Placental invasion mismatch underlines pregnancy disorders and cancers

Mammalian placentas vary dramatically in invasiveness, parallel aggressive cancers, and are dysregulated in pregnancy disorders, yet whether they share regulatory architecture remains unclear. We investigated single-cell transcriptomes of the maternal-fetal interface across nine mammals spanning all major placental morphotypes and integrated it with thirteen cancers and five pregnancy complications. A conserved cellular framework is deployed through three discrete regulatory programs: a cancer-like program in hemochorials, endothelial-cooperation program in endotheliochorials, and collagen-rich invasion-suppressing program in epitheliochorials. Aggressive cancers selectively converge on hemochorial program, and we functionally validated share invasion regulators including the VGLL3-TEAD1 interaction and APOE. Pregnancy disorders are partially, mismatched deployments of these programs; placental APOE knockdown in mice phenocopies preeclampsia with concurrent collapse of both M1/M2 macrophage programs. These findings unify placental diversity, cancer convergence, and obstetric disorders under a regulatory-mismatch principle, whereby evolved placental invasion programs becomes pathological when deployed outside their evolutionary context.