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

Abstract

Competing interests' statement S-MF has received funding from Gilead, Bayer AG, Merck, Black Belt Therapeutics and Alesta Therapeutics, has consulted for Fund+ and is in the advisory board of Alesta Therapeutics. TGPG has consulted for Boehringer Ingelheim. All other authors declare no competing interests. Resource AvailabilityThis study did not generate new unique reagents, except for genetically manipulated cell lines based on commercially available constructs. Reagents generated in this study will be made available on request through the lead author or the collaboration partner that generated the resource, but we may require payment and/or a completed Materials Transfer Agreement if there is potential for commercial application. Further requests for resources should be directed to the lead contact, Sarah-Maria Fendt

Regulation of fatty acid delivery to metastases by tumor endothelium

“…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.…”

“…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.…”

“…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 .…”

Phenotype-specific melanoma uptake of fatty acid from human adipocytes activates AXL and CAV1-dependent β-catenin nuclear accumulation

“…Moreover, as activation of SRC is a pro-survival signal triggered by integrin-interactions with extracellular matrix that has been linked to BRAFi-resistance in vivo (Hirata et al, 2015), it is plausible that the ability of oleic acid to promote SRC activation via AXL provide a degree of adhesion mimicry that would suppress cell death in non-attached, metastasizing cancer cells. In this respect, the expression of AXL on therapy resistant cells in a wide variety of cancers known to invade or metastasize to adipose tissue (Hoy et al ., 2021) or via the lymphatic system may provide a key pro-survival mechanism that extends well beyond the ability of some fatty acids, such as palmitate (Altea-Manzano et al, 2023), to promote proliferation via fatty acid oxidation.…”

Fatty acid synthase (FASN) signalome: A molecular guide for precision oncology

“…Interestingly, the FASN end product palmitate appears to be involved in both processes. On the one hand, lipid‐rich environments such as the lung – a common metastatic site for many tumors – may be promoted by pathological conditions such as pre‐metastatic niche formation and obesity to further increase the availability of palmitate [341]. Palmitate, in turn, promotes the expression of lysine acetyltransferases such as KAT2a, which will channel the available acetyl‐CoA to acetylate the nuclear factor kappa B (NF‐κB) subunit p65 and activate a pro‐metastatic transcriptional program in the lung.…”