LAUSR

Significance Cellular invasion into adjacent tissue is observed in pregnancy, where the fetal placenta invades the mother’s endometrium, and in cancer, where tumor dissemination into stroma is a necessary step before metastasis. The behavior of the surrounding tissue, and its role in either facilitating or resisting this invasion, has not been as deeply studied as the role of the invading cells. The degree of placental invasion into the endometrium varies significantly between different eutherian mammals. Having previously shown that the endometrium of different mammals is significantly responsible for these differences, we identify cis-regulatory elements underlying these differences and show the functional effect of the corresponding transcriptional factors in regulating invasion. Among eutherian (placental) mammals, placental embedding into the maternal endometrium exhibits great differences, from being deeply invasive (e.g., humans) to noninvasive (e.g., cattle). The degree of invasion of placental trophoblasts is positively correlated with the rate of cancer malignancy. Previously, we have shown that fibroblasts from different species offer different levels of resistance to the invading trophoblasts as well as to cancer cell invasion. Here we present a comparative genomic investigation revealing cis-regulatory elements underlying these interspecies differences in invasibility. We identify transcription factors that regulate proinvasibility and antiinvasibility genes in stromal cells. Using an in vitro invasibility assay combined with CRISPR-Cas9 gene knockout, we found that the transcription factors GATA2 and TFDP1 strongly influence the invasibility of endometrial and skin fibroblasts. This work identifies genomic mechanisms explaining species differences in stromal invasibility, paving the way to therapies targeting stromal characteristics to regulate placental invasion, wound healing, and cancer dissemination.