Microenvironmental innate immune signaling and cell mechanical responses promote tumor growth

Zhou, Jun; Valentini, Erica; Boutros, Michael

doi:10.1016/j.devcel.2021.06.007

Cited by 24 publications

(14 citation statements)

References 107 publications

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“…Moreover, perturbations of Notch with Cas9.P2 on/off also increased ISC/EB numbers in the R2 region, highlighting regional differences when compared to neur (Figures 3D and S1B). These changes have been previously observed in LOF studies of these genes, confirming the specificity of the gRNAs used [22,26,27]. Interestingly, gRNA 2x against Mad failed to increase ISC/EB proliferation in the R2/R4 region, but did increase their numbers in the R5 region, highlighting regional specificity (Figures 3D and S2A,B).…”

Section: Cas9p2 On/off and U M Cas9 On Are Effective At Inducing Intestinal Tumorssupporting

confidence: 85%

“…With the precision of CRISPR-Cas in editing the genome, attempts at making patient specific mutations in fly using this strategy combined with drug screening could facilitate a more personalized approach for treatment. Additionally, with an in vivo fly model, other factors such the tumor microenvironment, host-microbe interaction, and changes in organelle/cellular trafficking pathways could also be taken into consideration in order to gain a better mechanistic understanding of tumorigenesis [21,22,51]. In summary, our study lends future support to using CRISPR-Cas editing to study tumor biology in Drosophila melanogaster, which serves as an important model organism.…”

Section: Effects Of High Cas9 Expression and Outlook On Applications Of Crispr Fly Modelsmentioning

confidence: 87%

“…Flies were kept on a standard cornmeal/agar diet with a 12 h:12 h light:dark cycle. One L of standard diet contained 44 g sugar syrup, 80 g malt, 80 g corn flour premium G750, 10 g soy flour, 18 g yeast, 2.4 g methly-4-hyroxybenzoate, 6.6 mL propionic acid, 0.66 mL phosphoric acid, and 8 g agar [22]. Flies requiring adult expression of transgenes were initially raised at 18 • C (permissive temperature) and switched to 29 • C (restrictive temperature) post eclosion for specific durations.…”

Section: Crispr/cas9 Mutagenesismentioning

confidence: 99%

“…Mutations in tumor suppressors such as Notch, neur, or Mad in progenitor cells are known to cause intestinal tumors [22,26]. To determine how effective Cas9.P2 and u M Cas9 are in inducing intestinal tumors, we quantified the tumor incidence rate in the population.…”

Section: Mutating Tumor Suppressors Increases Mitotic Cells and Tumor Incidencementioning

confidence: 99%

“…Of note, conserved pathways such as Notch and BMP/Dpp signaling have been reported to control various aspects of differentiation and proliferation [20]. To date, CRISPR-Cas9 studies in the Drosophila intestine have been limited [21,22]. Here, we performed an analysis of two popular Cas9 expression constructs (Cas9.P2 and u M Cas9) for their ability to specifically alter ISCs/EBs biology.…”

Section: Introductionmentioning

confidence: 99%

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Conditional CRISPR-Cas Genome Editing in Drosophila to Generate Intestinal Tumors

Bahuguna

Redhai

Zhou

et al. 2021

Cells

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CRISPR-Cas has revolutionized genetics and extensive efforts have been made to enhance its editing efficiency by developing increasingly more elaborate tools. Here, we evaluate the CRISPR-Cas9 system in Drosophila melanogaster to assess its ability to induce stem cell-derived tumors in the intestine. We generated conditional tissue-specific CRISPR knockouts using different Cas9 expression vectors with guide RNAs targeting the BMP, Notch, and JNK pathways in intestinal progenitors such as stem cells (ISCs) and enteroblasts (EBs). Perturbing Notch and BMP signaling increased the proliferation of ISCs/EBs and resulted in the formation of intestinal tumors, albeit with different efficiencies. By assessing both the anterior and posterior regions of the midgut, we observed regional differences in ISC/EB proliferation and tumor formation upon mutagenesis. Surprisingly, high continuous expression of Cas9 in ISCs/EBs blocked age-dependent increase in ISCs/EBs proliferation and when combined with gRNAs targeting tumor suppressors, it prevented tumorigenesis. However, no such effects were seen when temporal parameters of Cas9 were adjusted to regulate its expression levels or with a genetically modified version, which expresses Cas9 at lower levels, suggesting that fine-tuning Cas9 expression is essential to avoid deleterious effects. Our findings suggest that modifications to Cas9 expression results in differences in editing efficiency and careful considerations are required when choosing reagents for CRISPR-Cas9 mutagenesis studies. In summary, Drosophila can serve as a powerful model for context-dependent CRISPR-Cas based perturbations and to test genome-editing systems in vivo.

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Section: Cas9p2 On/off and U M Cas9 On Are Effective At Inducing Intestinal Tumorssupporting

confidence: 85%

Section: Effects Of High Cas9 Expression and Outlook On Applications Of Crispr Fly Modelsmentioning

confidence: 87%

Section: Crispr/cas9 Mutagenesismentioning

confidence: 99%

Section: Mutating Tumor Suppressors Increases Mitotic Cells and Tumor Incidencementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Conditional CRISPR-Cas Genome Editing in Drosophila to Generate Intestinal Tumors

Bahuguna

Redhai

Zhou

et al. 2021

Cells

Self Cite

View full text Add to dashboard Cite

show abstract

Synergistic Potential of Antigen-Specific Vaccines and Immunomodulatory Agents for Lung Cancer Treatment

Venkataramanan,

Raman,

Rangasamy

et al. 2024

Immunotherapy Against Lung Cancer

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ELFN1-AS1 promotes GDF15-mediated immune escape of colorectal cancer from NK cells by facilitating GCN5 and SND1 association

Han

Chen

et al. 2023

Discov Onc

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The ability of colorectal cancer (CRC) cells to escape from natural killer (NK) cell immune surveillance leads to anti-tumor treatment failure. The long non-coding RNA (lncRNA) ELFN1-AS1 is aberrantly expressed in multiple tumors suggesting a role as an oncogene in cancer development. However, whether ELFN1-AS1 regulates immune surveillance in CRC is unclear. Here, we determined that ELFN1-AS1 enhanced the ability of CRC cells to escape from NK cell surveillance in vitro and in vivo. In addition, we confirmed that ELFN1-AS1 in CRC cells attenuated the activity of NK cell by down-regulating NKG2D and GZMB via the GDF15/JNK pathway. Furthermore, mechanistic investigations demonstrated that ELFN1-AS1 enhanced the interaction between the GCN5 and SND1 protein and this influenced H3k9ac enrichment at the GDF15 promotor to stimulate GDF15 production in CRC cells. Taken together, our findings indicate that ELFN1-AS1 in CRC cells suppresses NK cell cytotoxicity and ELFN1-AS1 is a potential therapeutic target for CRC.

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Microenvironmental innate immune signaling and cell mechanical responses promote tumor growth

Cited by 24 publications

References 107 publications

Conditional CRISPR-Cas Genome Editing in Drosophila to Generate Intestinal Tumors

Conditional CRISPR-Cas Genome Editing in Drosophila to Generate Intestinal Tumors

Synergistic Potential of Antigen-Specific Vaccines and Immunomodulatory Agents for Lung Cancer Treatment

ELFN1-AS1 promotes GDF15-mediated immune escape of colorectal cancer from NK cells by facilitating GCN5 and SND1 association

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