Stromal lipid species dictate melanoma metastasis and tropism

Shilpa Gurung; Timothy Budden; Karthik Mallela; Benjamin Jenkins; Alex von Kriegsheim; Esperanza Manrique; David Millán-Esteban; Isabel Romero-Camarero; Fabio Amaral; Sarah Craig; Pedro Durao; Joanna Pozniak; Laura Stennett; Duncan Smith; Garry Ashton; Alex Baker; Kang Zeng; Gilbert Fruhwirth; Victoria Sanz-Moreno; Jair Marques; Albert Koulman; Jean Christophe Marine; Tim C.P. Somervaille; Luisa Motta; Caroline Gaudy-Marqueste; Eduardo Nagore; Amaya Virós

doi:10.1016/j.ccell.2025.04.001

Stromal lipid species dictate melanoma metastasis and tropism

Shilpa Gurung, Timothy Budden, Karthik Mallela, Benjamin Jenkins, Alex von Kriegsheim, Esperanza Manrique, David Millán-Esteban, Isabel Romero-Camarero, Fabio Amaral, Sarah Craig, Pedro Durao, Joanna Pozniak, Laura Stennett, Duncan Smith, Garry Ashton, Alex Baker, Kang Zeng, Gilbert Fruhwirth, Victoria Sanz-Moreno, Jair MarquesAlbert Koulman, Jean Christophe Marine, Tim C.P. Somervaille, Luisa Motta, Caroline Gaudy-Marqueste, Eduardo Nagore, Amaya Virós^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

1 Citation (Scopus)

Abstract

Cancer cells adapt to signals in the tumor microenvironment (TME), but the TME cues that impact metastasis and tropism are still incompletely understood. We show that abundant stromal lipids from young subcutaneous adipocytes, including phosphatidylcholines, are taken up by melanoma cells, where they upregulate melanoma PI3K-AKT signaling, fatty acid oxidation, oxidative phosphorylation (OXPHOS) leading to oxidative stress, resulting in decreased metastatic burden. High OXPHOS melanoma cells predominantly seed the lung and brain; decreasing oxidative stress with antioxidants shifts tropism from the lung to the liver. By contrast, the aged TME provides fewer total lipids but is rich in ceramides, leading to lower OXPHOS and high metastatic burden. Aged TME ceramides taken up by melanoma cells activate the S1P-STAT3-IL-6 signaling axis and promote liver tropism. Inhibiting OXPHOS in the young TME or blocking the IL-6 receptor in the aged TME reduces the age-specific patterns of metastasis imposed by lipid availability.

Original language	English
Article number	DOI: 10.1016/j.ccell.2025.04.001
Pages (from-to)	1108-1124.e11
Journal	CANCER CELL
Volume	43
Issue number	6
DOIs	https://doi.org/10.1016/j.ccell.2025.04.001
Publication status	Published - 24 Apr 2025

Keywords

aged skin
aging
lipid metabolism
liver tropism
melanoma
melanoma metastasis
metastasis
oxidative stress
OXPHOS
tropism

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ccell.2025.04.001

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Gurung, S., Budden, T., Mallela, K., Jenkins, B., von Kriegsheim, A., Manrique, E., Millán-Esteban, D., Romero-Camarero, I., Amaral, F., Craig, S., Durao, P., Pozniak, J., Stennett, L., Smith, D., Ashton, G., Baker, A., Zeng, K., Fruhwirth, G., Sanz-Moreno, V., ... Virós, A. (2025). Stromal lipid species dictate melanoma metastasis and tropism. CANCER CELL, 43(6), 1108-1124.e11. Article DOI: 10.1016/j.ccell.2025.04.001. https://doi.org/10.1016/j.ccell.2025.04.001

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title = "Stromal lipid species dictate melanoma metastasis and tropism",

abstract = "Cancer cells adapt to signals in the tumor microenvironment (TME), but the TME cues that impact metastasis and tropism are still incompletely understood. We show that abundant stromal lipids from young subcutaneous adipocytes, including phosphatidylcholines, are taken up by melanoma cells, where they upregulate melanoma PI3K-AKT signaling, fatty acid oxidation, oxidative phosphorylation (OXPHOS) leading to oxidative stress, resulting in decreased metastatic burden. High OXPHOS melanoma cells predominantly seed the lung and brain; decreasing oxidative stress with antioxidants shifts tropism from the lung to the liver. By contrast, the aged TME provides fewer total lipids but is rich in ceramides, leading to lower OXPHOS and high metastatic burden. Aged TME ceramides taken up by melanoma cells activate the S1P-STAT3-IL-6 signaling axis and promote liver tropism. Inhibiting OXPHOS in the young TME or blocking the IL-6 receptor in the aged TME reduces the age-specific patterns of metastasis imposed by lipid availability.",

keywords = "aged skin, aging, lipid metabolism, liver tropism, melanoma, melanoma metastasis, metastasis, oxidative stress, OXPHOS, tropism",

author = "Shilpa Gurung and Timothy Budden and Karthik Mallela and Benjamin Jenkins and {von Kriegsheim}, Alex and Esperanza Manrique and David Mill{\'a}n-Esteban and Isabel Romero-Camarero and Fabio Amaral and Sarah Craig and Pedro Durao and Joanna Pozniak and Laura Stennett and Duncan Smith and Garry Ashton and Alex Baker and Kang Zeng and Gilbert Fruhwirth and Victoria Sanz-Moreno and Jair Marques and Albert Koulman and Marine, {Jean Christophe} and Somervaille, {Tim C.P.} and Luisa Motta and Caroline Gaudy-Marqueste and Eduardo Nagore and Amaya Vir{\'o}s",

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doi = "10.1016/j.ccell.2025.04.001",

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Gurung, S, Budden, T, Mallela, K, Jenkins, B, von Kriegsheim, A, Manrique, E, Millán-Esteban, D, Romero-Camarero, I, Amaral, F, Craig, S, Durao, P, Pozniak, J, Stennett, L, Smith, D, Ashton, G, Baker, A, Zeng, K, Fruhwirth, G, Sanz-Moreno, V, Marques, J, Koulman, A, Marine, JC, Somervaille, TCP, Motta, L, Gaudy-Marqueste, C, Nagore, E & Virós, A 2025, 'Stromal lipid species dictate melanoma metastasis and tropism', CANCER CELL, vol. 43, no. 6, DOI: 10.1016/j.ccell.2025.04.001, pp. 1108-1124.e11. https://doi.org/10.1016/j.ccell.2025.04.001

TY - JOUR

T1 - Stromal lipid species dictate melanoma metastasis and tropism

AU - Gurung, Shilpa

AU - Budden, Timothy

AU - Mallela, Karthik

AU - Jenkins, Benjamin

AU - von Kriegsheim, Alex

AU - Manrique, Esperanza

AU - Millán-Esteban, David

AU - Romero-Camarero, Isabel

AU - Amaral, Fabio

AU - Craig, Sarah

AU - Durao, Pedro

AU - Pozniak, Joanna

AU - Stennett, Laura

AU - Smith, Duncan

AU - Ashton, Garry

AU - Baker, Alex

AU - Zeng, Kang

AU - Fruhwirth, Gilbert

AU - Sanz-Moreno, Victoria

AU - Marques, Jair

AU - Koulman, Albert

AU - Marine, Jean Christophe

AU - Somervaille, Tim C.P.

AU - Motta, Luisa

AU - Gaudy-Marqueste, Caroline

AU - Nagore, Eduardo

AU - Virós, Amaya

PY - 2025/4/24

Y1 - 2025/4/24

N2 - Cancer cells adapt to signals in the tumor microenvironment (TME), but the TME cues that impact metastasis and tropism are still incompletely understood. We show that abundant stromal lipids from young subcutaneous adipocytes, including phosphatidylcholines, are taken up by melanoma cells, where they upregulate melanoma PI3K-AKT signaling, fatty acid oxidation, oxidative phosphorylation (OXPHOS) leading to oxidative stress, resulting in decreased metastatic burden. High OXPHOS melanoma cells predominantly seed the lung and brain; decreasing oxidative stress with antioxidants shifts tropism from the lung to the liver. By contrast, the aged TME provides fewer total lipids but is rich in ceramides, leading to lower OXPHOS and high metastatic burden. Aged TME ceramides taken up by melanoma cells activate the S1P-STAT3-IL-6 signaling axis and promote liver tropism. Inhibiting OXPHOS in the young TME or blocking the IL-6 receptor in the aged TME reduces the age-specific patterns of metastasis imposed by lipid availability.

AB - Cancer cells adapt to signals in the tumor microenvironment (TME), but the TME cues that impact metastasis and tropism are still incompletely understood. We show that abundant stromal lipids from young subcutaneous adipocytes, including phosphatidylcholines, are taken up by melanoma cells, where they upregulate melanoma PI3K-AKT signaling, fatty acid oxidation, oxidative phosphorylation (OXPHOS) leading to oxidative stress, resulting in decreased metastatic burden. High OXPHOS melanoma cells predominantly seed the lung and brain; decreasing oxidative stress with antioxidants shifts tropism from the lung to the liver. By contrast, the aged TME provides fewer total lipids but is rich in ceramides, leading to lower OXPHOS and high metastatic burden. Aged TME ceramides taken up by melanoma cells activate the S1P-STAT3-IL-6 signaling axis and promote liver tropism. Inhibiting OXPHOS in the young TME or blocking the IL-6 receptor in the aged TME reduces the age-specific patterns of metastasis imposed by lipid availability.

KW - aged skin

KW - aging

KW - lipid metabolism

KW - liver tropism

KW - melanoma

KW - melanoma metastasis

KW - metastasis

KW - oxidative stress

KW - OXPHOS

KW - tropism

UR - http://www.scopus.com/inward/record.url?scp=105003541173&partnerID=8YFLogxK

U2 - 10.1016/j.ccell.2025.04.001

DO - 10.1016/j.ccell.2025.04.001

M3 - Article

AN - SCOPUS:105003541173

SN - 1535-6108

VL - 43

SP - 1108-1124.e11

JO - CANCER CELL

JF - CANCER CELL

IS - 6

M1 - DOI: 10.1016/j.ccell.2025.04.001

ER -

Stromal lipid species dictate melanoma metastasis and tropism

Abstract

Keywords

UN SDGs

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