Author Correction: Genomic deletion of malic enzyme 2 confers collateral lethality in pancreatic cancer.
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Published Erratum↗
Biomedical subjects
Andrea Viale
Publications and source records attributed to Andrea Viale.
GFER Represents a Target for Dual Disruption of Redox Homeostasis and Reactivation of the Immune Response in Pancreatic Adenocarcinoma.
UNLABELLED: Both metabolic dysregulation and the immunosuppressive tumor microenvironment of pancreatic ductal adenocarcinoma (PDAC) contribute to the recalcitrance of this lethal disease to treatment. Accordingly, we aimed to identify and characterize a target that elicits an anticancer response through both disrupting cancer cell redox homeostasis and increasing the immunogenicity of PDAC. First, mitochondrial metabolic dependencies in PDAC were identified by using a CRISPR-Cas9 screening system with a custom single-guide RNA library. Functional validation analyses revealed GFER, a mitochondrial FAD-dependent sulfhydryl oxidase, as an essential regulator of tumor growth. In vitro and in vivo methodologies demonstrated that GFER depletion perturbed redox homeostasis and stimulated tumor immunogenicity, including sensitization to immune checkpoint blockade. In patient-derived xenograft models of PDAC, the growth-inhibitory response induced by GFER depletion was mediated by an altered oxidative balance that released damaged mitochondrial DNA into the cytoplasm of tumor cells, leading to the activation of the cGAS-STING pathway and expression of type I IFNs. This effect was recapitulated in a mouse immunocompetent syngeneic PDAC model, in which GFER depletion suppressed tumor growth and promoted T-cell infiltration to enhance tumor-killing effects. Consequently, GFER depletion significantly increased the antitumor efficacy of immune checkpoint blockade. Overall, these findings identify GFER as a critical node for both mitochondrial redox homeostasis and immunomodulation in PDAC and reveal a therapeutic opportunity for sensitizing PDAC to immune checkpoint blockade. SIGNIFICANCE: GFER is essential for mitochondrial redox balance and suppressing tumor immunogenicity in pancreatic tumors, with the combination of GFER inhibition with immune checkpoint blockade resulting in a strong antitumor response.
Animals↗
Author Correction: Synthetic vulnerabilities of mesenchymal subpopulations in pancreatic cancer.
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Published Erratum↗
Evolutionary fingerprints of epithelial-to-mesenchymal transition.
Mesenchymal plasticity has been extensively described in advanced epithelial cancers; however, its functional role in malignant progression is controversial1-5. The function of epithelial-to-mesenchymal transition (EMT) and cell plasticity in tumour heterogeneity and clonal evolution is poorly understood. Here we clarify the contribution of EMT to malignant progression in pancreatic cancer. We used somatic mosaic genome engineering technologies to trace and ablate malignant mesenchymal lineages along the EMT continuum. The experimental evidence clarifies the essential contribution of mesenchymal lineages to pancreatic cancer evolution. Spatial genomic analysis, single-cell transcriptomic and epigenomic profiling of EMT clarifies its contribution to the emergence of genomic instability, including events of chromothripsis. Genetic ablation of mesenchymal lineages robustly abolished these mutational processes and evolutionary patterns, as confirmed by cross-species analysis of pancreatic and other human solid tumours. Mechanistically, we identified that malignant cells with mesenchymal features display increased chromatin accessibility, particularly in the pericentromeric and centromeric regions, in turn resulting in delayed mitosis and catastrophic cell division. Thus, EMT favours the emergence of genomic-unstable, highly fit tumour cells, which strongly supports the concept of cell-state-restricted patterns of evolution, whereby cancer cell speciation is propagated to progeny within restricted functional compartments. Restraining the evolutionary routes through ablation of clones capable of mesenchymal plasticity, and extinction of the derived lineages, halts the malignant potential of one of the most aggressive forms of human cancer.
Animals↗