DNA Damage Promotes Epithelial Hyperplasia and Fate Mis-specification via Fibroblast Inflammasome Activation
Copyright © 2020 Elsevier Inc. All rights reserved..
DNA crosslinking agents are commonly used in cancer chemotherapy; however, responses of normal tissues to these agents have not been widely investigated. We reveal in mouse interfollicular epidermal, mammary and hair follicle epithelia that genotoxicity does not promote apoptosis but paradoxically induces hyperplasia and fate specification defects in quiescent stem cells. DNA damage to skin causes epithelial and dermal hyperplasia, tissue expansion, and proliferation-independent formation of abnormal K14/K10 dual-positive suprabasal cells. Unexpectedly, this behavior is epithelial cell non-autonomous and independent of an intact immune system. Instead, dermal fibroblasts are both necessary and sufficient to induce the epithelial response, which is mediated by activation of a fibroblast-specific NLRP3 inflammasome and subsequent IL-1β production. Thus, genotoxic agents that are used chemotherapeutically to promote cancer cell death can have the opposite effect on wild-type epithelia by inducing, via a non-autonomous IL-1β-driven mechanism, both hyperplasia and stem cell lineage defects.
| Errataetall: |
CommentIn: Dev Cell. 2020 Dec 7;55(5):515-517. - PMID 33290689 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:55 |
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| Enthalten in: |
Developmental cell - 55(2020), 5 vom: 07. Dez., Seite 558-573.e6 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Seldin, Lindsey [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 11.03.2021 Date Revised 30.03.2024 published: Print-Electronic CommentIn: Dev Cell. 2020 Dec 7;55(5):515-517. - PMID 33290689 Citation Status MEDLINE |
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| doi: |
10.1016/j.devcel.2020.09.021 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM316283185 |
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| 520 | |a DNA crosslinking agents are commonly used in cancer chemotherapy; however, responses of normal tissues to these agents have not been widely investigated. We reveal in mouse interfollicular epidermal, mammary and hair follicle epithelia that genotoxicity does not promote apoptosis but paradoxically induces hyperplasia and fate specification defects in quiescent stem cells. DNA damage to skin causes epithelial and dermal hyperplasia, tissue expansion, and proliferation-independent formation of abnormal K14/K10 dual-positive suprabasal cells. Unexpectedly, this behavior is epithelial cell non-autonomous and independent of an intact immune system. Instead, dermal fibroblasts are both necessary and sufficient to induce the epithelial response, which is mediated by activation of a fibroblast-specific NLRP3 inflammasome and subsequent IL-1β production. Thus, genotoxic agents that are used chemotherapeutically to promote cancer cell death can have the opposite effect on wild-type epithelia by inducing, via a non-autonomous IL-1β-driven mechanism, both hyperplasia and stem cell lineage defects | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a DNA damage | |
| 650 | 4 | |a IL-1β | |
| 650 | 4 | |a chemotherapy | |
| 650 | 4 | |a epidermis | |
| 650 | 4 | |a hair follicle | |
| 650 | 4 | |a hyperplasia | |
| 650 | 4 | |a inflammasome | |
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