Dysfunctional EGFR and oxidative stress-induced PKD1 signaling drive formation of DCLK1+ pancreatic stem cells.
Dysfunctional EGFR and oxidative stress-induced PKD1 signaling drive formation of DCLK1+ pancreatic stem cells.
复制标题
DOI：
10.1016/j.isci.2020.102019
复制
发表时间：
2021-01-22
期刊：
影响因子：
5.8
通讯作者：
Storz P
中科院分区：
文献类型：
--
作者：
Fleming Martinez AK;Döppler HR;Bastea LI;Edenfield B;Patel T;Leitges M;Liou GY;Storz P
双皮质素样激酶 1 (DCLK1) 阳性的胰腺癌干细胞在癌前阶段发育，可能导致胰腺癌治疗缺乏疗效。尽管 PanIN 细胞表达致癌 KRas 并且表皮生长因子受体 (EGFR) 活性增加，但我们证明，在 DCLK1+ PanIN 细胞中，EGFR 信号传导不会传播到细胞核。在 PanIN 类器官培养物或 p48cre;KrasG12D 小鼠中模拟厄洛替尼阻断 EGFR 导致 DCLK1+ PanIN 细胞显着增加。作为 EGFR 抑制导致 DCLK1+ 细胞形成的机制，我们发现过氧化氢的增加有助于激活蛋白激酶 D1 (PKD1)。然后，活跃的 PKD1 驱动病变中 DCLK1+ 细胞的干性和丰度。我们的数据表明了一种导致 DCLK1+ 胰腺癌干细胞发育的信号机制，可用于在潜在的治疗方法中针对该人群。有关此图的Figure360 作者演示，请参阅 https://doi.org/10.1016/j.isci.2020.102019。 DCLK1+ PanIN 细胞消除了 EGFR 信号传导并增加了氧化应激 抑制 EGFR 信号传导会增加 DCLK1+ 细胞、氧化应激和 PKD1 PKD1 有助于 PanIN 病变中 DCLK1+ 干细胞的丰度 PKD1 会增加干细胞标记物，包括 OCT4 和 CD133；干细胞研究；癌症
Doublecortin-like kinase 1 (DCLK1)-positive pancreatic cancer stem cells develop at a precancerous stage and may contribute to the lack of efficacy of pancreatic cancer therapy. Although PanIN cells express oncogenic KRas and have an increased activity of epidermal growth factor receptor (EGFR), we demonstrate that, in DCLK1+ PanIN cells, EGFR signaling is not propagated to the nucleus. Mimicking blockage of EGFR with erlotinib in PanIN organoid culture or in p48cre;KrasG12D mice led to a significant increase in DCLK1+ PanIN cells. As a mechanism of how EGFR inhibition leads to formation of DCLK1+ cells, we identify an increase in hydrogen peroxide contributing to activation of Protein Kinase D1 (PKD1). Active PKD1 then drives stemness and abundance of DCLK1+ cells in lesions. Our data suggest a signaling mechanism that leads to the development of DCLK1+ pancreatic cancer stem cells, which can be exploited to target this population in potential therapeutic approaches. For a Figure360 author presentation of this figure, see https://doi.org/10.1016/j.isci.2020.102019. DCLK1+ PanIN cells have abrogated EGFR signaling and increased oxidative stress Inhibition of EGFR signaling increases DCLK1+ cells, oxidative stress, and PKD1 PKD1 contributes to the abundance of DCLK1+ stem cells in PanIN lesions Stem cell markers, including OCT4 and CD133, are increased by PKD1 Cell Biology; Stem Cell Research; Cancer
登录
查看更多内容
影响因子：
9.2
作者：
Reed, Nathan A.;Cai, Dawen;Verhey, Kristen J.
通讯作者：
Verhey, Kristen J.
影响因子：
3.7
作者：
Qu D;Johnson J;Chandrakesan P;Weygant N;May R;Aiello N;Rhim A;Zhao L;Zheng W;Lightfoot S;Pant S;Irvan J;Postier R;Hocker J;Hanas JS;Ali N;Sureban SM;An G;Schlosser MJ;Stanger B;Houchen CW
通讯作者：
Houchen CW
簇细胞，味觉化学细胞，在肠道中编排寄生虫2型免疫力。
DOI：
10.1126/science.aaf1648
发表时间：
2016-03-18
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Howitt MR;Lavoie S;Michaud M;Blum AM;Tran SV;Weinstock JV;Gallini CA;Redding K;Margolskee RF;Osborne LC;Artis D;Garrett WS
通讯作者：
Garrett WS
蛋白激酶D1驱动胰腺腺泡细胞重编程和进展到上皮内肿瘤。
影响因子：
16.6
作者：
Liou, Geou-Yarh;Doeppler, Heike;Braun, Ursula B.;Panayiotou, Richard;Buzhardt, Michele Scotti;Radisky, Derek C.;Crawford, Howard C.;Fields, Alan P.;Murray, Nicole R.;Wang, Q. Jane;Leitges, Michael;Storz, Peter
通讯作者：
Storz, Peter
影响因子：
11.2
作者：
Li, Chenwei;Heidt, David G.;Simeone, Diane M.
通讯作者：
Simeone, Diane M.