Transcriptome-wide in vitro effects of aspirin on patient-derived normal colon organoids
<jats:title>Abstract</jats:title> <jats:sec> <jats:title /> <jats:p>Mechanisms underlying aspirin chemoprevention of colorectal cancer remain unclear. Prior studies have been limited because of the inability of precl...
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| Format: | Article |
| Language: | English |
| Published: |
American Association for Cancer Research (AACR)
2023
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| Online Access: | https://hdl.handle.net/1721.1/147040 |
| _version_ | 1811084806180569088 |
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| author | Devall, Matthew AM Drew, David A Dampier, Christopher H Plummer, Sarah J Eaton, Stephen Bryant, Jennifer Díez-Obrero, Virginia Mo, Jiancheng Kedrin, Dmitriy Zerjav, Dylan C Takacsi-Nagy, Oliver Jennelle, Lucas T Ali, Mourad W Yilmaz, Ömer H Moreno, Victor Powell, Steven M Chan, Andrew T Peters, Ulrike Casey, Graham |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Devall, Matthew AM Drew, David A Dampier, Christopher H Plummer, Sarah J Eaton, Stephen Bryant, Jennifer Díez-Obrero, Virginia Mo, Jiancheng Kedrin, Dmitriy Zerjav, Dylan C Takacsi-Nagy, Oliver Jennelle, Lucas T Ali, Mourad W Yilmaz, Ömer H Moreno, Victor Powell, Steven M Chan, Andrew T Peters, Ulrike Casey, Graham |
| author_sort | Devall, Matthew AM |
| collection | MIT |
| description | <jats:title>Abstract</jats:title>
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<jats:p>Mechanisms underlying aspirin chemoprevention of colorectal cancer remain unclear. Prior studies have been limited because of the inability of preclinical models to recapitulate human normal colon epithelium or cellular heterogeneity present in mucosal biopsies. To overcome some of these obstacles, we performed in vitro aspirin treatment of colon organoids derived from normal mucosal biopsies to reveal transcriptional networks relevant to aspirin chemoprevention. Colon organoids derived from 38 healthy individuals undergoing endoscopy were treated with 50 μmol/L aspirin or vehicle control for 72 hours and subjected to bulk RNA sequencing. Paired regression analysis using DESeq2 identified differentially expressed genes (DEG) associated with aspirin treatment. Cellular composition was determined using CIBERSORTx. Aspirin treatment was associated with 1,154 significant (q &lt; 0.10) DEGs prior to deconvolution. We provide replication of these findings in an independent population-based RNA-sequencing dataset of mucosal biopsies (BarcUVa-Seq), where a significant enrichment for overlap of DEGs was observed (P &lt; 2.2E−16). Single-cell deconvolution revealed changes in cell composition, including a decrease in transit-amplifying cells following aspirin treatment (P = 0.01). Following deconvolution, DEGs included novel putative targets for aspirin such as TRABD2A (q = 0.055), a negative regulator of Wnt signaling. Weighted gene co-expression network analysis identified 12 significant modules, including two that contained hubs for EGFR and PTGES2, the latter being previously implicated in aspirin chemoprevention. In summary, aspirin treatment of patient-derived colon organoids using physiologically relevant doses resulted in transcriptome-wide changes that reveal altered cell composition and improved understanding of transcriptional pathways, providing novel insight into its chemopreventive properties.</jats:p>
</jats:sec>
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<jats:title>Prevention Relevance:</jats:title>
<jats:p>Numerous studies have highlighted a role for aspirin in colorectal cancer chemoprevention, though the mechanisms driving this association remain unclear. We addressed this by showing that aspirin treatment of normal colon organoids diminished the transit-amplifying cell population, inhibited prostaglandin synthesis, and dysregulated expression of novel genes implicated in colon tumorigenesis.</jats:p>
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| first_indexed | 2024-09-23T12:57:52Z |
| format | Article |
| id | mit-1721.1/147040 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T12:57:52Z |
| publishDate | 2023 |
| publisher | American Association for Cancer Research (AACR) |
| record_format | dspace |
| spelling | mit-1721.1/1470402023-01-11T03:24:03Z Transcriptome-wide in vitro effects of aspirin on patient-derived normal colon organoids Devall, Matthew AM Drew, David A Dampier, Christopher H Plummer, Sarah J Eaton, Stephen Bryant, Jennifer Díez-Obrero, Virginia Mo, Jiancheng Kedrin, Dmitriy Zerjav, Dylan C Takacsi-Nagy, Oliver Jennelle, Lucas T Ali, Mourad W Yilmaz, Ömer H Moreno, Victor Powell, Steven M Chan, Andrew T Peters, Ulrike Casey, Graham Massachusetts Institute of Technology. Department of Biology <jats:title>Abstract</jats:title> <jats:sec> <jats:title /> <jats:p>Mechanisms underlying aspirin chemoprevention of colorectal cancer remain unclear. Prior studies have been limited because of the inability of preclinical models to recapitulate human normal colon epithelium or cellular heterogeneity present in mucosal biopsies. To overcome some of these obstacles, we performed in vitro aspirin treatment of colon organoids derived from normal mucosal biopsies to reveal transcriptional networks relevant to aspirin chemoprevention. Colon organoids derived from 38 healthy individuals undergoing endoscopy were treated with 50 μmol/L aspirin or vehicle control for 72 hours and subjected to bulk RNA sequencing. Paired regression analysis using DESeq2 identified differentially expressed genes (DEG) associated with aspirin treatment. Cellular composition was determined using CIBERSORTx. Aspirin treatment was associated with 1,154 significant (q &lt; 0.10) DEGs prior to deconvolution. We provide replication of these findings in an independent population-based RNA-sequencing dataset of mucosal biopsies (BarcUVa-Seq), where a significant enrichment for overlap of DEGs was observed (P &lt; 2.2E−16). Single-cell deconvolution revealed changes in cell composition, including a decrease in transit-amplifying cells following aspirin treatment (P = 0.01). Following deconvolution, DEGs included novel putative targets for aspirin such as TRABD2A (q = 0.055), a negative regulator of Wnt signaling. Weighted gene co-expression network analysis identified 12 significant modules, including two that contained hubs for EGFR and PTGES2, the latter being previously implicated in aspirin chemoprevention. In summary, aspirin treatment of patient-derived colon organoids using physiologically relevant doses resulted in transcriptome-wide changes that reveal altered cell composition and improved understanding of transcriptional pathways, providing novel insight into its chemopreventive properties.</jats:p> </jats:sec> <jats:sec> <jats:title>Prevention Relevance:</jats:title> <jats:p>Numerous studies have highlighted a role for aspirin in colorectal cancer chemoprevention, though the mechanisms driving this association remain unclear. We addressed this by showing that aspirin treatment of normal colon organoids diminished the transit-amplifying cell population, inhibited prostaglandin synthesis, and dysregulated expression of novel genes implicated in colon tumorigenesis.</jats:p> </jats:sec> 2023-01-10T17:26:22Z 2023-01-10T17:26:22Z 2021 2023-01-10T17:19:11Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/147040 Devall, Matthew AM, Drew, David A, Dampier, Christopher H, Plummer, Sarah J, Eaton, Stephen et al. 2021. "Transcriptome-wide in vitro effects of aspirin on patient-derived normal colon organoids." Cancer Prevention Research, 14 (12). en 10.1158/1940-6207.CAPR-21-0041 Cancer Prevention Research Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf American Association for Cancer Research (AACR) PMC |
| spellingShingle | Devall, Matthew AM Drew, David A Dampier, Christopher H Plummer, Sarah J Eaton, Stephen Bryant, Jennifer Díez-Obrero, Virginia Mo, Jiancheng Kedrin, Dmitriy Zerjav, Dylan C Takacsi-Nagy, Oliver Jennelle, Lucas T Ali, Mourad W Yilmaz, Ömer H Moreno, Victor Powell, Steven M Chan, Andrew T Peters, Ulrike Casey, Graham Transcriptome-wide in vitro effects of aspirin on patient-derived normal colon organoids |
| title | Transcriptome-wide in vitro effects of aspirin on patient-derived normal colon organoids |
| title_full | Transcriptome-wide in vitro effects of aspirin on patient-derived normal colon organoids |
| title_fullStr | Transcriptome-wide in vitro effects of aspirin on patient-derived normal colon organoids |
| title_full_unstemmed | Transcriptome-wide in vitro effects of aspirin on patient-derived normal colon organoids |
| title_short | Transcriptome-wide in vitro effects of aspirin on patient-derived normal colon organoids |
| title_sort | transcriptome wide in vitro effects of aspirin on patient derived normal colon organoids |
| url | https://hdl.handle.net/1721.1/147040 |
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