Dysfunctional EGFR and oxidative stress-induced PKD1 signaling drive formation of DCLK1+ pancreatic stem cells.

Autor:	Fleming Martinez AK; Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Mayo Clinic, Jacksonville, FL 32224, USA., Döppler HR; Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Mayo Clinic, Jacksonville, FL 32224, USA., Bastea LI; Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Mayo Clinic, Jacksonville, FL 32224, USA., Edenfield B; Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Mayo Clinic, Jacksonville, FL 32224, USA., Patel T; Department of Transplantation, Mayo Clinic Comprehensive Cancer Center, Mayo Clinic, Jacksonville, FL 32224, USA., Leitges M; Division of Biomedical Sciences/Faculty of Medicine, Craig L Dobbin Genetics Research Centre, Memorial University of Newfoundland, St. John`s, Newfoundland A1B 3V6, Canada., Liou GY; Department of Biological Sciences, Center for Cancer Research & Therapeutic Development, Clark Atlanta University, Atlanta, GA 30314, USA., Storz P; Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Mayo Clinic, Jacksonville, FL 32224, USA.
Jazyk:	angličtina
Zdroj:	IScience [iScience] 2021 Jan 05; Vol. 24 (1), pp. 102019. Date of Electronic Publication: 2021 Jan 05 (Print Publication: 2021).
DOI:	10.1016/j.isci.2020.102019
Abstrakt:	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 p48 cre ;Kras G12D 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. Competing Interests: The authors declare no competing interests. (© 2020 The Author(s).)
Databáze:	MEDLINE
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