文章基本信息

标题：Dysfunctional EGFR and oxidative stress-induced PKD1 signaling drive formation of DCLK1+ pancreatic stem cells
本地全文：下载
作者：Alicia K. Fleming Martinez ; Heike R. Döppler ; Ligia I. Bastea 等
期刊名称：iScience
印刷版ISSN：2589-0042
出版年度：2021
卷号：24
期号：1
页码：1-27
DOI：10.1016/j.isci.2020.102019
语种：English
出版社：Elsevier
摘要：SummaryDoublecortin-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;KrasG12Dmice 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.Graphical AbstractDisplay OmittedFor a Figure360 author presentation of this figure, seehttps://doi.org/10.1016/j.isci.2020.102019.Highlights•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 PKD1Cell Biology; Stem Cell Research; Cancer