Stromal lipid species dictate melanoma metastasis and tropism
Shilpa Gurung, Timothy Budden, Karthik Mallela, Benjamin H. Jenkins, Alex von Kriegsheim, Esperanza Manrique, David Millán-Esteban, Isabel Romero-Camarero, Fabio M. R. Amaral, Sarah Craig, Pedro Durao, Joanna Poźniak, Laura Stennett, Duncan L. Smith, Garry Ashton, Alex R. Baker, Kang Zeng, Gilbert O. Fruhwirth, Victoria Sanz‐Moreno, Jair Marques, Albert Koulman, Jean‐Christophe Marine, Tim C. P. Somervaille, Luisa Motta, Caroline Gaudy‐Marqueste, Eduardo Nagore, Amaya Virós
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.