Department of Biomedical Engineering, University of Connecticut Health, Farmington, CT 06030.
Cancer Systems Biology Center, Yale University, West Haven, CT 06516.
Proc Natl Acad Sci U S A. 2022 Feb 8;119(6). doi: 10.1073/pnas.2111256119.
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.
在真兽类（有胎盘）哺乳动物中，胎盘植入母体子宫内膜的程度差异很大，从深度浸润（例如人类）到非浸润（例如牛）。胎盘滋养层的浸润程度与癌症恶性程度呈正相关。此前，我们已经表明，来自不同物种的成纤维细胞对入侵的滋养层以及癌细胞的入侵提供了不同程度的抵抗力。在这里，我们进行了一项比较基因组研究，揭示了这些物种间浸润性差异的顺式调控元件。我们鉴定了调节基质细胞中促浸润性和抗浸润性基因的转录因子。使用体外浸润性测定法结合 CRISPR-Cas9 基因敲除，我们发现转录因子 GATA2 和 TFDP1 强烈影响子宫内膜和成纤维细胞的浸润性。这项工作确定了解释基质细胞浸润性物种差异的基因组机制，为针对基质特征的疗法铺平了道路，以调节胎盘浸润、伤口愈合和癌症扩散。
