Regulation of cancer cell metabolism Mak, Tak W; Cairns, Rob A; Harris, Isaac S
Nature reviews. Cancer,
02/2011, Letnik:
11, Številka:
2
Journal Article
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Interest in the topic of tumour metabolism has waxed and waned over the past century of cancer research. The early observations of Warburg and his contemporaries established that there are ...fundamental differences in the central metabolic pathways operating in malignant tissue. However, the initial hypotheses that were based on these observations proved inadequate to explain tumorigenesis, and the oncogene revolution pushed tumour metabolism to the margins of cancer research. In recent years, interest has been renewed as it has become clear that many of the signalling pathways that are affected by genetic mutations and the tumour microenvironment have a profound effect on core metabolism, making this topic once again one of the most intense areas of research in cancer biology.
Genomic sequencing studies of breast and other cancers have identified patterns of mutations that have been attributed to the endogenous mutator activity of APOBEC3B (A3B), a member of the AID/APOBEC ...family of cytidine deaminases. A3B gene expression is increased in many cancers, but its upstream drivers remain undefined. Furthermore, there exists a common germ-line deletion polymorphism ( A3B ᵈᵉˡ), which has been associated with a paradoxical increase in breast cancer risk. To examine causes and consequences of A3B expression and its constitutive absence in breast cancer, we analyzed two large clinically annotated genomic datasets The Cancer Genome Atlas (TCGA) and the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC). We confirmed that A3B expression is associated with aggressive clinicopathologic characteristics and adverse outcomes and show that A3B expression is highly correlated with proliferative features (mitosis and cell cycle-related gene expression) in breast and 15 of 16 other solid tumor types. However, breast cancers arising in homozygous A3B ᵈᵉˡ individuals with A3B absent did not differ in these features, indicating that A3B expression is a reflection rather than a direct cause of increased proliferation. Using gene set enrichment analysis (GSEA), we detected a pattern of immune activation in A3B ᵈᵉˡ breast cancers, which seems to be related to hypermutation arising in A3B ᵈᵉˡ carriers. Together, these results provide an explanation for A3B overexpression and its prognostic effect, giving context to additional study of this mutator as a cancer biomarker or putative drug target. In addition, although immune features of A3B ᵈᵉˡ require additional study, these findings nominate the A3B ᵈᵉˡ polymorphism as a potential predictor for cancer immunotherapy.
Significance Somatic mutagenesis is fundamental to the development and evolution of cancers. APOBEC3B (A3B) is a cellular deaminase, which is overexpressed in cancers and believed to be an important cause of cancer-associated mutations. The factors responsible for A3B up-regulation are unknown. Interestingly, a germ-line deletion polymorphism exists, such that a significant proportion of the global population does not express A3B protein. Using large human cancer datasets, we show that A3B expression is strongly associated with cellular proliferation. Furthermore, we identify a pattern of immune activation related to hypermutation in tumors arising in A3B deletion carriers suggesting that these patients could respond differently to immune-directed therapies. These results provide important context for the ongoing study of A3B as a therapeutic target or biomarker.
Caspase functions in cell death and disease McIlwain, David R; Berger, Thorsten; Mak, Tak W
Cold Spring Harbor perspectives in biology,
2013-Apr-01, 2013-04-01, 20130401, Letnik:
5, Številka:
4
Journal Article
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Caspases are a family of endoproteases that provide critical links in cell regulatory networks controlling inflammation and cell death. The activation of these enzymes is tightly controlled by their ...production as inactive zymogens that gain catalytic activity following signaling events promoting their aggregation into dimers or macromolecular complexes. Activation of apoptotic caspases results in inactivation or activation of substrates, and the generation of a cascade of signaling events permitting the controlled demolition of cellular components. Activation of inflammatory caspases results in the production of active proinflammatory cytokines and the promotion of innate immune responses to various internal and external insults. Dysregulation of caspases underlies human diseases including cancer and inflammatory disorders, and major efforts to design better therapies for these diseases seek to understand how these enzymes work and how they can be controlled.
Gastric cancer displays marked molecular heterogeneity with aggressive behavior and treatment resistance. Therefore, good in vitro models that encompass unique subtypes are urgently needed for ...precision medicine development. Here, we have established a primary gastric cancer organoid (GCO) biobank that comprises normal, dysplastic, cancer, and lymph node metastases (n = 63) from 34 patients, including detailed whole-exome and transcriptome analysis. The cohort encompasses most known molecular subtypes (including EBV, MSI, intestinal/CIN, and diffuse/GS, with CLDN18-ARHGAP6 or CTNND1-ARHGAP26 fusions or RHOA mutations), capturing regional heterogeneity and subclonal architecture, while their morphology, transcriptome, and genomic profiles remain closely similar to in vivo tumors, even after long-term culture. Large-scale drug screening revealed sensitivity to unexpected drugs that were recently approved or in clinical trials, including Napabucasin, Abemaciclib, and the ATR inhibitor VE-822. Overall, this new GCO biobank, with linked genomic data, provides a useful resource for studying both cancer cell biology and precision cancer therapy.
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•Living biobank includes 17 normal and 46 gastric cancer organoid lines•Organoid biobank encompasses most of the known molecular subtypes of gastric cancer•Organoids recapitulate the genomic and transcriptomic features of original tumors•High-throughput screen revealed potential target drugs for personalized therapy
Leung and colleagues established a biobank of patient-derived gastric cancer organoids that encompasses a diverse array of subtypes and maintained long-term similarity to the original tumors. They used the organoids to perform large-scale drug screening that identified potential target drugs and could guide patient drug selection.
The interaction between tumor and the immune system is still poorly understood. Significant clinical responses have been achieved in cancer patients treated with antibodies against the CTLA4 and ...PD-1/PD-L1 checkpoints; however, only a small portion of patients responded to the therapies, indicating a need to explore additional co-inhibitory molecules for cancer treatment. B7-H3, a member of the B7 superfamily, was previously shown by us to inhibit T-cell activation and autoimmunity. In this study, we have analyzed the function of BT-H3 in tumor immunity. Expression of B7-H3 was found in multiple tumor lines, tumor-infiltrating dendritic cells, and macrophages. B7-H3-deficient mice or mice treated with an antagonistic antibody to B7-H3 showed reduced growth of multiple tumors, which depended on NK and CD8^＋ T cells. With a putative receptor expressed by cytotoxic lymphocytes, B7-H3 inhibited their activation, and its deficiency resulted in increased cytotoxic lymphocyte function in tumor-bearing mice. Combining blockades of B7-H3 and PD-1 resulted in further enhanced therapeutic control of late-stage tumors. Taken together, our results indicate that the B7-H3 checkpoint may serve as a novel target for immunotherapy against cancer.
Despite development of new antiviral drugs, viral infections are still a major health problem. The most potent antiviral defense mechanism is the innate production of type I interferon (IFN-I), which ...not only limits virus replication but also promotes antiviral T cell immunity through mechanisms, which remain insufficiently studied. Using the murine lymphocytic choriomeningitis virus model system, we show here that IFN-I signaling on T cells prevented their rapid elimination in vivo. Microarray analyses uncovered that IFN-I triggered the expression of selected inhibitory NK-cell-receptor ligands. Consequently, T cell immunity of IFN-I receptor (IFNAR)-deficient T cells could be restored by NK cell depletion or in NK-cell-deficient hosts (Nfil3–/–). The elimination of Ifnar1–/– T cells was dependent on NK-cell-mediated perforin expression. In summary, we identified IFN-I as a key player regulating the protection of T cells against regulatory NK cell function.
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•Ifnar1–/– T cells proliferate in vitro, but not in vivo, suggesting cell interaction•Microarray analyses identify MHC molecules as being regulated by type I interferons•NK cell deficiency rescues expansion and function of IFN-I unresponsive T cells•NK-cell-mediated killing of activated Ifnar1–/– CD8+ T cells depends on perforin
Type I interferons (IFN-I) are important for promoting antiviral T cell immunity, but the mechanisms behind IFN-I action have been unclear. Xu et al. show that IFN-I protects antiviral T cells from regulatory cytotoxic effects of natural killer cells and promotes their expansion and antiviral effector functions.
The success of checkpoint inhibitors has accelerated the clinical implementation of a vast mosaic of single agents and combination immunotherapies. However, the lack of clinical translation for a ...number of immunotherapies as monotherapies or in combination with checkpoint inhibitors has clarified that new strategies must be employed to advance the field. The next chapter of immunotherapy should examine the immuno-oncology therapeutic failures, and consider the complexity of immune cell-cancer cell interactions to better design more effective anticancer drugs. Herein, we briefly review the history of immunotherapy and checkpoint blockade, highlighting important clinical failures. We discuss the critical aspects - beyond T cell co-receptors - of immune processes within the tumour microenvironment (TME) that may serve as avenues along which new therapeutic strategies in immuno-oncology can be forged. Emerging insights into tumour biology suggest that successful future therapeutics will focus on two key factors: rescuing T cell homing and dysfunction in the TME, and reappropriating mononuclear phagocyte function for TME inflammatory remodelling. New drugs will need to consider the complex cell networks that exist within tumours and among cancer types.
Estrogen is a key regulator of normal function of female reproductive system and plays a pivotal role in the development and progression of breast cancer. Here, we demonstrate that JMJD2B (also known ...as KDM4B) constitutes a key component of the estrogen signaling pathway. JMJD2B is expressed in a high proportion of human breast tumors, and that expression levels significantly correlate with estrogen receptor (ER) positivity. In addition, 17-beta-estradiol (E2) induces JMJD2B expression in an ERα dependent manner. JMJD2B interacts with ERα and components of the SWI/SNF-B chromatin remodeling complex. JMJD2B is recruited to ERα target sites, demethylates H3K9me3 and facilitates transcription of ER responsive genes including MYB, MYC and CCND1. As a consequence, knockdown of JMJD2B severely impairs estrogen-induced cell proliferation and the tumor formation capacity of breast cancer cells. Furthermore, Jmjd2b-deletion in mammary epithelial cells exhibits delayed mammary gland development in female mice. Taken together, these findings suggest an essential role for JMJD2B in the estrogen signaling, and identify JMJD2B as a potential therapeutic target in breast cancer.
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