provide a physiologically relevant framework for ongoing in vivo studies in cancer.
The implementation of spatial transcriptomic analyses in human tumor samples adds tissue-level context to immune heterogeneity by revealing structured spatial organization of macrophages within tumors. Overall, the results obtained so far establish a foundation that incrementally advances the state of the art and supports continued mechanistic and translational work in the next phases of the project.