Identifying genes underlying parallel evolution of stromal resistance to placental and cancer invasion

Abstract

Stromal regulation of cancer dissemination is now well recognized, however causal stromal genes and factors have yet not been identified. Placental invasion into endometrial stroma phenotypically is similar to cancer dissemination. There are also vast differences in the extent of placental invasion across mammals, with human pregnancies at the higher extreme end of invasiveness. We have previously demonstrated that epitheliochorial species, characterized by non-invasive placentation, have acquired stromal resistance to placental invasion, correlating with low cancer malignancy rates. Similarly, decidualization of human endometrial fibroblasts confers resistance to placental invasion. We hypothesized that both trajectories may convergently use similar pathways, using endometrial fibroblasts from 9 species to identify putative ELI-D1 genes underlying stromal vulnerability to invasion. ELI-D1 were negatively enriched in T1-T2 stage transition in many human cancers, typically preceding dissemination, bioinformatically validating their contribution to dissemination-preceding fibroblast activation in cancers. Finally, we have identified candidate transcriptional regulators underlying variation in ELI-D1 genes across eutherians, functionally showing that a key transcriptional regulator of ELI-D1 genes across species, Nr2f6, can regulate stromal resistance to invasion in human fibroblasts. Our comparative approach provides us with a putative, limited, gene-set linked to stromal vulnerability in human cancers, providing therapeutic opportunities to target cancer dissemination.