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

Project Information

MEFHISTO

Grant agreement ID: 101088887

DOI

10.3030/101088887

EC signature date 30 May 2023

Start date 1 September 2023

End date 31 August 2028

Funded under

• European Research Council (ERC)

Total cost

€ 2 000 000,00

EU contribution

€ 2 000 000,00

Coordinated by

UNIVERSITA VITA-SALUTE SAN RAFFAELE
Italy

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

Reporting period: 2023-09-01 to 2026-02-28

Summary of the context and overall objectives of the project

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.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

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.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

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.