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Stromal lipid species dictate melanoma metastasis and tropism [MFP_RNA_seq]

ABSTRACT: Cancer cells adapt to signals in the tumor microenvironment (TME), but the TME cues that impact metastasis and tropism are unknown. We show that stromal lipids from young adipocytes are taken up by melanoma cells, and lipids increase melanoma oxidative phosphorylation (OXPHOS) and oxidative stress, which decreases metastatic burden. In contrast, the aged TME provides fewer lipids, leading to lower OXPHOS and higher metastatic capacity. Young adipocytes transfer phosphatidylcholine (PC) to melanoma cells, where PC upregulates PI3K/AKT and mitochondrial OXPHOS. Melanoma cells with high OXPHOS predominantly seed the lung and brain, but do not colonise the liver, and decreasing oxidative stress with antioxidant supplements shifts tropism from the lung to the liver. In contrast, although the aged stroma has fewer total lipids, it has more ceramides, which activate the S1P/STAT3/IL6 signalling axis to direct melanoma liver tropism. Inhibiting OXPHOS in the young stroma and blocking IL6 receptor in the aged stroma reduces the age-specific patterns of metastasis imposed by stromal lipids.

ORGANISM(S): Mus musculus

PROVIDER: GSE292629 | GEO | 2025/03/26

REPOSITORIES: GEO

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Project description:Advancing age is associated with substantial increases in the incidence rates of common diseases affecting the prostate including benign prostatic hyperplasia (BPH) and prostate carcinoma. However, to date, there is no established molecular explanation for the age-dependent increases in these pathologies. The prostate is comprised of a functional secretory epithelium supported by a spectrum of cell types and structural elements comprising the stroma. As reciprocal interactions between epithelium and stromal constituents are essential for normal organogenesis and serve to maintain normal functions, discordance within the stromal could permit or promote disease processes. In this study we sought to identify aging-associated alterations in the mouse prostate that could influence pathology. We quantitated transcript levels in microdissected periglandular stroma from young (4 month-old) and old (20-24 month-old) C57BL/6 mice, and identified a significant change in the expression of 1259 genes (p<0.05). These included increases in transcripts encoding genes associated with inflammation (e.g., Ccl8, Ccl12), genotoxic/ oxidative stress (e.g., Apod, Serpinb5) and paracrine-acting proteins (e.g., Cyr61). The expression of several collagen genes (e.g., Col1a1 and Col3a1) exhibited age associated declines. By immunofluorescence and electron microscopy we determined that the aged prostate contains an abundant disorganized collagen matrix and a significant increase in inflammatory infiltrates comprised of macrophages, T cells and, to a lesser extent, B cells. These findings demonstrated that during normal aging the prostate stroma exhibits phenotypic and molecular characteristics plausibly contributing to the striking age associated pathologies affecting the prostate through oxidative stress and inflammatory cell damage. Custom Agilent 44K whole mouse genome expression oligonucleotide microarrays as well as custom mouse cDNA microarrays were used to measure transcript levels in microdissected periglandular stroma from young (4 month-old) and old (20-24 month-old) C57BL/6 mice. All samples were laser-capture microdissected and total RNA isolated and amplified prior to hybridization against a reference pool of normal adult mouse tissues.

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Stromal lipid species dictate melanoma metastasis and tropism [MFP_RNA_seq]

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