Gene expression profile of Dclk1+ cells in intestinal tumors

Yamaga, Yuichi; Fukuda, Akira; Nakanishi, Yuki; Goto, Norihiro; Matsumoto, Y; Yoshioka, Taiyo; Maruno, Takahisa; Chiba, Tsutomu; Seno, Hiroshi

doi:10.1016/j.dld.2018.06.011

Cited by 10 publications

(10 citation statements)

References 45 publications

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“…While previous reports show IL-25 expression by tuft cells in the intestinal epithelium (13)(14)(15) and IL17RB (the receptor for IL-25) expression by ILC2s (16,23), we noticed IL17RB expression by tuft cells. Although the previous transcriptome analysis showed up-regulated Il17rb mRNA expression in tuft cells (18)(19)(20), our work shows that IL17RB is distinctively expressed in Dclk1 + intestinal epithelial cells at the protein level and that IL17RB marks mouse intestinal TSCs. Identification of IL17RB enables further analysis of two distinct subsets of tuft cell-like tumor cells: highly differentiated tuft cell-like tumor cells (Lgr5 − IL17RB + cells) and tuft cell-like tumor cells with TCS potential (Lgr5 + IL17RB + cells).…”

Section: Discussioncontrasting

confidence: 80%

“…To identify the cell surface marker distinctively expressed by Dclk1 + tumor cells, we focused on IL17RB. Our microarray data showed that Il17rb mRNA expression is up-regulated in Dclk1 + cells (18) and that Dclk1 + tumor cells in the intestinal adenomas show similar mRNA and protein expression patterns to Dclk1 + tuft cells in the normal intestine (18). Other investigators have also shown by microarray analysis of Trpm5 + cells (19) and by single-cell RNA sequencing of small intestinal epithelial cells Significance Cancer stem cells, capable of self-renewing and giving rise to progeny cells in the tumor, have attracted attention as potential therapeutic targets.…”

Section: Il17rb Marks Mouse Intestinal Tscs In An Il-13-dependent Manmentioning

confidence: 74%

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Lineage tracing and targeting of IL17RB ⁺ tuft cell-like human colorectal cancer stem cells

Goto

Fukuda

Yamaga

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Cancer stem cell (CSC)-specific markers may be potential therapeutic targets. We previously identified that Dclk1, a tuft cell marker, marks tumor stem cells (TSCs) in mouse intestinal adenomas. Based on the analysis of mouse Dclk1 + tumor cells, we aimed to identify a CSC-specific cell surface marker in human colorectal cancers (hCRCs) and validate the therapeutic effect of targeting it. IL17RB was distinctively expressed by Dclk1 + mouse intestinal tumor cells. Using Il17rb-CreERT2-IRES-EGFP mice, we show that IL17RB marked intestinal TSCs in an IL13-dependent manner. Tuft cell-like cancer cells were detected in a subset of hCRCs. In these hCRCs, lineage-tracing experiments in CRISPR-Cas9-mediated IL17RB-CreERT2 knockin organoids and xenograft tumors revealed that IL17RB marks CSCs that expand independently of IL-13. We observed up-regulation of POU2F3, a master regulator of tuft cell differentiation, and autonomous tuft cell-like cancer cell differentiation in the hCRCs. Furthermore, long-term ablation of IL17RBexpressing CSCs strongly suppressed the tumor growth in vivo. These findings reveal insights into a CSC-specific marker IL17RB in a subset of hCRCs, and preclinically validate IL17RB + CSCs as a cancer therapeutic target.C ancer stem cells (CSCs), capable of self-renewal and giving rise to progeny cells in cancers, have attracted attention as promising targets for anticancer therapeutics. The traditional xenotransplantation assays used to investigate the properties of CSCs have technical and conceptual limitations (1). Recent studies have shown that leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) marks CSCs in human colorectal cancers (hCRCs) in vivo by lineage tracing of LGR5-CreERT2 knockin hCRC organoids generated by CRISPR-Cas9-mediated gene editing (2, 3). Because most of the CSC markers are also expressed by normal stem cells (4-7), long-term CSC targeting may disrupt normal tissue homeostasis [e.g., liver injury after long-term LGR5-targeting (8)], whereas short-term CSC targeting leads to tumor regrowth (2,9). Hence, identification of CSC-specific markers is essential. We previously showed that Dclk1, a differentiated tuft cell marker in normal intestine, marks tumor stem cells (TSCs) in mouse intestinal adenomas by lineage-tracing experiments (10). However, whether DCLK1 marks CSCs in hCRCs has not been elucidated by in vivo lineage tracing of the tumors. Furthermore, feasible strategies to target DCLK1 + cells are necessary to realize a novel CSC-targeted therapy for hCRCs. Identification of a specific cell surface marker in Dclk1 + cells can facilitate the sorting analysis of Dclk1 + tumor cells and can also have the potential for future antibody therapeutics.The IL-17 receptor family includes five members (IL17RA to IL17RE) (11). The heterodimer of IL17RA and IL17RC serves as a receptor for IL-17A and IL-17F to mediate Th17 immune response, and the heterodimer of IL17RA and IL17RB serves as a receptor for IL-25 to mediate Th2 immune response (12).Recent studies showed that...

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Section: Discussioncontrasting

confidence: 80%

Section: Il17rb Marks Mouse Intestinal Tscs In An Il-13-dependent Manmentioning

confidence: 74%

Lineage tracing and targeting of IL17RB ⁺ tuft cell-like human colorectal cancer stem cells

Goto

Fukuda

Yamaga

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

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“…Many of the most significant 11q23.1 trans-eQTL targets, such as LRMP, SH2D7 and ALOX5 , have not previously been associated with specific expression in this cell-type, potentiating their status as a marker in the colonic epithelium. Additional markers of the tuft cell-like cluster include HCK and HPGDS, for which there is some orthogonal evidence of expression within tuft cells 29 , 30 . This improves our confidence that cluster 11 represents this cell-type and is not an artefact of the analysis.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional dynamics of colorectal cancer risk associated variation at 11q23.1 correlate with tuft cell abundance and marker expression in silico

Harris

Rajasekaran

Blackmur

et al. 2022

Sci Rep

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Colorectal cancer (CRC) is characterised by heritable risk that is not well understood. Heritable, genetic variation at 11q23.1 is associated with increased colorectal cancer (CRC) risk, demonstrating eQTL effects on 3 cis- and 23 trans-eQTL targets. We sought to determine the relationship between 11q23.1 cis- and trans-eQTL target expression and test for potential cell-specificity. scRNAseq from 32,361 healthy colonic epithelial cells was aggregated and subject to weighted gene co-expression network analysis (WGCNA). One module (blue) included 19 trans-eQTL targets and was correlated with POU2AF2 expression only. Following unsupervised clustering of single cells, the expression of 19 trans-eQTL targets was greatest and most variable in cluster number 11, which transcriptionally resembled tuft cells. 14 trans-eQTL targets were found to demarcate this cluster, 11 of which were corroborated in a second dataset. Intra-cluster WGCNA and module preservation analysis then identified twelve 11q23.1 trans-eQTL targets to comprise a network that was specific to cluster 11. Finally, linear modelling and differential abundance testing showed 11q23.1 trans-eQTL target expression was predictive of cluster 11 abundance. Our findings suggest 11q23.1 trans-eQTL targets comprise a POU2AF2-related network that is likely tuft cell-specific and reduced expression of these genes correlates with reduced tuft cell abundance in silico.

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“…Many of the most significant 11q23.1 trans-eQTL targets, such as LRMP, SH2D7 and ALOX5 , have not previously been associated with specific expression in this cell-type, potentiating their status as a marker in the colonic epithelium. Additional markers of the tuft cell-like cluster include HCK and HPGDS , for which there is some orthogonal evidence of expression within tuft cells (Gerbe et al, 2011; Yamaga et al, 2018). This improves our confidence that cluster 11 represents this cell-type and is not an artefact of the analysis.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional dynamics of colorectal cancer risk associated variation at 11q23.1 are correlated with tuft cell abundance and marker expression in silico

Harris

Rajasekaran

Blackmur

et al. 2022

Preprint

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Colorectal cancer (CRC) is characterised by heritable risk that is not well understood. Heritable, genetic variation at 11q23.1 is associated with increased colorectal cancer (CRC) risk, demonstrating eQTL effects on 3 cis- and 23 trans-eQTL targets. We sought to determine the relationship between 11q23.1 cis- and trans-eQTL target expression and test for potential cell-specificity. scRNAseq from 32,361 healthy colonic epithelial cells was aggregated and subject to weighted gene co-expression network analysis (WGCNA). One module (blue) included 19 trans-eQTL targets and was correlated with C11orf53 expression only. Following unsupervised clustering of single cells, the expression of 19 trans-eQTL targets was greatest and most variable in cluster number 11, which transcriptionally resembled tuft cells. 14 trans-eQTL targets were found to demarcate this cluster, 11 of which were corroborated in a second dataset. Intra-cluster WGCNA and module preservation analysis then identified twelve 11q23.1 trans-eQTL targets to comprise a network that was specific to cluster 11. Finally, linear modelling and differential abundance testing showed 11q23.1 trans-eQTL target expression was predictive of cluster 11 abundance. Our findings suggest 11q23.1 trans-eQTL targets comprise a C11orf53-related network that is likely tuft cell-specific and reduced expression of these genes correlates with reduced tuft cell abundance in silico.

show abstract

Gene expression profile of Dclk1+ cells in intestinal tumors

Abstract: We revealed factors that are highly expressed in Dclk1 intestinal tumor cells, which may help to develop cancer stem cell-targeted therapy in future.

Cited by 10 publications

References 45 publications

Lineage tracing and targeting of IL17RB ⁺ tuft cell-like human colorectal cancer stem cells

Lineage tracing and targeting of IL17RB ⁺ tuft cell-like human colorectal cancer stem cells

Transcriptional dynamics of colorectal cancer risk associated variation at 11q23.1 correlate with tuft cell abundance and marker expression in silico

Transcriptional dynamics of colorectal cancer risk associated variation at 11q23.1 are correlated with tuft cell abundance and marker expression in silico

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Gene expression profile of Dclk1+ cells in intestinal tumors

Abstract: We revealed factors that are highly expressed in Dclk1 intestinal tumor cells, which may help to develop cancer stem cell-targeted therapy in future.

Cited by 10 publications

References 45 publications

Lineage tracing and targeting of IL17RB + tuft cell-like human colorectal cancer stem cells

Lineage tracing and targeting of IL17RB + tuft cell-like human colorectal cancer stem cells

Transcriptional dynamics of colorectal cancer risk associated variation at 11q23.1 correlate with tuft cell abundance and marker expression in silico

Transcriptional dynamics of colorectal cancer risk associated variation at 11q23.1 are correlated with tuft cell abundance and marker expression in silico

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Product

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Lineage tracing and targeting of IL17RB ⁺ tuft cell-like human colorectal cancer stem cells

Lineage tracing and targeting of IL17RB ⁺ tuft cell-like human colorectal cancer stem cells