LRP2 Expression in Melanoma Is Associated With a Transitory Cell State, Increased T Cell Infiltration, and Is Upregulated by IFNy Signaling

TY - JOUR

T1 - LRP2 Expression in Melanoma Is Associated With a Transitory Cell State, Increased T Cell Infiltration, and Is Upregulated by IFNy Signaling

AU - Rasmussen, Martin Qvist

AU - Bønnelykke-Behrndtz, Marie Louise

AU - Merrild, Camilla

AU - Tvilling, Ida Kathrine Sneum

AU - Christensen, Julie Nelly

AU - Nielsen, Morten Muhlig

AU - Georgsen, Jeanette Bæhr

AU - Naumann, Nina

AU - Gudbergsson, Johann Mar

AU - Etzerodt, Anders

AU - Pedersen, Jakob Skou

AU - Jenkins, Russell W

AU - Degn, Søren Egedal

AU - Moestrup, Søren Kragh

AU - Schmidt, Henrik

AU - Steiniche, Torben

AU - Madsen, Mette

PY - 2025/9

Y1 - 2025/9

N2 - Low density lipoprotein receptor-related protein 2 (LRP2) is a 600 kilodalton multi-ligand endocytic membrane receptor ex-pressed in several cell types during fetal development, including neuroepithelial cells, and in select absorptive epithelial cellsin the adult. In epithelial cancers, LRP2 expression is associated with a differentiated tumor cell state and better prognosis. Inprevious work, we found that while LRP2 is not expressed in benign naevi, it is frequently acquired in melanoma. However, themolecular 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 lineageand neural crest transcriptional programs. Further, we reveal that melanoma LRP2 expression is increased in T cell-inflamedtumors and is directly upregulated through interferon-gamma signaling. Correlation of melanoma LRP2 expression with clin-icopathological variables demonstrates that LRP2 expression is associated with low Breslow thickness and low clinical stage inprimary melanomas. Taken together, the present study describes the characteristics of LRP2- expressing melanoma and revealsinterferon-gamma signaling as a novel strong positive regulator of LRP2 expression in melanoma.

AB - Low density lipoprotein receptor-related protein 2 (LRP2) is a 600 kilodalton multi-ligand endocytic membrane receptor ex-pressed in several cell types during fetal development, including neuroepithelial cells, and in select absorptive epithelial cellsin the adult. In epithelial cancers, LRP2 expression is associated with a differentiated tumor cell state and better prognosis. Inprevious work, we found that while LRP2 is not expressed in benign naevi, it is frequently acquired in melanoma. However, themolecular 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 lineageand neural crest transcriptional programs. Further, we reveal that melanoma LRP2 expression is increased in T cell-inflamedtumors and is directly upregulated through interferon-gamma signaling. Correlation of melanoma LRP2 expression with clin-icopathological variables demonstrates that LRP2 expression is associated with low Breslow thickness and low clinical stage inprimary melanomas. Taken together, the present study describes the characteristics of LRP2- expressing melanoma and revealsinterferon-gamma signaling as a novel strong positive regulator of LRP2 expression in melanoma.

KW - LRP2

KW - differentiation

KW - epigenetics

KW - inflammation

KW - interferon

KW - megalin

KW - melanoma

UR - https://www.scopus.com/pages/publications/105015542264

U2 - 10.1111/pcmr.70053

DO - 10.1111/pcmr.70053

M3 - Journal article

C2 - 40913277

SN - 1755-1471

VL - 38

JO - Pigment Cell & Melanoma Research

JF - Pigment Cell & Melanoma Research

IS - 5

M1 - e70053

ER -