A palmitate-rich metastatic niche enables metastasis growth via p65 acetylation resulting in pro-metastatic NF-κB signaling

Altea-Manzano, Patricia; Doglioni, Ginevra; Liu, Yawen; Cuadros, Alejandro M.; Nolan, Emma; Fernández-García, Juan; Wu, Qi; Planque, Mélanie; Laue, Kathrin; Cidre‐Aranaz, Florencia; Liu, Xiao-Zheng; Marín-Béjar, Oskar; Elsen, Joke Van; Vermeire, Ines; Broekaert, Dorien; Demeyer, Sofie; Spotbeen, Xander; Idkowiak, Jakub; Montagne, Aurélie; Demicco, Margherita; Alkan, H. Furkan; Rabas, Nick; Riera-Domingo, Carla; Richard, François; Geukens, Tatjana; Schepper, Maxim De; Leduc, Sophia; Hatse, Sigrid; Lambrechts, Yentl; Kay, Emily; Lilla, Sérgio; Alekseenko, Alisa; Geldhof, Vincent; Boeckx, Bram; Arregui, Celia de la Calle; Floris, Giuseppe; Swinnen, Johannes V.; Marine, Jean-Christophe; Lambrechts, Diether; Mazzone, Massimiliano; Zanivan, Sara; Cools, Jan; Wildiers, Hans; Baud, Véronique; Grünewald, Thomas G.P.; Ben‐David, Uri; Desmedt, Christine; Malanchi, Ilaria; Fendt, Sarah-Maria

doi:10.1038/s43018-023-00513-2

Cited by 36 publications

(16 citation statements)

References 95 publications

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“…The changing nutrient composition within the early metastatic microenvironment is a critical factor in metastatic progression. Recent studies have demonstrated the importance of fatty acids in metastasis, including their enrichment in the lung metastatic microenvironment [5][6][7] . However, how fatty acids are delivered to early metastatic tumors is poorly understood.…”

Section: Discussionmentioning

confidence: 99%

“…Long-chain fatty acids have been found to accumulate during tumor progression, including at the metastatic site 2, 6 . Multiple sources of fatty acids within tumors have been described, including stromal cell release and de novo synthesis within tumor cells 6, 27 . However, several groups have linked elevated dietary intake of lipids with cancer progression 6, 28, 29 , suggesting that the blood may be a significant source of free fatty acids in tumors.…”

Section: Discussionmentioning

confidence: 99%

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Regulation of fatty acid delivery to metastases by tumor endothelium

Edwards,

Wang,

Song

et al. 2024

Preprint

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Tumor metastasis, the main cause of death in cancer patients, requires outgrowth of tumor cells after their dissemination and residence in microscopic niches. Nutrient sufficiency is a determinant of such outgrowth. Fatty acids (FA) can be metabolized by cancer cells for their energetic and anabolic needs but impair the cytotoxicity of T cells in the tumor microenvironment (TME), thereby supporting metastatic progression. However, despite the important role of FA in metastatic outgrowth, the regulation of intratumoral FA is poorly understood. In this report, we show that tumor endothelium actively promotes tumor growth and restricts anti-tumor cytolysis by transferring FA into developing metastatic tumors. This process uses transendothelial fatty acid transport via endosome cargo trafficking in a mechanism that requires mTORC1 activity. Thus, tumor burden was significantly reduced upon endothelial-specific targeted deletion of Raptor, a unique component of the mTORC1 complex (RptorECKO). In vivo trafficking of a fluorescent palmitic acid analog to tumor cells and T cells was reduced in RptorECKO lung metastatic tumors, which correlated with improved markers of T cell cytotoxicity. Combination of anti-PD1 with RAD001/everolimus, at a low dose that selectively inhibits mTORC1 in endothelial cells, impaired FA uptake in T cells and reduced metastatic disease, corresponding to improved anti-tumor immunity. These findings describe a novel mechanism of transendothelial fatty acid transfer into the TME during metastatic outgrowth and highlight a target for future development of therapeutic strategies.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Regulation of fatty acid delivery to metastases by tumor endothelium

Edwards,

Wang,

Song

et al. 2024

Preprint

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“…Why are both mechanisms at play here? Previous studies have begun to reveal the importance of metabolic adaptations -and of lipid metabolic adaptations in particular -in metastasis (47,(73)(74)(75). The balance between FA synthesis and FA uptake is not sufficiently understood, and could be of much clinical importance.…”

Section: Discussionmentioning

confidence: 99%

Inactivation of p53 drives breast cancer brain metastasis by altering fatty acid metabolism

Laue,

Pozzi,

Cohen-Sharir

et al. 2023

Preprint

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Brain metastasis (BM) is a dire prognosis across cancer types. It is largely unknown why some tumors metastasize to the brain whereas others do not. We analyzed genomic and transcriptional data from clinical samples of breast cancer BM (BCBM) and found that nearly all of them carried p53-inactivating genetic alterations through mutations, copy-number loss, or both. Importantly, p53 pathway activity was already perturbed in primary tumors giving rise to BCBM, often by loss of the entire 17p chromosome-arm. This association was recapitulated across other carcinomas. Experimentally, p53 knockout was sufficient to drastically increase BCBM formation and growthin vivo, providing a causal link between p53 inactivation and brain tropism. Mechanistically, p53-deficient BC cells exhibited altered lipid metabolism, particularly increased fatty acid (FA) synthesis and uptake, which are characteristic of brain-metastasizing cancer cells. FA metabolism was further enhanced by astrocytes in a p53-dependent manner, as astrocyte-conditioned medium increased FASN, SCD1, and CD36 expression and activity, and enhanced the survival, proliferation and migration of p53-deficient cancer cells. Consequently, these cells were more sensitive than p53-competent cells to FA synthesis inhibitors, in isogenic cell cultures, in BCBM-derived spheroids, and across dozens of BC cell lines. Lastly, a significant association was observed between p53 inactivation, astrocyte infiltration, and SCD1 expression in clinical human BCBM samples. In summary, our study identifies p53 inactivation as a driver of BCBM and potentially of BM in general; suggests a p53-dependent effect of astrocytes on BC cell behavior; and reveals FA metabolism as an underlying, therapeutically-targetable molecular mechanism.

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“…We showed that unlike normal cells, high density cultures of breast cancer cells or cancer-associated fibroblasts secrete lipids containing monounsaturated fatty acid in the extracellular environment in quantities that prevent ferroptosis when supplemented to colony-forming cells ( Figure 1 and 2E ). Recently, it has been shown that primary breast tumours can secrete a factor that increases palmitate production in the lung, conditioning the metastatic niche to favour cancer cell growth 39 . Furthermore, it has been shown that the pro-metastatic effect of high fat diets relies on CD36-dependent MUFA uptake 40 .…”

Section: Discussionmentioning

confidence: 99%

Breast cancer secretes anti-ferroptotic MUFAs and depends on selenoprotein synthesis for metastasis

Ackermann

Shokry

Deshmukh

et al. 2023

Preprint

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The limited availability of therapeutic options for patients with triple-negative breast cancer (TNBC) contributes to the high rate of metastatic recurrence and poor prognosis. Ferroptosis is a type of cell death caused by iron-dependent lipid peroxidation counteracted by the antioxidant activity of selenoproteins. Here, we show that TNBC cells secrete an anti-ferroptotic factor in the extracellular environment when cultured at high cell densities but are primed to ferroptosis when forming colonies from single cells. We found that secretion of the anti-ferroptotic factor, identified as monounsaturated fatty acid (MUFA) containing lipids, and the vulnerability to ferroptosis of single cells depends on the expression of stearyl-CoA desaturase (SCD) that is proportional to cell density. Finally, we show that the inhibition of tRNAsec selenocysteinilation, an essential step for selenoprotein production, causes ferroptosis and impairs the lung seeding of circulating TNBC cells that are no longer protected by the MUFA-rich environment of the primary tumour.

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A palmitate-rich metastatic niche enables metastasis growth via p65 acetylation resulting in pro-metastatic NF-κB signaling

Cited by 36 publications

References 95 publications

Regulation of fatty acid delivery to metastases by tumor endothelium

Regulation of fatty acid delivery to metastases by tumor endothelium

Inactivation of p53 drives breast cancer brain metastasis by altering fatty acid metabolism

Breast cancer secretes anti-ferroptotic MUFAs and depends on selenoprotein synthesis for metastasis

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