Deep phenotyping of the prostate tumor microenvironment reveals molecular stratifiers of relapse linked to inflammatory chemokine expression and aberrant metabolism

Abstract

Understanding the molecular characteristics and changes of the tumor microenvironment (TME) associated with aggressive prostate cancer (PCa) is essential for precise diagnosis and treatment. We interrogated spatially resolved integrated transcriptomics and metabolomics data to build molecular signatures capable of discriminating patients with aggressive, potentially relapsing, and metastasizing PCa. We report two signatures characterized by upregulated expression of immune response related genes with increased activity in relapsing patients. The signatureRelapsewas active in cancer, stroma, and glandular tissue while the other was a feature of morphologically normal appearing glands (NAG) adjacent to aggressive cancer and was named the NAG signature. The NAG signature scored high in regions with upregulated expression of pro-inflammatory chemokines and in glandular regions enriched with Club-like cells and immune cell infiltration in the surrounding stroma. Regions which scored high for both NAG and relapse were associated with loss of normal prostate secretory gland functions such as reduced expression of genes necessary for citrate secretion and reduced levels of citrate and zinc. Our findings suggest that aggressive PCa is associated with an increased inflammatory status linked to chemokine production and Club-like cells.