Cancer Cell CD44 Mediates Macrophage/Monocyte-Driven Regulation of Head and Neck Cancer Stem Cells.
Cancer Cell CD44 Mediates Macrophage/Monocyte-Driven Regulation of Head and Neck Cancer Stem Cells.
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DOI：
10.1158/0008-5472.can-20-1079
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发表时间：
2020-10-01
期刊：
影响因子：
11.2
通讯作者：
Jimeno A
中科院分区：
文献类型：
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作者：
Gomez KE;Wu F;Keysar SB;Morton JJ;Miller B;Chimed TS;Le PN;Nieto C;Chowdhury FN;Tyagi A;Lyons TR;Young CD;Zhou H;Somerset HL;Wang XJ;Jimeno A
肿瘤微环境（TME）中的肿瘤相关巨噬细胞（TAM）与癌症干细胞（CSC）合作以维持干性。我们最近确定了CD 44作为定义头颈部鳞状细胞癌（HNSCC）CSC的表面标志物。PI 3 K-4 EBP 1-SOX 2激活和信号转导调节CSC特性，但该途径的上游分子控制以及HNSCC中TAM和CSC之间的潜在串扰机制仍在很大程度上未知。由于CD 44是TME中的分子介导剂，我们在此提出TAM影响的CD 44信号传导可以通过PI 3 K-4 EBP 1-SOX 2途径介导干性，可能是通过调节主要的CD 44配体透明质酸（HA）的可用性。使用HNSCC IHC鉴定TAM/CSC关系，并使用体外共培养球体模型和体内小鼠模型鉴定TAM通过CD 44对CSC功能的影响。患者HNSCC来源的TAM分别与非侵入性和侵入性边缘区域的CSC标志物表达呈正相关和负相关。TAM增加HA的可用性并增加癌细胞侵袭。HA与CD 44的结合增加了PI 3 K-4 EBP 1-SOX 2信号传导和CSC分数，而CD 44-VCAM-1结合促进了Ezrin/PI 3 K的侵袭性信号传导。在体内，靶向CD 44降低了PI 3 K-4 EBP 1-SOX 2信号传导、肿瘤生长和CSC。同基因和人源化小鼠模型中的TAM消耗也减少了生长和CSC数量。最后，CD 44亚型转换调节上皮-间充质可塑性，因为CD 44 s和CD 44 v8 -10分别决定了侵袭性和致瘤性表型。我们已经建立了TAM和CSC在HNSCC中的机制联系，该机制联系由响应于细胞外信号的CD 44细胞内信号传导介导。
Tumor-associated macrophages (TAM) in the tumor microenvironment (TME) cooperate with cancer stem cells (CSC) to maintain stemness. We recently identified CD44 as a surface marker defining head and neck squamous cell carcinoma (HNSCC) CSC. PI3K-4EBP1-SOX2 activation and signaling regulate CSC properties, yet the upstream molecular control of this pathway and the mechanisms underlying crosstalk between TAM and CSC in HNSCC remain largely unknown. Because CD44 is a molecular mediator in the TME, we propose here that TAM-influenced CD44 signaling could mediate stemness via the PI3K-4EBP1-SOX2 pathway, possibly by modulating availability of hyaluronic acid (HA), the main CD44 ligand. HNSCC IHC was used to identify TAM/CSC relationships, and in vitro co-culture spheroid models and in vivo mouse models were used to identify the influence of TAM on CSC function via CD44. Patient HNSCC-derived TAM were positively and negatively associated with CSC marker expression at non-invasive and invasive edge regions, respectively. TAM increased availability of HA and increased cancer cell invasion. HA binding to CD44 increased PI3K-4EBP1-SOX2 signaling and the CSC fraction, whereas CD44-VCAM-1 binding promoted invasive signaling by Ezrin/PI3K. In vivo, targeting CD44 decreased PI3K-4EBP1-SOX2 signaling, tumor growth, and CSC. TAM depletion in syngeneic and humanized mouse models also diminished growth and CSC numbers. Lastly, a CD44 isoform switch regulated epithelial-to-mesenchymal plasticity as CD44s and CD44v8-10 determined invasive and tumorigenic phenotypes, respectively. We have established a mechanistic link between TAM and CSC in HNSCC that is mediated by CD44 intracellular signaling in response to extracellular signals.