Inducible formation of leader cells driven by CD44 switching gives rise to collective invasion and metastases in luminal breast carcinomas
Inducible formation of leader cells driven by CD44 switching gives rise to collective invasion and metastases in luminal breast carcinomas
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由 CD44 转换驱动的前导细胞的诱导形成导致管腔乳腺癌的集体侵袭和转移
DOI：
10.1038/s41388-019-0899-y
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发表时间：
2019-11-14
期刊：
影响因子：
8
通讯作者：
Gao, Feng
中科院分区：
文献类型：
--
作者：
Yang, Cuixia;Cao, Manlin;Gao, Feng
集体侵袭邻近组织是腔内乳腺癌的一个特征，大约20%的病例最终会发生转移。目前尚不清楚侵袭性较弱的腔状型乳腺癌如何转变为浸润性癌症。我们的研究表明，CD44(Hi)癌细胞是集体侵袭腔癌细胞的主要亚群，并有效地促进CD44(Lo)/跟随细胞的集体侵袭。CD44(Hi)/Leader亚群表现出不同于CD44(Lo)/追随者细胞的多种杂合上皮/间充质基因的特异性基因特征和集体侵袭的关键功能共调节因子。然而，CD44(Hi)/Leader细胞表现为部分上皮-间充质转化(EMT)表型，随着集体迁移很容易转变为CD44(Lo)表型，反之亦然；这种现象是自发的，对肿瘤微环境敏感。CD44(Lo)到CD44(Hi)的转换伴随着CD44s到CD44v的转换，但非癌症干细胞到癌症干细胞(CSCs)的转换并不伴随。因此，目前发现的CD44(Hi)领导细胞在乳腺肿瘤中并不是一个稳定的亚群。这种可塑性和产生CD44(Hi)癌细胞的能力增强了迁移和侵袭行为，这可能是管腔型乳腺癌从原位向侵袭行为转变的原因。
Collective invasion into adjacent tissue is a hallmark of luminal breast cancer, and similar to 20% of these cases eventually undergo metastasis. How less aggressive luminal-like breast cancer transitions to invasive cancer remains unclear. Our study revealed that CD44(hi) cancer cells are the leading subpopulation in collectively invading luminal cancer cells and efficiently promote the collective invasion of CD44(lo)/follower cells. The CD44(hi)/leader subpopulation showed a specific gene signature of various hybrid epithelial/mesenchymal genes and key functional coregulators of collective invasion, which was distinct from that of CD44(lo)/follower cells. However, the CD44(hi)/leader cells, which showed a partial epithelial-mesenchymal transition (EMT) phenotype, readily switched to the CD44(lo) phenotype along with collective migration and vice versa; this phenomenon was spontaneous and sensitive to the tumor microenvironment. The CD44(lo)-to-CD44(hi) conversion was accompanied by a shift in CD44s to CD44v but not a conversion of non-cancer stem cells to cancer stem cells (CSCs). Therefore, the CD44(hi) leader cells, as currently identified, are not a stable subpopulation in breast tumors. This plasticity and ability to generate CD44(hi) carcinoma cells with enhanced migratory and invasive behavior might be responsible for the transition from in situ to invasive behavior of luminal-type breast cancer.