Mechanism of tandem duplication formation in BRCA1-mutant cells

1、Mechanism of tandem duplication formation in BRCA1-mutant cells.

Small, approximately 10-kilobase microhomology-mediated tandem duplications are abundant in the genomes of BRCA1-linked but not BRCA2-linked breast cancer. Here Nicholas A. Willis at Beth Israel Deaconess Medical Center and Harvard Medical School in Massachusetts, USA and his colleagues define the mechanism underlying this rearrangement signature. They show that, in primary mammalian cells, BRCA1, but not BRCA2, suppresses the formation of tandem duplications at a site-specific chromosomal replication fork barrier imposed by the binding of Tus proteins to an array of Ter sites. BRCA1 has no equivalent role at chromosomal double-stranded DNA breaks, indicating that tandem duplications form specifically at stalled forks. Tandem duplications in BRCA1 mutant cells arise by a replication restart-bypass mechanism terminated by end joining or by microhomology-mediated template switching, the latter forming complex tandem duplication breakpoints. Solitary DNA ends form directly at Tus–Ter, implicating misrepair of these lesions in tandem duplication formation. Furthermore, BRCA1 inactivation is strongly associated with ~10 kilobase tandem duplications in ovarian cancer. This tandem duplicator phenotype may be a general signature of BRCA1-deficient cancer.
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2、NFS1 undergoes positive selection in lung tumours and protects cells from ferroptosis.

Environmental nutrient levels impact cancer cell metabolism, resulting in context-dependent gene essentiality. Here, using loss-of-function screening based on RNA interference, Samantha W. Alvarez at New York University School of Medicine in New York, USA and her colleagues show that environmental oxygen levels are a major driver of differential essentiality between in vitro model systems and in vivo tumours. Above the 3–8% oxygen concentration typical of most tissues, they find that cancer cells depend on high levels of the iron–sulfur cluster biosynthetic enzyme NFS1. Mammary or subcutaneous tumours grow despite suppression of NFS1, whereas metastatic or primary lung tumours do not. Consistent with a role in surviving the high oxygen environment of incipient lung tumours, NFS1 lies in a region of genomic amplification present in lung adenocarcinoma and is most highly expressed in well-differentiated adenocarcinomas. NFS1 activity is particularly important for maintaining the iron–sulfur co-factors present in multiple cell-essential proteins upon exposure to oxygen compared to other forms of oxidative damage. Furthermore, insufficient iron–sulfur cluster maintenance robustly activates the iron-starvation response and, in combination with inhibition of glutathione biosynthesis, triggers ferroptosis, a non-apoptotic form of cell death. Suppression of NFS1 cooperates with inhibition of cysteine transport to trigger ferroptosis in vitro and slow tumour growth. Therefore, lung adenocarcinomas select for expression of a pathway that confers resistance to high oxygen tension and protects cells from undergoing ferroptosis in response to oxidative damage.
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3、Cyclin D–CDK4 kinase destabilizes PD-L1 via Cul3SPOP to control cancer immune surveillance.

Treatments that target immune checkpoints, such as the one mediated by programmed cell death protein 1 (PD-1) and its ligand PD-L1, have been approved for treating human cancers with durable clinical benefit. However, many cancer patients fail to respond to anti-PD-1/PD-L1 treatment, and the underlying mechanism(s) is not well understood. Recent studies revealed that response to PD-1/PD-L1 blockade might correlate with PD-L1 expression levels in tumor cells. Hence, it is important to mechanistically understand the pathways controlling PD-L1 protein expression and stability, which can offer a molecular basis to improve the clinical response rate and efficacy of PD-1/PD-L1 blockade in cancer patients. Here, Jinfang Zhang at Beth Israel Deaconess Medical Center, Harvard Medical School in Boston, USA and her colleagues report that PD-L1 protein abundance is regulated by cyclin D-CDK4 and the Cullin 3SPOP E3 ligase via proteasome-mediated degradation. Inhibition of CDK4/6 in vivo elevates PD-L1 protein levels, largely by inhibiting cyclin D–CDK4-mediated phosphorylation of SPOP and thereby promoting SPOP degradation by APC/CCdh1. Loss-of-function mutations in SPOP compromise ubiquitination-mediated PD-L1 degradation, leading to increased PD-L1 levels and reduced numbers of tumor-infiltrating lymphocytes (TILs) in mouse tumors and in primary human prostate cancer specimens. Notably, combining CDK4/6 inhibitor treatment with anti-PD-1 immunotherapy enhances tumor regression and dramatically improves overall survival rates in mouse tumor models. Their study uncovers a novel molecular mechanism for regulating PD-L1 protein stability by a cell cycle kinase and reveals the potential for using combination treatment with CDK4/6 inhibitors and PD-1/PD-L1 immune checkpoint blockade to enhance therapeutic efficacy for human cancers.
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4、PD-1 is a haploinsufficient suppressor of T cell lymphomagenesis.

T cell non-Hodgkin lymphomas are a heterogeneous group of highly aggressive malignancies with poor clinical outcomes. T cell lymphomas originate from peripheral T cells and are frequently characterized by genetic gain-of-function variants in T cell receptor (TCR) signalling molecules. Although these oncogenic alterations are thought to drive TCR pathways to induce chronic proliferation and cell survival programmes, it remains unclear whether T cells contain tumour suppressors that can counteract these events. Here Tim Wartewig at Technische Universität München in München, Germany and his colleagues show that the acute enforcement of oncogenic TCR signalling in lymphocytes in a mouse model of human T cell lymphoma drives the strong expansion of these cells in vivo. However, this response is short-lived and robustly counteracted by cell-intrinsic mechanisms. A subsequent genome-wide in vivo screen using T cell-specific transposon mutagenesis identified PDCD1, which encodes the inhibitory receptor programmed death-1 (PD-1), as a master gene that suppresses oncogenic T cell signalling. Mono- and bi-allelic deletions of PDCD1 are also recurrently observed in human T cell lymphomas with frequencies that can exceed 30%, indicating high clinical relevance. Mechanistically, the activity of PD-1 enhances levels of the tumour suppressor PTEN and attenuates signalling by the kinases AKT and PKC in pre-malignant cells. By contrast, a homo- or heterozygous deletion of PD-1 allows unrestricted T cell growth after an oncogenic insult and leads to the rapid development of highly aggressive lymphomas in vivo that are readily transplantable to recipients. Thus, the inhibitory PD-1 receptor is a potent haploinsufficient tumour suppressor in T cell lymphomas that is frequently altered in human disease. These findings extend the known physiological functions of PD-1 beyond the prevention of immunopathology after antigen-induced T cell activation, and have implications for T cell lymphoma therapies and for current strategies that target PD-1 in the broader context of immuno-oncology.
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5、A neoantigen fitness model predicts tumour response to checkpoint blockade immunotherapy.

Checkpoint blockade immunotherapies enable the host immune system to recognize and destroy tumour cells. Their clinical activity has been correlated with activated T-cell recognition of neoantigens, which are tumour-specific, mutated peptides presented on the surface of cancer cells. Here Marta Łuksza at Institute for Advanced Study, Princeton in New Jersey, USA and his colleagues present a fitness model for tumours based on immune interactions of neoantigens that predicts response to immunotherapy. Two main factors determine neoantigen fitness: the likelihood of neoantigen presentation by the major histocompatibility complex (MHC) and subsequent recognition by T cells. They estimate these components using the relative MHC binding affinity of each neoantigen to its wild type and a nonlinear dependence on sequence similarity of neoantigens to known antigens. To describe the evolution of a heterogeneous tumour, they evaluate its fitness as a weighted effect of dominant neoantigens in the subclones of the tumour. Their model predicts survival in anti-CTLA-4-treated patients with melanoma and anti-PD-1-treated patients with lung cancer. Importantly, low-fitness neoantigens identified by their method may be leveraged for developing novel immunotherapies. By using an immune fitness model to study immunotherapy, they reveal broad similarities between the evolution of tumours and rapidly evolving pathogens.
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