Decoding spatial mTOR signalling reveals distinct roles in the tumour microenvironment

Abstract

Abstract The tumour microenvironment comprises a variety of cell types that interact with malignant cells, influencing both cancer progression and the patient response to therapy. Given the intricate interactions among these components, assessing how signalling pathways contribute to cancer progression by acting on different components of the TME is particularly complex. Multiplexed imaging allows simultaneous assessment of signalling in multiple of these components. Here, we utilise a highly multiplexed dataset of 61 markers across 746 colorectal tumours to investigate how complex mTOR signalling in different tissue compartments influences patient prognosis. We found that mTOR pathway signalling in immune cells correlates with favourable patient survival. Advanced spatially-aware analysis of signalling activities using graph neural networks revealed that the positive association between immune mTOR signalling and patient survival was more pronounced in tumours with features of a more differentiated morphology. Integrative analysis using TCGA data and spatial transcriptomics confirmed a role for immune mTOR signalling in immune activation, accompanied by reduced TGF-β signalling. Our work highlights the importance of adopting a personalised approach to targeting mTOR in cancer patients and establishes a framework for studying cell type-specific signalling in the TME.