Translational Control of Tumor-Associated Macrophage Immunosuppressive and Pro-metastatic Functions

Purpose and Aims Tumor-Associated Macrophages (TAMs) associate with tumor progression and poor survival.

TAMs exhibit states spanning from anti-tumor/immunostimulating to pro-tumor/immunosuppressive and can therefore play contradictory roles in cancer. Yet, how such distinct TAM phenotypes manifest is largely unknown. Our preliminary data unraveled TAM pro-tumor phenotypes controlled by MNK2. MNK2 selectively modulates mRNA translation, suggesting altered mRNA translation underlying TAM phenotypes.

Further preliminary data indicate MNK1 and MNK2 having distinct and overlapping activities on TAM phenotypes.

We, therefore, aim to untangle the role of mRNA translation downstream of MNK1 and MNK2 in TAMs using multiple in vivo and in vitro models as well as patient samples.ExecutionWe will study mRNA abundance and translation depending on MNK1 and MNK2 in TAMs from primary tumors and their lung metastasis using in-house state-of-the-art methods to identify drivers or suppressors for pro-tumor TAM phenotypes.

The potential of identified targets to modulate TAM frequences/activities will be evaluated in mouse models together with their potential as prognostic biomarkers in human cancers.

All techniques are available, and the majority of the project should be executed within five years.Significance We will identify genes dictating TAM phenotypes in mouse and human breast cancer. Importantly, our approach uniquely assesses the contribution of mRNA translation to TAM phenotypes.