Most tumors have an aberrantly activated lipid metabolism 1 , 2 , which enables them to synthesize, elongate and desaturate fatty acids to support proliferation. However, only particular subsets of cancer cells are sensitive toward approaches targeting fatty acid metabolism, and in particular fatty acid desaturation 3 . This suggests that many cancer cells harbor an unexplored plasticity in their fatty acid metabolism. Here, we discover that some cancer cells can exploit an alternative fatty acid desaturation pathway. We identify various cancer cell lines, murine hepatocellular carcinomas (HCC), and primary human liver and lung carcinomas that desaturate palmitate to the unusual fatty acid sapienate to support membrane biosynthesis during proliferation. Accordingly, we found that sapienate biosynthesis enables cancer cells to bypass the known stearoyl-CoA desaturase (SCD)-dependent fatty acid desaturation. Thus, only by targeting both desaturation pathways the in vitro and in vivo proliferation of sapienate synthesizing cancer cells is impaired. Our discovery explains metabolic plasticity in fatty acid desaturation and constitutes an unexplored metabolic rewiring in cancers.

Extracellular matrix (ECM) is a major component of the local environment, i.e. the niche, that can determine cell behavior 1 . During metastatic growth, cancer cells shape the ECM of the metastatic niche by hydroxylating collagen to promote their own metastatic growth 2 , 3 . However, only particular nutrients might support the ability of cancer cells to hydroxylate collagen because nutrients dictate which enzymatic reactions are active in cancer cells 4 , 5 . Here, we discovered that breast cancer cells rely on the nutrient pyruvate to drive collagen-based ECM remodeling in the lung metastatic niche. Specifically, we discovered that pyruvate uptake induces the production of α-ketoglutarate. This metabolite in turn activated collagen hydroxylation by increasing the activity of the enzyme collagen prolyl-4-hydroxylase (P4HA). Strikingly, inhibition of pyruvate metabolism was sufficient to impair collagen hydroxylation and consequently the growth of breast cancer-derived lung metastases in different mouse models. In summary, we provide a mechanistic understanding of the link between collagen remodeling and the nutrient environment in the metastatic niche.

α-Synuclein is an intrinsically disordered protein whose aggregation in the form of amyloid fibers is directly implicated in Parkinson's disease and other neurological disorders. α-Synuclein is composed of three different regions. The central region (61−95), called NAC, is responsible for protein fibrillation. The N-terminal region (1−61) has some helical propensity and can be divided into H1 (1−31) and H2 (32−61), while the highly acidic C-terminal region (96−140) is completely disordered. It has been postulated that the acidic character of the C-terminus, as well as the interaction between the soluble N-and C-terminal parts, protects the NAC region from fibrillation. In consequence, N-and C-terminal deletions increase α-synuclein fibrillation. Both N-and C-terminal truncations are common in synucleinopathies, but despite their clinical relevance, to date, there are no systematic and exhaustive studies that quantify the effect of these truncations in fiber nucleation and elongation. In this work, we measured both nucleation and fibrillation elongation kinetics in order to study the influence of N-and C-terminal deletions, including the simultaneous deletion of several regions, in α-synuclein fibrillation. We also tested whether the fibrillation prone mutation A53T had an additional effect when combined with truncations. Furthermore, our cross-seeding experiments showed that the deletions studied induce changes in fiber morphology. Our results unravel then the role of the different α-synuclein regions and the A53T mutation in the nucleation and elongation of amyloid fibers.

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