Activation of CD44 signaling in leader cells induced by tumor-associated macrophages drives collective detachment in luminal breast carcinomas.
Activation of CD44 signaling in leader cells induced by tumor-associated macrophages drives collective detachment in luminal breast carcinomas.
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肿瘤相关巨噬细胞诱导的前导细胞中 CD44 信号的激活驱动管腔乳腺癌的集体脱离
DOI：
10.1038/s41419-022-04986-4
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发表时间：
2022-06-09
影响因子：
9
通讯作者：
Yang, Cuixia
中科院分区：
文献类型：
--
作者：
Gao, Feng;Zhang, Guoliang;Liu, Yiwen;He, Yiqing;Sheng, Yumeng;Sun, Xiaodan;Du, Yan;Yang, Cuixia
癌细胞在入侵前沿的集体脱离可以产生有效的转移扩散。然而，癌细胞簇如何从前沿脱落仍然是未知的。我们以前报道过，在乳腺癌（BrCas）的动态表达在集体侵入边缘与肿瘤相关的巨噬细胞（TAMs）。在本研究中，我们首次观察到高表达的CD 44（CD 44 high）癌细胞团位于BrCa循环血管中，并伴有CD 206 + TAM。接下来，我们鉴定了癌细胞簇可以被TAM诱导转化为侵袭性CD 44 high状态，从而引起CD 44相关信号传导介导的内聚脱离。然后，我们使用3D器官型培养和小鼠模型表明，破坏CD 44信号传导抑制TAMs触发的内聚分离。此外，我们的机制研究表明，CD 44 high状态的获得是由TAM释放的CCL 8诱导的MDM 2/p53通路激活介导的。阻断CCL 8可以抑制信号级联反应，从而降低CD 44介导的粘附性脱离和扩散。我们的研究结果揭示了BrCas集体转移的一种新机制，这可能有助于寻找潜在的靶点。
Collective detachment of cancer cells at the invading front could generate efficient metastatic spread. However, how cancer cell clusters shed from the leading front remains unknown. We previously reported that the dynamic expression of CD44 in breast cancers (BrCas) at collectively invading edges was associated with tumor-associated macrophages (TAMs). In this study, we first observed that the highly expressed CD44 (CD44high) cancer cell clusters were located in the BrCa circulating vessels, accompanied by CD206+ TAMs. Next, we identified that the cancer cell clusters can be converted to an invasive CD44high state which was induced by TAMs, thus giving rise to CD44-associated signaling mediated cohesive detachment. Then, we showed that disrupting CD44-signaling inhibited the TAMs triggered cohesive detaching using 3D organotypic culture and mouse models. Furthermore, our mechanistic study showed that the acquisition of CD44high state was mediated by the MDM2/p53 pathway activation which was induced by CCL8 released from TAMs. Blocking of CCL8 could inhibit the signaling cascade which decreased the CD44-mediated cohesive detachment and spread. Our findings uncover a novel mechanism underlying collective metastasis in BrCas that may be helpful to seek for potential targets.
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影响因子：
21.3
作者：
Legg, JW;Lewis, CA;Isacke, CM
通讯作者：
Isacke, CM
影响因子：
28.2
作者：
Liu X;Taftaf R;Kawaguchi M;Chang YF;Chen W;Entenberg D;Zhang Y;Gerratana L;Huang S;Patel DB;Tsui E;Adorno-Cruz V;Chirieleison SM;Cao Y;Harney AS;Patel S;Patsialou A;Shen Y;Avril S;Gilmore HL;Lathia JD;Abbott DW;Cristofanilli M;Condeelis JS;Liu H
通讯作者：
Liu H
肝癌的发生需要通过 CD44 增强的生长因子信号传导抑制 p53
影响因子：
50.3
作者：
Dhar D;Antonucci L;Nakagawa H;Kim JY;Glitzner E;Caruso S;Shalapour S;Yang L;Valasek MA;Lee S;Minnich K;Seki E;Tuckermann J;Sibilia M;Zucman-Rossi J;Karin M
通讯作者：
Karin M
影响因子：
5.7
作者：
Ijuin T;Takeuchi Y;Shimono Y;Fukumoto M;Tokuda E;Takenawa T
通讯作者：
Takenawa T
影响因子：
64.5
作者：
Cheung KJ;Gabrielson E;Werb Z;Ewald AJ
通讯作者：
Ewald AJ