Cancer cells incorporate and remodel exogenous palmitate into structural and oncogenic signaling lipids

Abstract

De novo lipogenesis is considered the primary source of fatty acids for lipid synthesis in cancer cells, even in the presence of exogenous fatty acids. Here, we have used an isotopic fatty acid labeling strategy coupled with metabolomic profiling platforms to comprehensively map palmitic acid incorporation into complex lipids in cancer cells. We show that cancer cells and tumors robustly incorporate and remodel exogenous palmitate into structural and oncogenic glycerophospholipids, sphingolipids, and ether lipids. We also find that fatty acid incorporation into oxidative pathways is reduced in aggressive human cancer cells, and instead shunted into pathways for generating structural and signaling lipids. Our results demonstrate that cancer cells do not solely rely on de novo lipogenesis, but also utilize exogenous fatty acids for generating lipids required for proliferation and protumorigenic lipid signaling.

Subcutaneous Adipocytes Promote Melanoma Cell Growth by Activating the Akt Signaling Pathway

“…In melanoma, reducing endogenous palmitic acid/fatty acid levels by inactivating lipolytic enzyme monoacylglycerol lipase (42) or by inhibiting fatty acid synthase activity (43) causes tumorigenic impairments. Interestingly, these melanoma cells can uptake, incorporate, and utilize the exogenous palmitic acid to fuel the cancer cells pathogenicity, reduce, or reverse the impairments (13,42). Besides melanoma, other cancers such as breast cancer cells, prostate cancer cells, and ovarian carcinoma cells can also incorporate and utilize exogenous palmitic acid to fuel the cancer cells pathogenicity (13).…”

“…Interestingly, these melanoma cells can uptake, incorporate, and utilize the exogenous palmitic acid to fuel the cancer cells pathogenicity, reduce, or reverse the impairments (13,42). Besides melanoma, other cancers such as breast cancer cells, prostate cancer cells, and ovarian carcinoma cells can also incorporate and utilize exogenous palmitic acid to fuel the cancer cells pathogenicity (13). We focused on melanoma cells in this study because malignant melanoma grows in the anatomical vicinity of subcutaneous adipose tissue (10), which may serve as an exogenous source of the fatty acids to the cancer cells.…”

“…The high level of palmitic acid in melanoma cells may due to a high rate of de novo lipogenesis (12). Recently, an isotopic fatty acid tracing-based metabolomics study revealed that cancer cells including melanoma incorporated exogenous palmitic acid into structural and signaling lipids (13), suggesting that exogenous fatty acids, such as palmitic acid, also play an important role in melanoma pathogenesis.…”

“…1C). Because Oil Red O stains neutral lipids, the staining may also recapitulate any transferred fatty acids such as palmitic acid, which can be incorporated into different lipid species including the neutral lipids in melanoma (13). To examine if the lipid accumulation in B16F10 cells was derived from the adipocytes in the co-culture system, we co-cultured B16F10 cells with the isolated adipocytes that had been loaded with fluorescently labeled fatty acid BODIPY FLC16.…”

Acquired resistance to metformin in breast cancer cells triggers transcriptome reprogramming toward a degradome-related metastatic stem-like profile

“…[81][82][83] The overexpression of MAGL in nonaggressive cancer cells is sufficient to increase their pathogenicity by recapitulating this fatty acid network, thus revealing how cancer cells can co-opt a lipolytic enzyme to translate their lipogenic state into an array of protumorigenic signals. Indeed, MAGL's unique role of providing lipolytic sources of free fatty acids (FFAs) for the synthesis of oncogenic signaling lipids that promote cancer aggressiveness, together with the fact that MAGL blockade impairs cell migration, invasiveness, and tumorigenicity by lowering the levels of FFAs and protumorigenic signaling lipids, [84][85][86] strongly suggest that, in response to the expected chronic inactivation of several lipogenic enzymes and lipogenesis imposed by metformin, the metformin-refractory MCF-7/MET-R cells re-activate the very same lipogenic state that is commonly controlled by metformin's targets (AMPK, acetylCoA carboxylase, mTOR) via MAGL. The serine proteinase degradome gene FREM1 (FRAS1-related extracellular matrix 1/signalase-like 1) 87,88 and Wnt-induced signaling protein-2 (WISP2/CCN5), a gene coding for a metalloproteinase substrate implicated in the modification of the ECM, invasion, and angiogenesis that has been linked to a variety of human cancer types and may contribute to cancer metastasis, 89,90 were also significantly upregulated in the metformin-refractory MCF-7/ MET-R cells ( Table 2).…”