Intercellular interaction dictates cancer cell ferroptosis via NF2–YAP signalling

Abstract

SUMMARY Ferroptosis, a cell death process driven by cellular metabolism and iron-dependent lipid peroxidation, is implicated in various diseases such as ischemic organ damage and cancer 1 , 2 . As a central regulator of ferroptosis, the enzyme glutathione peroxidase 4 (GPX4) protects cells from ferroptosis by neutralizing lipid peroxides, which are byproducts of cellular metabolism; as such, inhibiting GPX4 directly, or indirectly by depriving its substrate glutathione or building blocks of glutathione (such as cysteine), can trigger ferroptosis 3 . Ferroptosis contributes to the antitumour function of multiple tumour suppressors including p53, BAP1, and fumarase 4 - 7 . Counterintuitively, mesenchymal cancer cells, which are prone to metastasis and often resistant to various treatments, have shown to be highly susceptible to ferroptosis 8 , 9 . Here, we demonstrate that ferroptosis can be regulated non-cell autonomously by cadherin-mediated intercellular contacts. In epithelial cells, E-cadherin-mediated intercellular interaction suppresses ferroptosis through intracellular Merlin-Hippo signalling. Antagonizing this signalling axis unleashes the activity of the proto-oncogenic transcriptional co-activator YAP to promote ferroptosis through upregulation of multiple ferroptosis modulators, including acyl-CoA synthetase long chain family member 4 (ACSL4) and transferrin receptor. This finding provides mechanistic insights into the observations that epithelial mesenchymal transition (EMT)/metastasis-prone cancer cells are highly sensitive to ferroptosis 8 . Importantly, the regulation of ferroptosis by cell-cell contact and Merlin-YAP signalling is not limited to epithelial cells; a similar mechanism also modulates ferroptosis in some non-epithelial cells. Finally, we found that genetic inactivation of the tumour suppressor Merlin, a frequent tumourigenic event in mesothelioma 10 , 11 , renders cancer cells more sensitive to ferroptosis in an orthotopic mouse model of malignant mesothelioma. Together, this study unveils the role of intercellular interaction and intracellular Merlin-YAP signalling in dictating ferroptotic death; it also suggests that malignant mutations in Merlin-YAP signalling can serve as biomarkers predicting cancer cell responsiveness to future ferroptosis-inducing therapies.

Cell density-dependent ferroptosis in breast cancer is induced by accumulation of polyunsaturated fatty acid-enriched triacylglycerides

“…Another mechanism of the impact of cell density on ferroptosis reported recently involves E-cadherin-mediated ferroptosis suppression via NF2-YAP signaling 44 . However, the proposed signaling modulating ferroptosis sensitivity may not apply to our cellular systems since E-cadherin levels in HMLE cells were not affected by cell density and HMLE-Twist1 cells do not express E-cadherin, but still show density-dependent ferroptosis-sensitivity.…”

Inhibiting xCT/SLC7A11 induces ferroptosis of myofibroblastic hepatic stellate cells and protects against liver fibrosis

“…The aggregate data suggest that MF-HSCs may be more dependent on xCT to maintain levels of GSH that GPX4 requires to detoxify lipid peroxides than hepatocytes. It is interesting to note that Hippo transducers (YAP/TAZ) and ataxia telangiectasia mutated (ATM), factors previously shown to be critical for HSC transdifferentiation 36,37 , were also recently found to be critical for ferroptosis [38][39][40] , providing a potential mechanistic link between MF-HSC differentiation and ferroptosis vulnerability. Conversely, the relative resistance of hepatocytes to ferroptosis caused by xCT inhibition is supported by recent studies of hepatocyte toxicity caused by acetaminophen overdose, which revealed that hepatocytes predominately rely on the trans-sulfuration pathway to supply cystine to the redox system, and only induce xCT to import extracellular cystine when the trans-sulfuration pathway is impaired and unable to fulfill demands for GSH synthesis.…”

Systematic identification of a nuclear receptor-enriched predictive signature for erastin-induced ferroptosis

“…As such, a variety of cellular and molecular components and processes, such as metabolic heterogeneity [11], mesenchymal properties [9], differentiation status [12], p53 status [13], transcription factors [14,15], signaling pathways (e.g. MAPK [16], ATM [17] or YAP [18]), integrins [19], GSH regulators [20], and levels of monounsaturated fatty acid [21], have been examined as determinants of ferroptosis vulnerability in a diverse range of cell model systems. Despite this, the variation in the susceptibility of cancer cells to ferroptosis, via either XCT or GPX4 inhibition, depending on cellular and molecular characteristics has not yet been fully understood.…”