TY - JOUR
T1 - Transcriptome-wide in vitro effects of aspirin on patient-derived normal colon organoids
AU - Devall, Matthew A.M.
AU - Drew, David A.
AU - Dampier, Christopher H.
AU - Plummer, Sarah J.
AU - Eaton, Stephen
AU - Bryant, Jennifer
AU - Díez-Obrero, Virginia
AU - Mo, Jiancheng
AU - Kedrin, Dmitriy
AU - Zerjav, Dylan C.
AU - Takacsi-Nagy, Oliver
AU - Jennelle, Lucas T.
AU - Ali, Mourad W.
AU - Yilmaz, Ömer H.
AU - Moreno, Victor
AU - Powell, Steven M.
AU - Chan, Andrew T.
AU - Peters, Ulrike
AU - Casey, Graham
N1 - Funding Information:
D.A. Drew reports grants from NIH/National Institute of Diabetes and Digestive and Kidney Diseases and Massachusetts General Hospital during the conduct of the study. C.H. Dampier reports grants from NCI during the conduct of the study. D.C. Zerjav reports grants from NIH during the conduct of the study. O. Takacsi-Nagy is currently employed by and owns equity in ArsenalBio. L.T. Jennelle reports grants from NIH/NCI during the conduct of the study; personal fees from PPD Inc. and University of Virginia outside the submitted work. O.H. Yilmaz reports grants from NIH NCI during the conduct of the study. V. Moreno reports grants from Agency for Management of University and Research Grants (AGAUR) of the Catalan Government, Instituto de Salud Carlos III, Spanish Association Against Cancer (AECC) Scientific Foundation, and NIH during the conduct of the study. A.T. Chan reports personal fees from Bayer Pharma AG, Pfizer Inc., and Boehringer Ingelheim outside the submitted work. G. Casey reports grants from NIH and other support from University of Virginia during the conduct of the study. No disclosures were reported by the other authors.
Funding Information:
This work was supported by funding through NIH grants: NIH/NCI R01 CA201407 (U. Peter and G. Casey), NIH/NCI R01 CA143237 and NIH/NCI R01 CA204279 (G. Casey), NIH/NIDDK K01 DK120742 and NIH/NCI L30 CA209764 (D.A. Drew), NIH/NCI R35 CA253185 and R01 CA137178 and the Stuart and Suzanne Steele MGH Research Scholar Award (A.T. Chan). NIH/NCI R01 CA211184 and NIH/NCI CA254314 (?.H.Yilmaz). Study sponsors had no role in the study design, collection, analysis, or interpretation of data.
Funding Information:
This work was supported by funding through NIH grants: NIH/NCI R01 CA201407 (U. Peter and G. Casey), NIH/NCI R01 CA143237 and NIH/NCI R01 CA204279 (G. Casey), NIH/NIDDK K01 DK120742 and NIH/NCI L30 CA209764 (D.A. Drew), NIH/NCI R35 CA253185 and R01 CA137178 and the Stuart and Suzanne Steele MGH Research Scholar Award (A.T. Chan). NIH/NCI R01 CA211184 and NIH/NCI CA254314 (O.€H. Yilmaz). Study sponsors had no role in the study design, collection, analysis, or interpretation of data.
Publisher Copyright:
©2021 American Association for Cancer Research
PY - 2021/12
Y1 - 2021/12
N2 - Mechanisms underlying aspirin chemoprevention of transit-amplifying cells following aspirin treatment (P ¼ colorectal cancer remain unclear. Prior studies have been 0.01). Following deconvolution, DEGs included novel limited because of the inability of preclinical models to putative targets for aspirin such as TRABD2A (q ¼ recapitulate human normal colon epithelium or cellular 0.055), a negative regulator of Wnt signaling. Weighted heterogeneity present in mucosal biopsies. To overcome gene co-expression network analysis identified 12 signifsome of these obstacles, we performed in vitro aspirin icant modules, including two that contained hubs for treatment of colon organoids derived from normal mucoEGFR and PTGES2, the latter being previously implicated sal biopsies to reveal transcriptional networks relevant to in aspirin chemoprevention. In summary, aspirin treat-aspirin chemoprevention. Colon organoids derived from ment of patient-derived colon organoids using physiolog-38 healthy individuals undergoing endoscopy were treated ically relevant doses resulted in transcriptome-wide with 50 mmol/L aspirin or vehicle control for 72 hours and changes that reveal altered cell composition and improved subjected to bulk RNA sequencing. Paired regression understanding of transcriptional pathways, providing analysis using DESeq2 identified differentially expressed novel insight into its chemopreventive properties. genes (DEG) associated with aspirin treatment. Cellular composition was determined using CIBERSORTx. Aspirin Prevention Relevance: Numerous studies have highlight-treatment was associated with 1,154 significant (q < 0.10) ed a role for aspirin in colorectal cancer chemoprevention, DEGs prior to deconvolution. We provide replication of though the mechanisms driving this association remain these findings in an independent population-based RNA-unclear. We addressed this by showing that aspirin treat-sequencing dataset of mucosal biopsies (BarcUVa-Seq), ment of normal colon organoids diminished the transit-where a significant enrichment for overlap of DEGs was amplifying cell population, inhibited prostaglandin syntheobserved (P < 2.2E–16). Single-cell deconvolution revealed sis, and dysregulated expression of novel genes implicated in changes in cell composition, including a decrease in colon tumorigenesis.
AB - Mechanisms underlying aspirin chemoprevention of transit-amplifying cells following aspirin treatment (P ¼ colorectal cancer remain unclear. Prior studies have been 0.01). Following deconvolution, DEGs included novel limited because of the inability of preclinical models to putative targets for aspirin such as TRABD2A (q ¼ recapitulate human normal colon epithelium or cellular 0.055), a negative regulator of Wnt signaling. Weighted heterogeneity present in mucosal biopsies. To overcome gene co-expression network analysis identified 12 signifsome of these obstacles, we performed in vitro aspirin icant modules, including two that contained hubs for treatment of colon organoids derived from normal mucoEGFR and PTGES2, the latter being previously implicated sal biopsies to reveal transcriptional networks relevant to in aspirin chemoprevention. In summary, aspirin treat-aspirin chemoprevention. Colon organoids derived from ment of patient-derived colon organoids using physiolog-38 healthy individuals undergoing endoscopy were treated ically relevant doses resulted in transcriptome-wide with 50 mmol/L aspirin or vehicle control for 72 hours and changes that reveal altered cell composition and improved subjected to bulk RNA sequencing. Paired regression understanding of transcriptional pathways, providing analysis using DESeq2 identified differentially expressed novel insight into its chemopreventive properties. genes (DEG) associated with aspirin treatment. Cellular composition was determined using CIBERSORTx. Aspirin Prevention Relevance: Numerous studies have highlight-treatment was associated with 1,154 significant (q < 0.10) ed a role for aspirin in colorectal cancer chemoprevention, DEGs prior to deconvolution. We provide replication of though the mechanisms driving this association remain these findings in an independent population-based RNA-unclear. We addressed this by showing that aspirin treat-sequencing dataset of mucosal biopsies (BarcUVa-Seq), ment of normal colon organoids diminished the transit-where a significant enrichment for overlap of DEGs was amplifying cell population, inhibited prostaglandin syntheobserved (P < 2.2E–16). Single-cell deconvolution revealed sis, and dysregulated expression of novel genes implicated in changes in cell composition, including a decrease in colon tumorigenesis.
UR - http://www.scopus.com/inward/record.url?scp=85116022451&partnerID=8YFLogxK
U2 - 10.1158/1940-6207.CAPR-21-0041
DO - 10.1158/1940-6207.CAPR-21-0041
M3 - Article
C2 - 34389629
AN - SCOPUS:85116022451
SN - 1940-6207
VL - 14
SP - 1089
EP - 1100
JO - Cancer Prevention Research
JF - Cancer Prevention Research
IS - 12
ER -