Cysteine depletion induces pancreatic tumor ferroptosis in mice

By Michael A. Badgley, Daniel M. Kremer, H. C. Maurer, Kathleen E. DelGiorno, Ho-Joon Lee, V. Purohit, Irina Sagalovskiy, Alice Ma, Jonathan Kapilian, Christina E. M. Firl and 20 more. Science, 2020

1,078 citations recorded by the source corpus.

Ferroptotic cell death and cancer Cell death can occur through different mechanisms, several of which are being explored as potential targets for cancer treatment. One form of cell death that has attracted recent interest is ferroptosis, which is triggered by high intracellular levels of lipid reactive oxygen species. Pancreatic cancer cells have high levels of reactive oxygen species but manage to avoid ferroptosis by importing extracellular cysteine. Studying mice bearing pancreatic tumors, Badgley et al. found that administration of a drug inhibiting cysteine import induced tumor-selective ferroptosis and inhibited tumor growth. Further work will be required to determine whether this therapeutic strategy will be effective in human pancreatic cancer, a tumor type for which new treatments are urgently needed. Science, this issue p. 85 A drug that lowers intracellular cysteine levels inhibits growth of pancreatic tumors in mice by inducing a specific form of cell death. 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.

Subfields: Molecular Biology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/42d8b72ba42005377d75f1c249c62312872703aa

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Molecular Biology

In Pulmonary and Respiratory Medicine

Citations in the corpus

Ferroptosis in cancer: from molecular mechanisms to therapeutic strategies (2024, methodology): “53 Additionally, Ubellacker et al. found that melanoma cells in the lymph are prone to forming metastases in blood because lymph protects metastasizing melanoma cells from ferroptosis.”
Metabolic reprogramming and epigenetic modifications on the path to cancer (2021, background): “…bodies (Xia et al., 2017; Hopkins et al., 2018), choline (Romano et al., 2017), arginine (PoilletPerez et al., 2018), glutamine (Ishak Gabra et al., 2020), fructose (Goncalves et al., 2019; Zhao et al., 2020), or cysteine (Badgley et al., 2020) mediates the progression of multiple types of cancer.”
Autophagy, ferroptosis, pyroptosis, and necroptosis in tumor immunotherapy (2022, background): “For example, in genetic engineering mice, enhanced sensitivity of tumors to ferroptosis significantly inhibited the formation and progression of pancreatic cancer.(6) The KRAS mutation-driven lung cancer model, however, suggests that autophagy is necessary for maintaining mitochondrial function and ”
Ferroptosis turns 10: Emerging mechanisms, physiological functions, and therapeutic applications. (2022, neutral): “Knockout of SLC7A11 provided significant benefit in a mouse genetic model of pancreatic cancer, without inducing markers of other types of cell death beyond ferroptosis (Badgley et al., 2020).”
Ferroptosis surveillance independent of GPX4 and differentially regulated by sex hormones (2023, background): “Although controversies exist on how tumor cell ferroptosis may engage or dampen antitumor immunity,(21,22) multiple studies using immune-competent mice have unambiguously demonstrated the anticancer effect of ferroptosis induction for tumors of specific genetic background.(18,20,23) Therefore, under”
The cell biology of ferroptosis (2024, neutral): “For example, co-depletion of GSH and the metabolic intermediate coenzyme A (CoA) is necessary and sufficient to trigger ferroptosis in some cancer cells 69,70 .”