CRISPR/Cas9 and cancer

CRISPR/Cas9 has become a powerful method for making changes to the genome of many organisms. First discovered in bacteria as part of an adaptive immune system, CRISPR/Cas9 and modified versions have found widespread use in genome engineering and in the activation or repression of gen expression. As such, CRISPR/Cas9 promises to accelerate cancer research by providing an efficient technology to dissect mechanisms of tumorigenesis, identify targets for drug development, and possibly arm cells for cell-based therapies. Here, we review the current applications of the CRISPR/Cas9 technology for cancer research and therapy. We highlight the impact of CRISPR/Cas9 in generating organoid and mouse models of cancer. Finally, we provide an overview of the first clinical trials applying CRISPR/Cas9 as a therapeutic approach against cancer.

Mouse Models in Meningioma Research: A Systematic Review

Meningiomas are the most frequent primitive central nervous system tumors found in adults. Mouse models of cancer have been instrumental in understanding disease mechanisms and establishing preclinical drug testing. Various mouse models of meningioma have been developed over time, evolving in light of new discoveries in our comprehension of meningioma biology and with improvements in genetic engineering techniques. We reviewed all mouse models of meningioma described in the literature, including xenograft models (orthotopic or heterotopic) with human cell lines or patient derived tumors, and genetically engineered mouse models (GEMMs). Xenograft models provided useful tools for preclinical testing of a huge range of innovative drugs and therapeutic options, which are summarized in this review. GEMMs offer the possibility of mimicking human meningiomas at the histological, anatomical, and genetic level and have been invaluable in enabling tumorigenesis mechanisms, including initiation and progression, to be dissected. Currently, researchers have a range of different mouse models that can be used depending on the scientific question to be answered.

Ethical Considerations for Common Mouse Models of Cancer (Preprint)

BACKGROUND Animal Ethics Committees (AECs) are concerning possibilities for public participation in the regulation of animal research. AECs are accountable for approving and monitoring research within Accredited Animal Research Establishments (AARE) (https://www.animalethics.org.au/animal-ethics-committees). In the way of making mouse models of cancer, several new considerations should be mentioned before the study design. OBJECTIVE To consider both personnel and animal welfare decisions at each stage of making mouse models of cancer, it is essential to have comprehensive information on the animal models. METHODS Three main cancer models are including; chemically induced mouse models, genetically engineered mouse models (GEMMs), xenograft nude mice, and Avatar. Some genetic changes in GEMMs are passing through next generations and not only do they have pain and suffering but also, they impose some environmental changes on mice. RESULTS Several phenotypes are required regarding the target of tumor model that expressed research are typically wisely investigated, but those that have an influence on the animal's welfare but have little or no effect on the disease procedure are often less carefully considered. CONCLUSIONS Complete analysis and regulations of animal welfare can offer beneficial information for researchers. This information is similarly essential to allow members of the institutional animal care and use committee to make necessary cost: benefit ethical review of animal studies. CLINICALTRIAL Not Applicable

Microbiome-derived inosine modulates response to checkpoint inhibitor immunotherapy

Several species of intestinal bacteria have been associated with enhanced efficacy of checkpoint blockade immunotherapy, but the underlying mechanisms by which the microbiome enhances antitumor immunity are unclear. In this study, we isolated three bacterial species—Bifidobacterium pseudolongum, Lactobacillus johnsonii, and Olsenella species—that significantly enhanced efficacy of immune checkpoint inhibitors in four mouse models of cancer. We found that intestinal B. pseudolongum modulated enhanced immunotherapy response through production of the metabolite inosine. Decreased gut barrier function induced by immunotherapy increased systemic translocation of inosine and activated antitumor T cells. The effect of inosine was dependent on T cell expression of the adenosine A2A receptor and required costimulation. Collectively, our study identifies a previously unknown microbial metabolite immune pathway activated by immunotherapy that may be exploited to develop microbial-based adjuvant therapies.

Asparagine signals mitochondrial respiration and can be targeted to impair tumour growth

Mitochondrial respiration is critical for cell proliferation. In addition to producing ATP via the electron transport chain (ETC), respiration is required for the generation of TCA cycle-derived biosynthetic precursors, such as aspartate, an essential substrate for nucleotide synthesis. Because mTORC1 coordinates availability of biosynthetic precursors with anabolic metabolism, including nucleotide synthesis, a link between respiration and mTORC1 is fitting. Here we show that in addition to depleting intracellular aspartate, ETC inhibition depletes aspartate-derived asparagine and impairs mTORC1 activity. Providing exogenous asparagine restores mTORC1 activity, nucleotide synthesis, and proliferation in the context of ETC inhibition without restoring intracellular aspartate in a panel of cancer cell lines. As a therapeutic strategy, the combination of ETC inhibitor metformin, which limits tumour asparagine synthesis, and either asparaginase or dietary asparagine restriction, which limit tumour asparagine consumption, effectively impairs tumour growth in several mouse models of cancer. Because environmental asparagine is sufficient to restore proliferation with respiration impairment, both in vitro and in vivo, our findings suggest that asparagine synthesis is a fundamental purpose of mitochondrial respiration. Moreover, the results suggest that asparagine signals active respiration to mTORC1 to communicate biosynthetic precursor sufficiency and promote anabolism.