Intercellular interaction dictates cancer cell ferroptosis via Merlin-YAP signalling
By Jiao Wu, Alexander M. Minikes, Minghui Gao, H. Bian, Yong Li, Brent R. Stockwell, Zhi-Nan Chen, Xuejun Jiang. Nature, 2019
818 citations recorded by the source corpus.
Ferroptosis, a cell death process driven by cellular metabolism and iron-dependent lipid peroxidation, has been implicated in diseases such as ischaemic organ damage and cancer1,2. The enzyme glutathione peroxidase 4 (GPX4) is a central regulator of ferroptosis, and protects cells by neutralizing lipid peroxides, which are by-products of cellular metabolism. The direct inhibition of GPX4, or indirect inhibition by depletion of its substrate glutathione or the building blocks of glutathione (such as cysteine), can trigger ferroptosis3. Ferroptosis contributes to the antitumour function of several tumour suppressors such as p53, BAP1 and fumarase4–7. Counterintuitively, mesenchymal cancer cells—which are prone to metastasis, and often resistant to various treatments—are highly susceptible to ferroptosis8,9. Here we show that ferroptosis can be regulated non-cell-autonomously by cadherin-mediated intercellular interactions. In epithelial cells, such interactions mediated by E-cadherin suppress ferroptosis by activating the intracellular NF2 (also known as merlin) and Hippo signalling pathway. Antagonizing this signalling axis allows the proto-oncogenic transcriptional co-activator YAP to promote ferroptosis by upregulating several ferroptosis modulators, including ACSL4 and TFRC. This finding provides mechanistic insights into the observations that cancer cells with mesenchymal or metastatic property are highly sensitive to ferroptosis8. Notably, a similar mechanism also modulates ferroptosis in some non-epithelial cells. Finally, genetic inactivation of the tumour suppressor NF2, a frequent tumorigenic event in mesothelioma10,11, rendered cancer cells more sensitive to ferroptosis in an orthotopic mouse model of malignant mesothelioma. Our results demonstrate the role of intercellular interactions and intracellular NF2–YAP signalling in dictating ferroptotic death, and also suggest that malignant mutations in NF2–YAP signalling could predict the responsiveness of cancer cells to future ferroptosis-inducing therapies. Ferroptosis in cancer cells can be regulated by cadherin-mediated intercellular contacts, NF2–Hippo signalling, and activity of the YAP transcription co-activator.
Subfields: Cancer Research, Pulmonary and Respiratory Medicine
View Paper: https://www.semanticscholar.org/paper/8b28c614ccc2efd72fdd75f6b3d1fc5a75836741
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In Cancer Research
In Pulmonary and Respiratory Medicine
Citations in the corpus
- The Hippo signalling pathway and its implications in human health and diseases (2022, background): “110 Reportedly, other cell density transmitters for the Hippo pathway include E-cadherin, 111 annexin A2, 112 and the polarity-regulating kinase PAR1b.”
- Emerging mechanisms and disease relevance of ferroptosis (2020, background): “In xenograft mouse models for mesothelioma (loss of function of NF2 mutation occurs in N35% of patients with mesothelioma), although loss of NF2 function increases mesothelioma tumor growth and metastasis, it renders tumor cells more sensitive to GPX4 inactivation [86].”
- Oncogenic activation of PI3K-AKT-mTOR signaling suppresses ferroptosis via SREBP-mediated lipogenesis (2020, background): “Intriguingly, it has been reported recently that oncogenic mutations in the E cadherin-NF2-HippoYAP pathway, also a frequently mutated signaling pathway in human cancer, instead sensitize cancer cells to ferroptosis (18).”
- Autophagy-Dependent Ferroptosis: Machinery and Regulation (2020, background): “, 2017), cell adhesion (Wu et al., 2019a; Yang et al., 2019b), and autophagy (discussed below) also play a context-dependent role in the control of oxidative injury-mediated ferroptosis.”