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My lab will develop genetic models of liver and lung cancer using small RNA tools, such as RNAi-mediated silencing and CRISPR/Cas9-mediated genome editing. The CRISPR/Cas9 system allows us to quickly generate somatic loss-of-function mutations in tumor suppressor genes or gain-of-function mutations in oncogenes. Our approach presents a new avenue for rapid development of cancer models, functional genomics, and proof-of-concept targeted cancer therapy. My laboratory will engage in the following areas of research over the next few years:

Discover and correct liver cancer genes using CRISPR-mediated genome editing

Many candidate cancer genes are being discovered through cancer genome-sequencing efforts, and simple genetic methods are needed to validate candidate cancer genes in vivo. CRISPR/Cas genome-editing has been successfully used in many organisms, including mouse and human cells. We will use in vivo CRISPR/Cas-mediated genome editing tools to discover, validate, and correct liver cancer genes in the mouse. To identify potential liver cancer therapeutic targets, we will devise novel CRISPR strategies to delete candidate oncogenes and test the effect on liver cancer progression. Because our approach allows us to perform genetic tests without breeding mice, our approach will speed up cancer gene discovery and drug target validation for liver cancer.

Characterize response and resistance to KRAS inhibition using in vivo RNAi and genome editing

KRAS is mutated in >30% of lung cancer. While most studies in the literature use inducible Kras cDNA, conditional shRNA system allows knockdown of endogenous levels of Kras in vivo, offering a more physiologic model of Kras inhibition. We will model the response and resistance to Kras inhibition in mouse models using lentiviral-based tet-on shRNA in the lung. Our recent studies show that after long-term Kras inhibition by RNAi, Kras-driven tumors relapse and become Kras-independent. We will explore the molecular basis of resistance to Kras inhibition using gene expression profiling. To completely delete the oncogenic KRAS gene and compare the phenotype with RNAi-mediated knockdown, we plan to use CRISPR to generate floxed KRAS conditional knockout alleles in lung cancer cell lines. These small RNA-based experiments will generate in vivo and in vitro platforms to uncover important KRAS biology.

Investigate oncogenic and tumor suppressor miRNA networks in lung cancer

MicroRNAs (miRNAs) are small, non-coding RNAs that regulate mRNA translation or stability. Delineating miRNA networks can identify new miRNAs and miRNA antagonists for lung cancer treatment. We will cross-compare human lung adenocarcinoma miRNA expression profiles and cancer genome copy number analyses from TCGA (the Cancer Genome Atlas) to identify candidate miRNAs that drive or suppress tumor formation. We will use tet-on miRNA expression system to conditionally express miRNA at various stages of tumor progression and study the impact on tumor growth in vivo. Together, these studies will unveil miRNA networks in cancer using genetic tools.  

Rotation Projects

Our lab uses CRISPR tools to speed up cancer gene discovery and disease gene repair. Rotation projects are available to explore experimental techniques such as molecular cloning of CRISPR plasmids, measuring genome-editing efficiency, dissecting mice, and processing of mouse tumor/tissue for histology.

One or more keywords matched the following items that are connected to Xue, Wen
Item TypeName
Academic Article CRISPR-mediated direct mutation of cancer genes in the mouse liver.
Academic Article Genome editing with Cas9 in adult mice corrects a disease mutation and phenotype.
Academic Article Rapid modelling of cooperating genetic events in cancer through somatic genome editing.
Academic Article Precision cancer mouse models through genome editing with CRISPR-Cas9.
Academic Article Adenovirus-Mediated Somatic Genome Editing of Pten by CRISPR/Cas9 in Mouse Liver in Spite of Cas9-Specific Immune Responses.
Academic Article A versatile reporter system for CRISPR-mediated chromosomal rearrangements.
Academic Article Therapeutic genome editing by combined viral and non-viral delivery of CRISPR system components in vivo.
Academic Article Genomic Amplifications Cause False Positives in CRISPR Screens.
Academic Article Genome-Wide CRISPR Screen Identifies Regulators of Mitogen-Activated Protein Kinase as Suppressors of Liver Tumors in Mice.
Academic Article CRISPR/Cas9-mediated genome editing induces exon skipping by alternative splicing or exon deletion.
Academic Article Structure-guided chemical modification of guide RNA enables potent non-viral in vivo genome editing.
Academic Article Partial DNA-guided Cas9 enables genome editing with reduced off-target activity.
Academic Article CRISPR-Cas-related technologies in basic and translational liver research.
Academic Article Cas9-mediated allelic exchange repairs compound heterozygous recessive mutations in mice.
Academic Article In Vivo Genome Editing Partially Restores Alpha1-Antitrypsin in a Murine Model of AAT Deficiency.
Academic Article All-in-one adeno-associated virus delivery and genome editing by Neisseria meningitidis Cas9 in vivo.
Academic Article Understanding and repurposing CRISPR-mediated alternative splicing.
Grant CRISPR-based modular therapy for precision medicine
Grant Develop combinatorial non-viral and viral CRISPR delivery for lung diseases
Academic Article A Compact, High-Accuracy Cas9 with a Dinucleotide PAM for In?Vivo Genome Editing.
Academic Article CRISPR-SONIC: targeted somatic oncogene knock-in enables rapid in vivo cancer modeling.
Academic Article Real-time imaging of integrin ?4 dynamics using a reporter cell line generated by Crispr/Cas9 genome editing.
Academic Article Tissue-restricted genome editing in vivo specified by microRNA-repressible anti-CRISPR proteins.
Academic Article Chemical modifications of adenine base editor mRNA and guide RNA expand its application scope.
Academic Article Improved prime editors enable pathogenic allele correction and cancer modelling in adult mice.
Academic Article Deletion and replacement of long genomic sequences using prime editing.
Academic Article AAV5 delivery of CRISPR-Cas9 supports effective genome editing in mouse lung airway.
Academic Article Self-inactivating, all-in-one AAV vectors for precision Cas9 genome editing via homology-directed repair in vivo.
Concept Clustered Regularly Interspaced Short Palindromic Repeats
Concept CRISPR-Cas Systems
Concept CRISPR-Associated Proteins
Academic Article Genome-wide detection of CRISPR editing in vivo using GUIDE-tag.
Academic Article A split prime editor with untethered reverse transcriptase and circular RNA template.
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