Aspirin reduces the incidence of metastasis in a pre-clinical study of braf mutant serrated colorectal neoplasia

ABSTRACT BACKGROUND Aspirin reduces the incidence of conventional adenomas driven by _APC_ mutation and thus colorectal cancer. The effect of aspirin on the ~20% of colorectal cancers

arising via _BRAF_ mutation is yet to be established. METHODS _Braf_V637E/+;_Villin_-CreERT2/+ mice were allocated to a control (_n_ = 86) or aspirin-supplemented (_n_ = 83) diet. After 14

months the incidence of murine serrated lesions, carcinoma and distant metastases were measured by histological examination. RNA was extracted from carcinomas from each cohort and subjected

to sequencing to identify differentially expressed genes and molecular pathways. RESULTS Aspirin did not reduce the incidence of murine serrated lesions or carcinoma when compared to

control, however, did significantly reduce lesion size (_P_ = 0.0042). Among the mice with carcinoma there was a significant reduction in the incidence of distant metastasis with aspirin

treatment (RR 0.69, 95% CI 0.48–0.90, _P_ = 0.0134). Key pathways underlying metastasis of carcinoma cells include NOTCH, FGFR and PI3K signalling, were significantly downregulated in

carcinomas sampled from mice on an aspirin-supplemented diet. CONCLUSIONS Aspirin reduces the incidence of metastatic _Braf_ mutant carcinoma, although this is not due to a reduction in

primary disease. The reduction in metastasis could be attributed to a delay or prevention of molecular changes within the primary site driving metastatic growth. Access through your

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BEING VIEWED BY OTHERS SMAD4 IS CRITICAL IN SUPPRESSION OF _BRAF-V600E_ SERRATED TUMORIGENESIS Article 27 August 2021 _BRAF__V600E_-MUTATED SERRATED COLORECTAL NEOPLASIA DRIVES

TRANSCRIPTIONAL ACTIVATION OF CHOLESTEROL METABOLISM Article Open access 21 September 2023 BRAFV600E DRIVES DEDIFFERENTIATION IN SMALL INTESTINAL AND COLONIC ORGANOIDS AND COOPERATES WITH

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meta-analysis. _Gut_ 64, 1419–1425 (2015). Article  CAS  PubMed  Google Scholar  Download references ACKNOWLEDGEMENTS We gratefully acknowledge the generous support of the Garry Whyte Sea

Angel PAF. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia Alexandra M. Kane, Cheng Liu, Lochlan J. Fennell, Diane M.

McKeone, Catherine E. Bond, Barbara A. Leggett & Vicki L. J. Whitehall * Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia Alexandra M. Kane, Cheng Liu, Lochlan

J. Fennell, Barbara A. Leggett & Vicki L. J. Whitehall * Conjoint Internal Medicine Laboratory, Pathology Queensland, Queensland Health, Brisbane, QLD, Australia Alexandra M. Kane &

 Vicki L. J. Whitehall * Envoi Specialist Pathologists, Brisbane, QLD, Australia Cheng Liu * Institute of Health and Biomedical Innovation and School of Biomedical Sciences, Queensland

University of Technology and Translational Research Institute, Brisbane, QLD, Australia Pamela M. Pollock * Flinders University, Adelaide, SA, Australia Graeme Young * Department of

Gastroenterology and Hepatology, The Royal Brisbane and Women’s Hospital, Queensland Health, Brisbane, QLD, Australia Barbara A. Leggett Authors * Alexandra M. Kane View author publications

You can also search for this author inPubMed Google Scholar * Cheng Liu View author publications You can also search for this author inPubMed Google Scholar * Lochlan J. Fennell View author

publications You can also search for this author inPubMed Google Scholar * Diane M. McKeone View author publications You can also search for this author inPubMed Google Scholar * Catherine

E. Bond View author publications You can also search for this author inPubMed Google Scholar * Pamela M. Pollock View author publications You can also search for this author inPubMed Google

Scholar * Graeme Young View author publications You can also search for this author inPubMed Google Scholar * Barbara A. Leggett View author publications You can also search for this author

inPubMed Google Scholar * Vicki L. J. Whitehall View author publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS A.K., P.P., G.Y., B.L. and V.W.

conceptualised and designed the study. A.K., C.L., L.F., D.M. and C.B. contributed to methodology and experiments. A.K. and L.F. analysed data. A.K. drafted manuscript. B.L. and V.W.

supervised the study. CORRESPONDING AUTHOR Correspondence to Alexandra M. Kane. ETHICS DECLARATIONS ETHICS APPROVAL All studies were approved by the QIMR Berghofer Animal Ethics Committee

(P2178). DATA AVAILABILITY The datasets generated and analysed during the current study are available from the corresponding author on reasonable request. COMPETING INTERESTS The authors

declare no competing interests. FUNDING INFORMATION Funding for this research was provided by a Cancer Council Queensland grant (grant number 1100701). This work was supported by Cancer

Council Queensland, National Health and Medical Research Council of Australia. ADDITIONAL INFORMATION PUBLISHER’S NOTE Springer Nature remains neutral with regard to jurisdictional claims in

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ABOUT THIS ARTICLE CITE THIS ARTICLE Kane, A.M., Liu, C., Fennell, L.J. _et al._ Aspirin reduces the incidence of metastasis in a pre-clinical study of _Braf_ mutant serrated colorectal

neoplasia. _Br J Cancer_ 124, 1820–1827 (2021). https://doi.org/10.1038/s41416-021-01339-4 Download citation * Received: 23 July 2020 * Revised: 17 February 2021 * Accepted: 25 February 2021

* Published: 29 March 2021 * Issue Date: 25 May 2021 * DOI: https://doi.org/10.1038/s41416-021-01339-4 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this

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