<scp>LRP2</scp> Expression in Melanoma Is Associated With a Transitory Cell State, Increased T Cell Infiltration, and Is Upregulated by <scp>IFNy</scp> Signaling
Low density lipoprotein receptor-related protein 2 (LRP2) is a 600 kilodalton multi-ligand endocytic membrane receptor expressed in several cell types during fetal development, including neuroepithelial cells, and in select absorptive epithelial cells in the adult. In epithelial cancers, LRP2 expression is associated with a differentiated tumor cell state and better prognosis. In previous work, we found that while LRP2 is not expressed in benign naevi, it is frequently acquired in melanoma. However, the molecular drivers of LRP2 expression in melanoma and characteristics of LRP2-expressing melanoma have yet to be described. Here, we show that LRP2 expression is related to a transitory melanoma cell state defined by co-expression of melanocyte lineage and neural crest transcriptional programs. Further, we reveal that melanoma LRP2 expression is increased in T cell-inflamed tumors and is directly upregulated through interferon-gamma signaling. Correlation of melanoma LRP2 expression with clinicopathological variables demonstrates that LRP2 expression is associated with low Breslow thickness and low clinical stage in primary melanomas. Taken together, the present study describes the characteristics of LRP2-expressing melanoma and reveals interferon-gamma signaling as a novel strong positive regulator of LRP2 expression in melanoma.
Authors
- Jeanette Bæhr Georgsen (ORCID: https://orcid.org/0000-0002-9452-2920)
- Johann Mar Gudbergsson (ORCID: https://orcid.org/0000-0003-2757-009X)
- Anders Etzerodt (ORCID: https://orcid.org/0000-0002-6757-2068)
- Russell W. Jenkins (ORCID: https://orcid.org/0000-0001-6110-2148)
- Nora Naumann
- Julie N. Christensen
- Marie Louise Bønnelykke‐Behrndtz (ORCID: https://orcid.org/0000-0003-0920-0175)
- Torben Steiniche (ORCID: https://orcid.org/0000-0001-5689-3555)
- Henrik Schmidt (ORCID: https://orcid.org/0000-0003-1080-3344)
- Søren K. Moestrup (ORCID: https://orcid.org/0000-0003-3862-2107)
- Jakob Skou Pedersen (ORCID: https://orcid.org/0000-0002-7236-4001)
- Søren E. Degn (ORCID: https://orcid.org/0000-0001-5409-045X)
- Martin Q. Rasmussen (ORCID: https://orcid.org/0009-0001-6655-1257)
- Mette Madsen (ORCID: https://orcid.org/0000-0001-7241-6505)
- Morten M. Nielsen (ORCID: https://orcid.org/0000-0001-5432-2396)
- Ida Tvilling
- Camilla Merrild (ORCID: https://orcid.org/0009-0009-7978-084X)
Institutions
- Broad Institute (US)
- Harvard University (US)
- Aarhus University (DK)
- Aarhus University Hospital (DK)
- Massachusetts General Hospital (US)
- Center for Systems Biology (US)
Publication Details
- Journal
- Pigment Cell & Melanoma Research
- Published
- 2025-09-01
- DOI
- https://doi.org/10.1111/pcmr.70053
- Primary Topic
- Cell Adhesion Molecules Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Dagmar Marshalls Fond
- Einar Willumsen Foundation
- Arkitekt Holger Hjortenberg og Hustru Dagmar Hjortenbergs Fond
- Aarhus Universitet
- Kræftens Bekæmpelse
- Novo Nordisk
- Dansk Kræftforsknings Fond
- Novo Nordisk Fonden
- Fabrikant Einar Willumsens Mindelegat
- Fonden til Lægevidenskabens Fremme
- Graduate School of Health, University of Technology Sydney