Vascular Tumor Recapitulated in Endothelial Cells from hiPSCs Engineered to Express the SERPINE1-FOSB Translocation (original) (raw)
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Circulation Research, 2015
Rationale: The participation of endothelial cells (EC) in many physiological and pathological processes is widely modeled using human EC cultures, but genetic manipulation of these untransformed cells has been technically challenging. Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 nuclease (Cas9) technology offers a promising new approach. However, mutagenized cultured cells require cloning to yield homogeneous populations, and the limited replicative lifespan of well-differentiated human EC presents a barrier for doing so. Objective: To create a simple but highly efficient method using CRISPR/Cas9 to generate biallelic gene disruption in untransformed human EC. Methods and Results: To demonstrate proof-of-principle, we used CRISPR/Cas9 to disrupt the gene for the class II transactivator. We used endothelial colony forming cell–derived EC and lentiviral vectors to deliver CRISPR/Cas9 elements to ablate EC expression of class II major h...
Three-dimensional CRISPR screening reveals epigenetic interaction with anti-angiogenic therapy
Communications Biology, 2021
Angiogenesis underlies development, physiology and pathogenesis of cancer, eye and cardiovascular diseases. Inhibiting aberrant angiogenesis using anti-angiogenic therapy (AAT) has been successful in the clinical treatment of cancer and eye diseases. However, resistance to AAT inevitably occurs and its molecular basis remains poorly understood. Here, we uncover molecular modifiers of the blood endothelial cell (EC) response to a widely used AAT bevacizumab by performing a pooled genetic screen using three-dimensional microcarrier-based cell culture and CRISPR–Cas9. Functional inhibition of the epigenetic reader BET family of proteins BRD2/3/4 shows unexpected mitigating effects on EC survival and/or proliferation upon VEGFA blockade. Moreover, transcriptomic and pathway analyses reveal an interaction between epigenetic regulation and anti-angiogenesis, which may affect chromosomal structure and activity in ECs via the cell cycle regulator CDC25B phosphatase. Collectively, our findin...
Nature communications, 2017
Genetically engineered mouse models that employ site-specific recombinase technology are important tools for cancer research but can be costly and time-consuming. The CRISPR-Cas9 system has been adapted to generate autochthonous tumours in mice, but how these tumours compare to tumours generated by conventional recombinase technology remains to be fully explored. Here we use CRISPR-Cas9 to generate multiple subtypes of primary sarcomas efficiently in wild type and genetically engineered mice. These data demonstrate that CRISPR-Cas9 can be used to generate multiple subtypes of soft tissue sarcomas in mice. Primary sarcomas generated with CRISPR-Cas9 and Cre recombinase technology had similar histology, growth kinetics, copy number variation and mutational load as assessed by whole exome sequencing. These results show that sarcomas generated with CRISPR-Cas9 technology are similar to sarcomas generated with conventional modelling techniques and suggest that CRISPR-Cas9 can be used to ...
Frontiers of CRISPR-Cas9 for Cancer Research and Therapy
Journal of Exploratory Research in Pharmacology, 2021
In recent years, gene editing technologies have made significant progress in understanding gene function and regulation. The Clustered regularly interspaced short palindromic repeats-CRISPR associated protein 9 (CRISPR-Cas9) system has emerged as a versatile tool for gene editing and genome engineering. In the last few years, CRISPR-Cas9 technology has been widely applied to cancer research, mainly to understand the mechanisms of oncogenesis, drug-target identification, and the development of various cell-based therapies. When combined with genome sequence information, this technology has also shown promise to cure heritable genetic disorders. This review summarizes some of the recent developments and preclinical applications of CRISPR-Cas9 technology in cancer research and therapy. We will discuss how CRISPR based approaches have been used as a tool to identify cancer-specific vulnerabilities and potential applications in cancer therapy.
CRISPR Cas System: an efficient tool for cancer modelling
Journal of the Pakistan Medical Association
The Clustered Regularly Interspaced Short Palindromic Repeats–Cas-9 (CRISPR-Cas9) system has been a revolutionising tool in the field of molecular genetics, which provides a versatile range of editing potentials. Researchers can produce breaks or alter genomes with ease using the system. Cancer is one of the multi-gene diseases whose genes need to be studied in detail. The CRISPR-Cas9 technology may also provide a promising potential in the field of cancer genetics. The current narrative review comprised 50 research articles which were keenly analysed and the applications and outcomes of CRISPR-Cas9 system in cancer genetics were comprehensively and critically discussed. It was concluded that application of the system had great potential to help understand cancer biology of various types and could be used for its genetic modelling. However, much work is still needed to be done to apply the technology for understanding...Continuous...
Application of CRISPR/Cas9 Technology in Cancer Treatment: A Future Direction
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Gene editing, especially with clustered regularly interspaced short palindromic repeats associated protein 9 (CRISPR-Cas9), has advanced gene function science. Gene editing’s rapid advancement has increased its medical/clinical value. Due to its great specificity and efficiency, CRISPR/Cas9 can accurately and swiftly screen the whole genome. This simplifies disease-specific gene therapy. To study tumor origins, development, and metastasis, CRISPR/Cas9 can change genomes. In recent years, tumor treatment research has increasingly employed this method. CRISPR/Cas9 can treat cancer by removing genes or correcting mutations. Numerous preliminary tumor treatment studies have been conducted in relevant fields. CRISPR/Cas9 may treat gene-level tumors. CRISPR/Cas9-based personalized and targeted medicines may shape tumor treatment. This review examines CRISPR/Cas9 for tumor therapy research, which will be helpful in providing references for future studies on the pathogenesis of malignancy a...
CRISPR-Cas9: a promising genetic engineering approach in cancer research
Therapeutic advances in medical oncology, 2018
Bacteria and archaea possess adaptive immunity against foreign genetic materials through clustered regularly interspaced short palindromic repeat (CRISPR) systems. The discovery of this intriguing bacterial system heralded a revolutionary change in the field of medical science. The CRISPR and CRISPR-associated protein 9 (Cas9) based molecular mechanism has been applied to genome editing. This CRISPR-Cas9 technique is now able to mediate precise genetic corrections or disruptions inandenvironments. The accuracy and versatility of CRISPR-Cas have been capitalized upon in biological and medical research and bring new hope to cancer research. Cancer involves complex alterations and multiple mutations, translocations and chromosomal losses and gains. The ability to identify and correct such mutations is an important goal in cancer treatment. In the context of this complex cancer genomic landscape, there is a need for a simple and flexible genetic tool that can easily identify functional ...
CRISPR-Cas9 as a Potential Cancer Therapy Agent: An Updat
Rovedar Publication, 2023
Cancer is the second leading cause of death globally and remains a major economic and social burden. Although our understanding of cancer at the molecular level continues to improve, more effort is needed to develop new therapeutic tools and approaches exploiting these advances. Due to its high efficiency and accuracy, the CRISPR-Cas9 genome editing technique has recently emerged as a cancer treatment strategy. Among its many applications, CRISPR-Cas9 has shown an unprecedented clinical potential to discover novel targets for cancer therapy and to dissect chemicalgenetic interactions, providing insight into how tumors respond to drug treatment. Moreover, CRISPR-Cas9 can be employed to rapidly engineer immune cells and oncolytic viruses for cancer immunotherapeutic applications. More importantly, the ability of CRISPR-Cas9 to accurately edit genes, not only in cell culture models and model organisms but also in humans, allows its use in therapeutic explorations this review, important considerations for the use of CRISPR/Cas9 in therapeutic properties are discussed, along with major challenges that will need to be addressed before clinical examinations for a complex and polygenic disease such as cancer. This review aimed to explore the potential of the CRISPR-Cas9 genome editing technique as a cancer treatment strategy. Specifically, we will discuss how CRISPR-Cas9 can be used to discover novel targets for cancer therapy and to dissect chemical-genetic interactions.
CRISPR based therapeutics: a new paradigm in cancer precision medicine
Molecular Cancer, 2022
Background Clustered regularly interspaced short palindromic repeat (CRISPR)-CRISPR-associated protein (Cas) systems are the latest addition to the plethora of gene-editing tools. These systems have been repurposed from their natural counterparts by means of both guide RNA and Cas nuclease engineering. These RNA-guided systems offer greater programmability and multiplexing capacity than previous generation gene editing tools based on zinc finger nucleases and transcription activator like effector nucleases. CRISPR-Cas systems show great promise for individualization of cancer precision medicine. Main body The biology of Cas nucleases and dead Cas based systems relevant for in vivo gene therapy applications has been discussed. The CRISPR knockout, CRISPR activation and CRISPR interference based genetic screens which offer opportunity to assess functions of thousands of genes in massively parallel assays have been also highlighted. Single and combinatorial gene knockout screens lead t...
CRISPR-Cas9 Applications in Cardiovascular Disease
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