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LRIG1 is a conserved EGFR regulator involved in melanoma development, survival and treatment resistance
Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.ORCID iD: 0000-0001-5824-6263
Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery. Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.ORCID iD: 0000-0001-6891-6996
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2021 (English)In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 40, p. 3707-3718Article in journal (Refereed) Published
Abstract [en]

Leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) is a pan-negative regulator of receptor tyrosine kinase (RTK) signaling and a tumor suppressor in several cancers, but its involvement in melanoma is largely unexplored. Here, we aim to determine the role of LRIG1 in melanoma tumorigenesis, RTK signaling, and BRAF inhibitor resistance. We find that LRIG1 is downregulated during early tumorigenesis and that LRIG1 affects activation of the epidermal growth factor receptor (EGFR) in melanoma cells. LRIG1-dependent regulation of EGFR signaling is evolutionary conserved to the roundworm C. elegans, where negative regulation of the EGFR-Ras-Raf pathway by sma-10/LRIG completely depends on presence of the receptor let-23/EGFR. In a cohort of metastatic melanoma patients, we observe an association between LRIG1 and survival in the triple wild-type subtype and in tumors with high EGFR expression. During in vitro development of BRAF inhibitor resistance, LRIG1 expression decreases; and mimics LRIG1 knockout cells for increased EGFR expression. Treating resistant cells with recombinant LRIG1 suppresses AKT activation and proliferation. Together, our results show that sma-10/LRIG is a conserved regulator of RTK signaling, add to our understanding of LRIG1 in melanoma and identifies recombinant LRIG1 as a potential therapeutic against BRAF inhibitor-resistant melanoma.

Place, publisher, year, edition, pages
Springer Nature, 2021. Vol. 40, p. 3707-3718
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Surgery Cancer and Oncology
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URN: urn:nbn:se:umu:diva-182828DOI: 10.1038/s41388-021-01808-3ISI: 000647099200001PubMedID: 33947959Scopus ID: 2-s2.0-85105305447OAI: oai:DiVA.org:umu-182828DiVA, id: diva2:1552742
Available from: 2021-05-06 Created: 2021-05-06 Last updated: 2024-04-18Bibliographically approved

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Billing, OlaHolmgren, YlvaNosek, DanielHedman, HåkanHemmingsson, Oskar

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