Paracrine WNT5A Signaling Inhibits Expansion of Tumor-Initiating Cells.
Paracrine WNT5A Signaling Inhibits Expansion of Tumor-Initiating Cells.
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DOI：
10.1158/0008-5472.can-14-2761
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发表时间：
2015-05-15
期刊：
影响因子：
11.2
通讯作者：
Zhang W
中科院分区：
文献类型：
--
作者：
Borcherding N;Kusner D;Kolb R;Xie Q;Li W;Yuan F;Velez G;Askeland R;Weigel RJ;Zhang W
目前还不清楚乳腺基底细胞和管腔细胞群之间的旁分泌通讯如何影响肿瘤的发生。在ErbB2诱导的乳腺肿瘤形成过程中，代表基底细胞亚群的丰富的乳腺干细胞与相应的腔前体细胞相比显示出更强的成瘤能力。对基础和腔内肿瘤起始细胞(TIC)来源的肿瘤的转录谱分析显示，在基础TIC来源的肿瘤中，非规范的Wnt配体Wnt5A优先丢失。Wnt5A杂合性缺失与乳腺癌患者的生存期缩短相关。在ErbB2诱导的乳腺癌小鼠模型中，Wnt5a杂合子促进了肿瘤的多样性和肺转移。作为转化生长因子β底物，腔细胞产生的WNT5A以RYK和转化生长因子βR1依赖的方式诱导前馈环激活Smad2，以旁分泌方式限制基础TIC的扩张，这可能是WNT5A在乳腺肿瘤发生中抑制作用的一个潜在解释。我们的结果证实Wnt5A/RYK模块是转化生长因子β/SMAD信号通路在乳腺发育和癌变过程中的空间调节因子，为研究正常乳腺组织中基底腔串扰提供的肿瘤抑制提供了一个新的视角。
It is not well understood how paracrine communication between basal and luminal cell populations in the mammary gland affects tumorigenesis. During ErbB2-induced mammary tumorigenesis, enriched mammary stem cells that represent a subpopulation of basal cells exhibit enhanced tumorigenic capacity compared to the corresponding luminal progenitors. Transcript profiling of tumors derived from basal and luminal tumor-initiating cells (TIC) revealed preferential loss of the noncanonical Wnt ligand WNT5A in basal TIC-derived tumors. Heterozygous loss of WNT5A was correlated with shorter survival of breast cancer patients. In a mouse model of ErbB2-induced breast cancer, Wnt5a heterozygosity promoted tumor multiplicity and pulmonary metastasis. As a TGFβ substrate, luminal cell-produced WNT5A induced a feed-forward loop to activate SMAD2 in a RYK and TGFβR1-dependent manner to limit the expansion of basal TIC in a paracrine fashion, a potential explanation for the suppressive effect of WNT5A in mammary tumorigenesis. Our results identify the WNT5A/RYK module as a spatial regulator of TGFβ/SMAD signaling pathway in the context of mammary gland development and carcinogenesis, offering a new perspective on tumor suppression provided by basal-luminal crosstalk in normal mammary tissue.