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Hair eruption initiates and commensal skin microbiota aggravate adverse events of anti-EGFR therapy


Klufa, Jörg; Bauer, Thomas; Hanson, Buck; Herbold, Craig; Starkl, Philipp; Lichtenberger, Beate; Srutkova, Dagmar; Schulz, Daniel; Vujic, Igor; Mohr, Thomas; Rappersberger, Klemens; Bodenmiller, Bernd; Kozakova, Hana; Knapp, Sylvia; Loy, Alexander; Sibilia, Maria (2019). Hair eruption initiates and commensal skin microbiota aggravate adverse events of anti-EGFR therapy. Science Translational Medicine, 11(522):eaax2693.

Abstract

Epidermal growth factor receptor (EGFR)–targeted anticancer therapy induces stigmatizing skin toxicities affecting patients’ quality of life and therapy adherence. The lack of mechanistic details underlying these adverse events hampers their management. We found that EGFR/ERK signaling is required in LRIG1-positive stem cells during de novo hair eruption to secure barrier integrity and prevent the invasion of commensal microbiota and inflammatory skin disease. EGFR-deficient epidermis is permissive for microbiota outgrowth and displays an atopic-like T<jats:sub>H</jats:sub>2-dominated signature. The opening of the follicular ostia during hair eruption allows invasion of commensal microbiota into the hair follicle, initiating an additional T<jats:sub>H</jats:sub>1 and T<jats:sub>H</jats:sub>17 response culminating in chronic folliculitis. Restoration of epidermal ERK signaling via prophylactic FGF7 treatment or transgenic SOS expression rescues the barrier defect in the absence of EGFR, highlighting a therapeutic anchor point. These data reveal that commensal skin microbiota provoke atopic-like inflammatory skin diseases by invading into the follicular opening of erupting hair.

Abstract

Epidermal growth factor receptor (EGFR)–targeted anticancer therapy induces stigmatizing skin toxicities affecting patients’ quality of life and therapy adherence. The lack of mechanistic details underlying these adverse events hampers their management. We found that EGFR/ERK signaling is required in LRIG1-positive stem cells during de novo hair eruption to secure barrier integrity and prevent the invasion of commensal microbiota and inflammatory skin disease. EGFR-deficient epidermis is permissive for microbiota outgrowth and displays an atopic-like T<jats:sub>H</jats:sub>2-dominated signature. The opening of the follicular ostia during hair eruption allows invasion of commensal microbiota into the hair follicle, initiating an additional T<jats:sub>H</jats:sub>1 and T<jats:sub>H</jats:sub>17 response culminating in chronic folliculitis. Restoration of epidermal ERK signaling via prophylactic FGF7 treatment or transgenic SOS expression rescues the barrier defect in the absence of EGFR, highlighting a therapeutic anchor point. These data reveal that commensal skin microbiota provoke atopic-like inflammatory skin diseases by invading into the follicular opening of erupting hair.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:07 Faculty of Science > Department of Quantitative Biomedicine
Dewey Decimal Classification:610 Medicine & health
Scopus Subject Areas:Health Sciences > General Medicine
Uncontrolled Keywords:General Medicine
Language:English
Date:11 December 2019
Deposited On:07 Feb 2020 10:11
Last Modified:29 Jul 2020 13:42
Publisher:American Association for the Advancement of Science
ISSN:1946-6234
OA Status:Closed
Publisher DOI:https://doi.org/10.1126/scitranslmed.aax2693
PubMed ID:31826981

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