Stromal PTEN inhibits the expansion of mammary epithelial stem cells through Jagged-1.
Stromal PTEN inhibits the expansion of mammary epithelial stem cells through Jagged-1.
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DOI：
10.1038/onc.2016.383
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发表时间：
2017-04-20
期刊：
影响因子：
8
通讯作者：
Ostrowski MC
中科院分区：
文献类型：
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作者：
Sizemore GM;Balakrishnan S;Hammer AM;Thies KA;Trimboli AJ;Wallace JA;Sizemore ST;Kladney RD;Woelke SA;Yu L;Fernandez SA;Chakravarti A;Leone G;Ostrowski MC
乳腺肿瘤微环境中的成纤维细胞是介导肿瘤发生和进展的癌发生的积极参与者。我们的小组之前已经证明，乳腺成纤维细胞中 PTEN 的遗传缺失会诱导致癌分泌组，从而重塑细胞外环境，加速 ErbB2 驱动的乳腺肿瘤进展。虽然这些先前的研究强调了基质 PTEN 的肿瘤抑制作用，但先前并未解决相邻正常上皮如何响应 PTEN 缺失而发生转变。为了识别这些早期事件，我们评估了具有和不具有基质 PTEN 表达的小鼠肿瘤前乳腺上皮内的表型和遗传变化。我们报告说，成纤维细胞特异性 PTEN 缺失极大地限制了乳腺导管的伸长并诱导异常的肺泡侧支。这些小鼠同时表现出富含乳腺上皮干细胞（MaSC）的基底/肌上皮群体的扩增和体外干细胞活性的增加。进一步的分析表明，NOTCH 信号传导（特别是通过 NOTCH3）在这些细胞中减弱。从机制上讲，JAGGED-1（NOTCH受体的跨膜配体）在PTEN缺失的成纤维细胞中下调，导致来自周围基质的NOTCH信号传导的旁分泌激活丧失。在 PTEN 无效的成纤维细胞中重新引入 JAGGED-1 表达足以消除观察到的集落形成活性的增加，这意味着基质 JAGGED-1 在调节乳腺干细胞特性中具有直接作用。重要的是，肿瘤同时表达低基质 JAG1 和低基质 PTEN 的乳腺癌患者比肿瘤单独表达低水平基质 JAG1 和低基质 PTEN 的乳腺癌患者表现出更短的复发时间，这表明晚期疾病中存在类似的基质信号传导。综合起来，这些结果揭示了一种新的基质 PTEN-to-JAGGED-1 轴，可维持乳腺上皮干细胞生态位，并随后抑制乳腺癌的发生和疾病进展。
Fibroblasts within the mammary tumor microenvironment are active participants in carcinogenesis mediating both tumor initiation and progression. Our group has previously demonstrated that genetic loss of PTEN in mammary fibroblasts induces an oncogenic secretome that remodels the extracellular milieu accelerating ErbB2-driven mammary tumor progression. While these prior studies highlighted a tumor suppressive role for stromal PTEN, how the adjacent normal epithelium transforms in response to PTEN loss was not previously addressed. To identify these early events, we have evaluated both phenotypic and genetic changes within the pre-neoplastic mammary epithelium of mice with and without stromal PTEN expression. We report that fibroblast-specific PTEN deletion greatly restricts mammary ductal elongation and induces aberrant alveolar side-branching. These mice concomitantly exhibit an expansion of the mammary epithelial stem cell (MaSC) enriched basal/myoepithelial population and an increase in in vitro stem cell activity. Further analysis revealed that NOTCH signaling, specifically through NOTCH3, is diminished in these cells. Mechanistically, JAGGED-1, a transmembrane ligand for the NOTCH receptor, is downregulated in the PTEN-null fibroblasts leading to a loss in the paracrine activation of NOTCH signaling from the surrounding stroma. Reintroduction of JAGGED-1 expression within the PTEN-null fibroblasts was sufficient to abrogate the observed increase in colony forming activity implying a direct role for stromal JAGGED-1 in regulation of mammary stem cell properties. Importantly, breast cancer patients whose tumors express both low stromal JAG1 and low stromal PTEN exhibit a shorter time to recurrence than those whose tumors express low levels of either alone suggesting similar stromal signaling in advanced disease. Combined, these results unveil a novel stromal PTEN-to-JAGGED-1 axis in maintaining the mammary epithelial stem cell niche, and subsequently inhibiting breast cancer initiation and disease progression.