PO.TB07.01 · 肿瘤生物学
SOX9和SEMA7A调控产后乳腺上皮细胞可塑性及其对产后乳腺癌的意义
SOX9 and SEMA7A regulate epithelial cell plasticity in the postpartum mammary gland with implications for postpartum breast cancer
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摘要 Abstract
中文摘要
产后乳腺癌(PPBCs)定义为分娩后十年内诊断的乳腺癌,与未生育女性所诊断的乳腺癌相比,其转移和死亡风险显著更高。临床前研究提示,产后乳腺退化(一个以广泛上皮细胞死亡、组织重塑和炎症为特征的时期)是这一不良预后的驱动因素。然而,在产后窗口期内调控细胞存活、可塑性和转化易感性的上皮程序仍未被完全理解。我们此前已发表:与PPBC进展相关的SEMA7A参与产后退化期间腔上皮祖细胞(LPCs)的存活。因此,我们利用单细胞RNA测序进一步界定小鼠乳腺在哺乳期和退化期表达SEMA7A的细胞,结果显示SEMA7A主要表达于内皮细胞(包括周细胞),而在乳腺上皮细胞上表达较少。我们还揭示了Sox9(一种已知在乳腺上皮细胞上表达的转录因子)在退化期乳腺的LPCs上表达。值得注意的是,LPCs已被提示为多种乳腺肿瘤的关键起源细胞。我们描述了SOX9在整个哺乳期和退化期的表达模式,显示在小鼠和人类样本中SOX9表达在退化过程中均发生变化。我们利用永生化乳腺上皮细胞的泌乳分化和退化体外功能模型,界定了SOX9与SEMA7A在这些上皮状态中的关系。我们发现,在整个分化和退化过程中SEMA7A在这些上皮细胞中表达较低,而乳腺上皮细胞中SOX9敲低导致SEMA7A表达增加并驱动间充质细胞表型,揭示了一条SOX9抑制SEMA7A介导的细胞可塑性的调控轴。乳腺癌数据集分析显示,这一轴的失调(导致SOX9和SEMA7A共表达)与转移风险相关。总之,这些发现揭示了产后乳腺中一条此前未被认识的SOX9-SEMA7A信号轴,并凸显了对正常发育的研究如何能揭示PPBC进展的机制,并指向新的预防途径。
查看英文原文 English abstract
Postpartum breast cancers (PPBCs), defined as breast cancers diagnosed within ten years of childbirth, carry a significantly higher risk of metastasis and mortality compared to breast cancers diagnosed in nulliparous women. Preclinical studies implicate postpartum mammary gland involution, a period marked by extensive epithelial cell death, tissue remodeling, and inflammation, as a driver of this poor prognosis. However, the epithelial programs that govern cell survival, plasticity, and transformation susceptibility during the postpartum window remain incompletely understood. We have previously published that SEMA7A, which is linked to PPBC progression, is involved in the survival of luminal progenitor cells (LPCs) during postpartum involution. Thus, we utilized single-cell RNA sequencing to further define SEMA7A-expressing cells in mouse mammary glands during both lactation and involution to show that SEMA7A is primarily expressed on cells of the endothelium, including pericytes, but less so on mammary epithelial cells. We also revealed that Sox9, a transcription factor that is known to be expressed on mammary epithelial cells, is expressed on LPCs in the mammary gland during involution. Notably, LPCs have been suggested as key cells-of-origin for several mammary tumors. We describe the expression pattern of SOX9 throughout lactation and involution, showing that SOX9 expression changes over the course of involution in both mouse and human samples. Functional in vitro models of lactogenic differentiation and involution with immortalized mammary epithelial cells were utilized to define the relationship between SOX9 and SEMA7A in these epithelial states. We found that SEMA7A is low in these epithelial cells across the differentiation and involution process and that SOX9 knockdown in mammary epithelial cells results in increased SEMA7A expression and drives mesenchymal cell phenotypes, uncovering a regulatory axis in which SOX9 restrains SEMA7A-mediated cellular plasticity. Analysis of breast cancer datasets shows that dysregulation of this axis, resulting in co-expression of SOX9 and SEMA7A, correlates with metastatic risk. Together, these findings reveal a previously unrecognized SOX9-SEMA7A signaling axis in the postpartum mammary gland and highlight how studies of normal development can uncover mechanisms of PPBC progression and point toward new avenues for prevention.
利益披露 Disclosure
L. M. Cozzens, None..
B. Hinckley, None..
T. R. Lyons, None.