Ferroptosis is a form of cell death that results from the catastrophic accumulation of lipid reactive oxygen species (ROS). Oncogenic signaling elevates lipid ROS production in many tumor types and is counteracted by metabolites that are derived from the amino acid cysteine. In this work, we show that the import of oxidized cysteine (cystine) via system xC– is a critical dependency of pancreatic ductal adenocarcinoma (PDAC), which is a leading cause of cancer mortality. PDAC cells used cysteine to synthesize glutathione and coenzyme A, which, together, down-regulated ferroptosis. Studying genetically engineered mice, we found that the deletion of a system xC– subunit, Slc7a11, induced tumor-selective ferroptosis and inhibited PDAC growth. This was replicated through the administration of cyst(e)inase, a drug that depletes cysteine and cystine, demonstrating a translatable means to induce ferroptosis in PDAC.

The term ferroptosis was coined in 2012 to describe an iron-dependent regulated form of cell death caused by the accumulation of lipid-based reactive oxygen species; this type of cell death was found to have molecular characteristics distinct from other forms of regulated cell death. Features of ferroptosis have been observed periodically over the last several decades, but these molecular features were not recognized as evidence of a distinct form of cell death until recently. Here, we describe the history of observations consistent with the current definition of ferroptosis, as well as the advances that contributed to the emergence of the concept of ferroptosis. We also discuss recent implications and applications of manipulations of the ferroptotic death pathway.

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TGF-β signals through Smad-dependent and non-Smad pathways, depending on cell context. In ovarian cancer cells, the clathrin adaptor Dab2 enhances internalization of the type I TGF-β receptor, restricts its lateral mobility, and inhibits TGF-β–mediated, cholesterol-dependent JNK activation.

The levels and intracellular localization of wild-type transforming growth factor b superfamily (TGFb-SF) receptors are tightly regulated by endocytic trafficking, shedding and degradation. In contrast, a main regulatory mechanism of mutation-bearing receptors involves their intracellular retention. Anti-Mü llerian hormone receptor II (AMHRII, also known as AMHR2) is the type-II receptor for anti-Mü llerian hormone (AMH), a TGFb-SF ligand that mediates Mü llerian duct regression in males. Here, we studied AMHRII processing and identified novel mechanisms of its constitutive negative regulation. Immunoblot analysis revealed that a significant portion of AMHRII was missing most of its extracellular domain (ECD) and, although glycosylated, was unfolded and retained in the endoplasmic reticulum. Exogenous expression of AMHRII, but not of type-II TGF-b receptor (TbRII, also known as TGFR2), resulted in its disulfide-bond-mediated homooligomerization and intracellular retention, and in a decrease in its AMH-binding capacity. At the plasma membrane, AMHRII differed from TbRII, forming high levels of non-covalent homomeric complexes, which exhibited a clustered distribution and restricted lateral mobility. This study identifies novel mechanisms of negative regulation of a type-II TGFb-SF receptor through cleavage, intracellular retention and/or promiscuous disulfide-bond mediated homo-oligomerization.