Multiplexed activation of endogenous genes by CRISPRa elicits potent antitumor immunity

Wang, Guangchuan; Chow, Ryan D.; Bai, Zhigang; Zhu, Lv‐yun; Errami, Youssef; Dai, Xiaoyun; Dong, Matthew B.; Ye, Lupeng; Xiao-ya, Zhang; Renauer, Paul; Park, Jonathan J.; Shen, Li; Ye, Hanghui; Fuchs, Charles S.; Chen, Sidi

doi:10.1038/s41590-019-0500-4

Cited by 90 publications

(80 citation statements)

References 63 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We also provided an analysis of the molecular transitions that take place in ISCs from early stages of human development into adulthood, and these findings highlight intriguing transcription factors, signaling pathways, and metabolic features. These features could be targeted to enhance HIO stem cell maturation in vitro through transcription factor overexpression [69], CRISPR inhibition/activation [70,71], or small molecule modulations, each of which could be adapted using high-throughput single-cell genomic [72] D R A F T or image-based [73] readouts. We also observe that HIOs mature after transplantation into a mouse host; however, we note that there are multiple cell types observed in developing intestine that are underrepresented or absent in HIOs, including endothelial and immune cell populations.…”

Section: Discussionmentioning

confidence: 99%

An organoid and multi-organ developmental cell atlas reveals multilineage fate specification in the human intestine

Kilik

Holloway

et al. 2020

Preprint

View full text Add to dashboard Cite

Human intestinal organoids (HIOs) generated from pluripotent stem cells provide extraordinary opportunities to explore development and disease. Here, we generate a single-cell transcriptome reference atlas from HIOs and from multiple developing human organs to quantify the specificity of HIO cell fate acquisition, and to explore alternative fates. We identify epithelium-mesenchyme interactions, transcriptional regulators involved in cell fate specification, and stem cell maturation features in the primary tissue that are recapitulated in HIOs. We use an HIO time course to reconstruct the molecular dynamics of intestinal stem cell emergence, as well as the specification of multiple mesenchyme subtypes. We find that the intestinal master regulator CDX2 correlates with distinct phases of epithelial and mesenchymal development, and CDX2 deletion perturbs the differentiation of both intestinal epithelium and mesenchyme. Collectively our data provides a comprehensive and quantitative assessment of HIO development, and illuminates the molecular machinery underlying endodermal and mesodermal cell fate specification.

show abstract

Section: Discussionmentioning

confidence: 99%

An organoid and multi-organ developmental cell atlas reveals multilineage fate specification in the human intestine

Kilik

Holloway

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Recent work has leveraged CRISPRa for multiplexed activation of TAAs to enhance anti-tumor immunity. Injection of an sgRNA library targeting known mutated genes into mouse cancer cells expressing dCas9-transcriptional activators led to increased expression and subsequent presentation of TAAs [166]. Tumor regression occurred because of increased T cell infiltration and tumor cell destruction in this transplant model.…”

Section: The Immune Environment and Immunotherapy Genetic Targetsmentioning

confidence: 85%

CRISPR and transposon in vivo screens for cancer drivers and therapeutic targets

2020

View full text Add to dashboard Cite

Human cancers harbor substantial genetic, epigenetic, and transcriptional changes, only some of which drive oncogenesis at certain times during cancer evolution. Identifying the cancer-driver alterations amongst the vast swathes of "passenger" changes still remains a major challenge. Transposon and CRISPR screens in vivo provide complementary methods for achieving this, and each platform has its own advantages. Here, we review recent major technological breakthroughs made with these two approaches and highlight future directions. We discuss how each genetic screening platform can provide unique insight into cancer evolution, including intratumoral heterogeneity, metastasis, and immune evasion, presenting transformative opportunities for targeted therapeutic intervention.

show abstract

“…CRISPRi approaches have been used to repress proto-oncogenes like Granulin [82], while activating tumor suppressors PTEN, DKK3, or CHEK2 greatly suppresses proliferation of cancer cells [83,84,85]. A recently described MAEGI approach overexpresses tumor antigens by CRISPRa to increase their presentation to the immune system resulting in efficient destruction of tumor cells by cytotoxic CD8+ lymphocytes [86].…”

Section: Rewriting Histone Epigenetic Marksmentioning

confidence: 99%

Dead Cas Systems: Types, Principles, and Applications

Brezgin

Kostyusheva

Kostyushev

et al. 2019

IJMS

View full text Add to dashboard Cite

The gene editing tool CRISPR-Cas has become the foundation for developing numerous molecular systems used in research and, increasingly, in medical practice. In particular, Cas proteins devoid of nucleolytic activity (dead Cas proteins; dCas) can be used to deliver functional cargo to programmed sites in the genome. In this review, we describe current CRISPR systems used for developing different dCas-based molecular approaches and summarize their most significant applications. We conclude with comments on the state-of-art in the CRISPR field and future directions.

show abstract

Multiplexed activation of endogenous genes by CRISPRa elicits potent antitumor immunity

Cited by 90 publications

References 63 publications

An organoid and multi-organ developmental cell atlas reveals multilineage fate specification in the human intestine

An organoid and multi-organ developmental cell atlas reveals multilineage fate specification in the human intestine

CRISPR and transposon in vivo screens for cancer drivers and therapeutic targets

Dead Cas Systems: Types, Principles, and Applications

Contact Info

Product

Resources

About