Metastasis is a multistep process requiring ongoing adaptations of cancer cells. A recent study by Wang et al. published in Cell identified polyunsaturated fatty acids as important players in this process; these lipids support metastatic dissemination and colonization but due to their relevance for ferroptosis also open novel therapeutic windows.

Metastasis, the major cause of cancer-associated mortality, is a complex multistep process. It requires permanent adaptations of cancer cells to the challenges of the changing environment. The necessary properties are sometimes counteracting. After primary tumor growth, a high cell motility is crucial for dissemination through blood and lymphatic vessels.1 A dormancy phase allows survival in a hostile environment before overt metastases grow often after a latency phase. Thereby the rate-limiting step is metastatic colonization starting from one or few cancer cells, which requires the switch back to an energy-demanding growth phase in a microenvironment with poor blood supply and thus low nutrient availability. In summary, metastasis requires a high cancer cell plasticity, which is often acquired by transient and partial activation of the epithelial-to-mesenchymal transition (EMT) program.2,3 Understanding the molecular processes underlying cancer cell plasticity will lead to novel therapeutic options, underscoring the high translational relevance of this topic.

A recent publication by Wang et al.4 addressed these critical points in metastasis, focusing on metabolic adaptations. By integrating the MetMap 500 dataset, which characterizes the metastatic potential of cancer cell lines of various cancer types, with the Cancer Therapeutics Response Portal (CTRP) dataset detailing their drug sensitivity, the authors uncovered a correlation between metastatic competence — both overall and organ-specific — and sensitivity to ferroptosis. Ferroptosis is a highly conserved cell death pathway, depending on an iron and oxygen radical-mediated peroxidation of phospholipids. Importantly, such phospholipids must be composed of polyunsaturated fatty acids (PUFAs).5,6 In contrast to PUFAs, saturated (SFAs) and monounsaturated fatty acids (MUFAs) are resistant to peroxidation and excess MUFAs can even protect cells from ferroptosis. Focusing on a mouse model for metastatic ovarian cancer, the authors demonstrate that lung metastases exhibit the highest sensitivity to ferroptosis, which is also correlated with a high PUFA lipid profile, compared to liver and peritoneal metastases. While ovarian cancer typically spreads via the peritoneal cavity, lung metastasis requires intra- and extravasation processes, exposing cells to an oxidative and ferroptosis-prone environment in the bloodstream.

To pinpoint pro-metastatic genes relevant to these different dissemination routes, the authors employed an in vivo CRISPR screen on ovarian cancer cells selected for high metastatic efficiency. They identified long-chain fatty acid coenzyme A ligase 4 (ACSL4) as a pivotal pro-metastatic gene that specifically enhances lung metastasis formation. This enzyme is responsible for activating PUFAs, preferentially arachidonic acid, to be incorporated into phospholipids, thereby enhancing ferroptosis sensitivity. The authors further demonstrated the importance of ACSL4 for maintaining membrane fluidity and facilitating migration, and confirmed that ACSL4 is indispensable for extravasation of disseminating cancer cells into lung parenchyma. These findings suggest a delicate balance where high PUFA content both enhances motility and increases susceptibility to ferroptosis.

While ACSL4 activity and PUFA incorporation are essential for dissemination, Wang et al. suggested that other PUFA-related metabolic pathways are critical for subsequent metastatic colonization, particularly given the elevated energy requirements. From their in vivo CRISPR screen, they identified ECH1 and ECI1 as key rate-limiting enzymes involved in β-oxidation of PUFAs, which are crucial for lung metastasis. This finding highlights the importance of PUFAs not only during the dissemination phase but also as crucial sources of energy and macromolecules during metastatic colonization, prior to the provision of nutrients via newly formed tumor blood vessels. The clinical significance of these enzymes (ACSL4, ECH1, ECI1) across various human cancers was indicated by their correlation with poor clinical outcomes, and the first in vivo studies have shown that the combined inhibition of these factors — whether genetically or pharmacologically — effectively inhibited lung metastasis.

The significance and elegance of this study lie in its ability to link fundamental mechanisms of lipid biochemistry, cellular plasticity, and the metastatic process, all of which bear high clinical relevance and suggest possibilities for innovative therapeutic interventions. This connection is well supported by recent research in the field.7,8,9 The strong relationship between metastatic competence and the upregulation of PUFA-containing phospholipids, which in turn enhances sensitivity to ferroptosis, extends previous findings that associate ferroptosis susceptibility with an aggressive, mesenchymal phenotype in cancer cells.10 The most intriguing discovery is that PUFAs not only augment membrane fluidity essential for cancer cell motility but also serve as initial fuel for β-oxidation, initiating the energy-intensive colonization process — particularly crucial before the formation of new blood vessels in growing metastases.

The reported results raise thought-provoking questions: Can the findings be generalized to other cancer types and extended by genetic mouse models giving rise to autochthonous metastasis from primary tumors? If there is no functional blood supply yet, where does the necessary oxygen for β-oxidation during the initial colonization phase come from? Linked to this question, is the availability of enough oxygen in the microenvironment a rate-limiting factor for the start of metastatic colonization and can this explain differences in the metastatic tropism for lung (high oxygen) vs liver also described in the publication? Furthermore, why is the availability of PUFAs critical, and what about SFAs and MUFAs as sources for β-oxidation in colonizing cancer cells?

Another significant question raised by the authors pertains to the mechanism underlying the upregulation of PUFA synthesis in metastatic cancer cells. A recent study by Schwab et al.8,11 addressed this question and complements the findings by Wang et al. It reveals that during EMT, PUFAs increase due to the upregulation of key production factors (FADS2 and ELOVL5) and the downregulation of factors critical for the synthesis of SFAs and MUFAs (FASN and SCD). The key regulator in this process is the EMT transcription factor Zeb1, which also upregulates ACSL4 expression. Thus, the increase in PUFAs, akin to the downregulation of E-cadherin, is likely an integral aspect of the EMT program regulated by the same transcription factors. Together, these studies present overlapping findings in a translationally significant context, highlighting that EMT-associated plasticity is vital for metastasis as it enables essential cellular, molecular, and metabolic adaptations. A critical aspect of this is the upregulation of PUFA synthesis and incorporation, which is necessary for both enhanced motility and energy supply during colonization. However, this support for metastatic processes comes at a cost: the increased sensitivity to ferroptosis.

The implications of these findings are profound and of high translational relevance, as they illuminate a therapeutic avenue against aggressive cancer types and metastases (Fig. 1). The identification of rate-limiting factors associated with PUFA functions in metastasis — ACSL4 for motility and ECI1 and ECH1 for β-oxidation — provides molecular targets for therapeutic intervention, as successfully tested in Wang et al.’s study. Additionally, the heightened sensitivity to ferroptosis provides opportunities to directly target metastatic cells with ferroptosis inducers. Schwab et al. demonstrated the synergistic potential of these inducers with inhibitors of SCD, a crucial enzyme for SFA and MUFA synthesis, thus promoting the incorporation of PFUAs and increasing ferroptosis sensitivity. The development of effective in vivo available pharmacological inhibitors targeting these factors could facilitate clinical trials for smart drug combinations aimed at combating metastasis.

Fig. 1: Central role of PUFAs as driver and target in metastasis.
figure 1

Increased amounts of PUFA-containing phospholipids (green) in cancer cells with a hybrid epithelial/mesenchymal (E/M) phenotype promote both dissemination and colonization, but also increase ferroptosis sensitivity. This opens therapeutic options by applying smart combinations with inhibitors (i) of rate-limiting enzymes for PUFA incorporation (ACSL4), β-oxidation (ECH1, ECI1) and ferroptosis protection (e.g., SCD, GPX4).

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