Placental invasion mismatch underlines pregnancy disorders and cancers

Li, X.; Chen, R.; Zhang, Y.; Sun, Y.; Du, W.; Yu, D.; Lu, Y.; Yang, Y.; Bi, X.; Zhu, J.; Sun, K.; Liang, J.; Jiang, L.; He, Y.; Sun, L.; Shen, J.; Kshitiz,; Zhang, D.; Zhang, G.

doi:10.64898/2026.07.06.736876

bioRxiv · 10.64898/2026.07.06.736876

Placental invasion mismatch underlines pregnancy disorders and cancers

Li, X.·Chen, R.·Zhang, Y.·Sun, Y.·Du, W.·Yu, D.·Lu, Y.·Yang, Y.·Bi, X.·Zhu, J.·Sun, K.·Liang, J.·Jiang, L.·He, Y.·Sun, L.·Shen, J.·Kshitiz,·Zhang, D.·Zhang, G.

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Abstract

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.

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Li, X., Chen, R., Zhang, Y., Sun, Y., Du, W., Yu, D., Lu, Y., Yang, Y., Bi, X., Zhu, J., Sun, K., Liang, J., Jiang, L., He, Y., Sun, L., Shen, J., Kshitiz,, Zhang, D., Zhang, G.. 2026-07-11. Placental invasion mismatch underlines pregnancy disorders and cancers. https://doi.org/10.64898/2026.07.06.736876

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