Aspirin rescues Wnt-driven stem-like phenotype in human intestinal organoids and increases the Wnt antagonist Dickkopf-1

Karen Dunbar; Asta Valanciute; Ana Lima; Paz Freile Vinuela; Thomas Jamieson; Vidya Rajasekaran; James Blackmur; Anna-maria Ochocka-fox; Alice Guazzelli; Patrizia Cammareri; Mark J. Arends; Owen J. Sansom; Kevin B. Myant; Susan M. Farrington; Malcolm G. Dunlop; Farhat V.N. Din

doi:10.1016/j.jcmgh.2020.09.010

Aspirin rescues Wnt-driven stem-like phenotype in human intestinal organoids and increases the Wnt antagonist Dickkopf-1

Karen Dunbar, Asta Valanciute, Ana Lima, Paz Freile Vinuela, Thomas Jamieson, Vidya Rajasekaran, James Blackmur, Anna-maria Ochocka-fox, Alice Guazzelli, Patrizia Cammareri, Mark J. Arends, Owen J. Sansom, Kevin B. Myant, Susan M. Farrington, Malcolm G. Dunlop, Farhat V.N. Din

Research output: Contribution to journal › Article › peer-review

Abstract / Description of output

Background & AimsAspirin reduces colorectal cancer (CRC) incidence and mortality. Understanding the biology responsible for this protective effect is key to developing biomarker-led approaches for rational clinical use. Wnt signaling drives CRC development from initiation to progression through regulation of epithelial-mesenchymal transition (EMT) and cancer stem cell populations. Here, we investigated whether aspirin can rescue these proinvasive phenotypes associated with CRC progression in Wnt-driven human and mouse intestinal organoids.MethodsWe evaluated aspirin-mediated effects on phenotype and stem cell markers in intestinal organoids derived from mouse (ApcMin/+ and Apcflox/flox) and human familial adenomatous polyposis patients. CRC cell lines (HCT116 and Colo205) were used to study effects on motility, invasion, Wnt signaling, and EMT.ResultsAspirin rescues the Wnt-driven cystic organoid phenotype by promoting budding in mouse and human Apc deficient organoids, which is paralleled by decreased stem cell marker expression. Aspirin-mediated Wnt inhibition in ApcMin/+ mice is associated with EMT inhibition and decreased cell migration, invasion, and motility in CRC cell lines. Chemical Wnt activation induces EMT and stem-like alterations in CRC cells, which are rescued by aspirin. Aspirin increases expression of the Wnt antagonist Dickkopf-1 in CRC cells and organoids derived from familial adenomatous polyposis patients, which contributes to EMT and cancer stem cell inhibition.ConclusionsWe provide evidence of phenotypic biomarkers of response to aspirin with an increased epithelial and reduced stem-like state mediated by an increase in Dickkopf-1. This highlights a novel mechanism of aspirin-mediated Wnt inhibition and potential phenotypic and molecular biomarkers for trials.

Original language	English
Pages (from-to)	465-489
Number of pages	25
Journal	Cellular and Molecular Gastroenterology and Hepatology
Volume	11
Issue number	2
Early online date	21 Sept 2020
DOIs	https://doi.org/10.1016/j.jcmgh.2020.09.010
Publication status	E-pub ahead of print - 21 Sept 2020

Keywords / Materials (for Non-textual outputs)

Epithelial-mesenchymal transition
Stem cells
Organoids
Migration
Invasion

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10.1016/j.jcmgh.2020.09.010Licence: Creative Commons: Attribution (CC-BY)

https://linkinghub.elsevier.com/retrieve/pii/S2352345X20301533

Asta Valanciute
- Deanery of Clinical Sciences - Research Fellow
- Centre for Inflammation Research
Person: Academic: Research Active (Research Assistant)

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Dunbar, K., Valanciute, A., Lima, A., Vinuela, P. F., Jamieson, T., Rajasekaran, V., Blackmur, J., Ochocka-fox, A., Guazzelli, A., Cammareri, P., Arends, M. J., Sansom, O. J., Myant, K. B., Farrington, S. M., Dunlop, M. G., & Din, F. V. N. (2020). Aspirin rescues Wnt-driven stem-like phenotype in human intestinal organoids and increases the Wnt antagonist Dickkopf-1. Cellular and Molecular Gastroenterology and Hepatology, 11(2), 465-489. Advance online publication. https://doi.org/10.1016/j.jcmgh.2020.09.010

@article{f706717fab614536a3d2f547cd460e89,

title = "Aspirin rescues Wnt-driven stem-like phenotype in human intestinal organoids and increases the Wnt antagonist Dickkopf-1",

abstract = "Background & AimsAspirin reduces colorectal cancer (CRC) incidence and mortality. Understanding the biology responsible for this protective effect is key to developing biomarker-led approaches for rational clinical use. Wnt signaling drives CRC development from initiation to progression through regulation of epithelial-mesenchymal transition (EMT) and cancer stem cell populations. Here, we investigated whether aspirin can rescue these proinvasive phenotypes associated with CRC progression in Wnt-driven human and mouse intestinal organoids.MethodsWe evaluated aspirin-mediated effects on phenotype and stem cell markers in intestinal organoids derived from mouse (ApcMin/+ and Apcflox/flox) and human familial adenomatous polyposis patients. CRC cell lines (HCT116 and Colo205) were used to study effects on motility, invasion, Wnt signaling, and EMT.ResultsAspirin rescues the Wnt-driven cystic organoid phenotype by promoting budding in mouse and human Apc deficient organoids, which is paralleled by decreased stem cell marker expression. Aspirin-mediated Wnt inhibition in ApcMin/+ mice is associated with EMT inhibition and decreased cell migration, invasion, and motility in CRC cell lines. Chemical Wnt activation induces EMT and stem-like alterations in CRC cells, which are rescued by aspirin. Aspirin increases expression of the Wnt antagonist Dickkopf-1 in CRC cells and organoids derived from familial adenomatous polyposis patients, which contributes to EMT and cancer stem cell inhibition.ConclusionsWe provide evidence of phenotypic biomarkers of response to aspirin with an increased epithelial and reduced stem-like state mediated by an increase in Dickkopf-1. This highlights a novel mechanism of aspirin-mediated Wnt inhibition and potential phenotypic and molecular biomarkers for trials.",

keywords = "Epithelial-mesenchymal transition, Stem cells, Organoids, Migration, Invasion",

author = "Karen Dunbar and Asta Valanciute and Ana Lima and Vinuela, {Paz Freile} and Thomas Jamieson and Vidya Rajasekaran and James Blackmur and Anna-maria Ochocka-fox and Alice Guazzelli and Patrizia Cammareri and Arends, {Mark J.} and Sansom, {Owen J.} and Myant, {Kevin B.} and Farrington, {Susan M.} and Dunlop, {Malcolm G.} and Din, {Farhat V.N.}",

year = "2020",

month = sep,

day = "21",

doi = "10.1016/j.jcmgh.2020.09.010",

language = "English",

volume = "11",

pages = "465--489",

journal = "Cellular and Molecular Gastroenterology and Hepatology",

issn = "2352-345X",

publisher = "Elsevier",

number = "2",

}

Dunbar, K, Valanciute, A, Lima, A, Vinuela, PF, Jamieson, T, Rajasekaran, V, Blackmur, J, Ochocka-fox, A, Guazzelli, A, Cammareri, P , Arends, MJ, Sansom, OJ, Myant, KB , Farrington, SM , Dunlop, MG & Din, FVN 2020, 'Aspirin rescues Wnt-driven stem-like phenotype in human intestinal organoids and increases the Wnt antagonist Dickkopf-1', Cellular and Molecular Gastroenterology and Hepatology, vol. 11, no. 2, pp. 465-489. https://doi.org/10.1016/j.jcmgh.2020.09.010

TY - JOUR

T1 - Aspirin rescues Wnt-driven stem-like phenotype in human intestinal organoids and increases the Wnt antagonist Dickkopf-1

AU - Dunbar, Karen

AU - Valanciute, Asta

AU - Lima, Ana

AU - Vinuela, Paz Freile

AU - Jamieson, Thomas

AU - Rajasekaran, Vidya

AU - Blackmur, James

AU - Ochocka-fox, Anna-maria

AU - Guazzelli, Alice

AU - Cammareri, Patrizia

AU - Arends, Mark J.

AU - Sansom, Owen J.

AU - Myant, Kevin B.

AU - Farrington, Susan M.

AU - Dunlop, Malcolm G.

AU - Din, Farhat V.N.

PY - 2020/9/21

Y1 - 2020/9/21

N2 - Background & AimsAspirin reduces colorectal cancer (CRC) incidence and mortality. Understanding the biology responsible for this protective effect is key to developing biomarker-led approaches for rational clinical use. Wnt signaling drives CRC development from initiation to progression through regulation of epithelial-mesenchymal transition (EMT) and cancer stem cell populations. Here, we investigated whether aspirin can rescue these proinvasive phenotypes associated with CRC progression in Wnt-driven human and mouse intestinal organoids.MethodsWe evaluated aspirin-mediated effects on phenotype and stem cell markers in intestinal organoids derived from mouse (ApcMin/+ and Apcflox/flox) and human familial adenomatous polyposis patients. CRC cell lines (HCT116 and Colo205) were used to study effects on motility, invasion, Wnt signaling, and EMT.ResultsAspirin rescues the Wnt-driven cystic organoid phenotype by promoting budding in mouse and human Apc deficient organoids, which is paralleled by decreased stem cell marker expression. Aspirin-mediated Wnt inhibition in ApcMin/+ mice is associated with EMT inhibition and decreased cell migration, invasion, and motility in CRC cell lines. Chemical Wnt activation induces EMT and stem-like alterations in CRC cells, which are rescued by aspirin. Aspirin increases expression of the Wnt antagonist Dickkopf-1 in CRC cells and organoids derived from familial adenomatous polyposis patients, which contributes to EMT and cancer stem cell inhibition.ConclusionsWe provide evidence of phenotypic biomarkers of response to aspirin with an increased epithelial and reduced stem-like state mediated by an increase in Dickkopf-1. This highlights a novel mechanism of aspirin-mediated Wnt inhibition and potential phenotypic and molecular biomarkers for trials.

AB - Background & AimsAspirin reduces colorectal cancer (CRC) incidence and mortality. Understanding the biology responsible for this protective effect is key to developing biomarker-led approaches for rational clinical use. Wnt signaling drives CRC development from initiation to progression through regulation of epithelial-mesenchymal transition (EMT) and cancer stem cell populations. Here, we investigated whether aspirin can rescue these proinvasive phenotypes associated with CRC progression in Wnt-driven human and mouse intestinal organoids.MethodsWe evaluated aspirin-mediated effects on phenotype and stem cell markers in intestinal organoids derived from mouse (ApcMin/+ and Apcflox/flox) and human familial adenomatous polyposis patients. CRC cell lines (HCT116 and Colo205) were used to study effects on motility, invasion, Wnt signaling, and EMT.ResultsAspirin rescues the Wnt-driven cystic organoid phenotype by promoting budding in mouse and human Apc deficient organoids, which is paralleled by decreased stem cell marker expression. Aspirin-mediated Wnt inhibition in ApcMin/+ mice is associated with EMT inhibition and decreased cell migration, invasion, and motility in CRC cell lines. Chemical Wnt activation induces EMT and stem-like alterations in CRC cells, which are rescued by aspirin. Aspirin increases expression of the Wnt antagonist Dickkopf-1 in CRC cells and organoids derived from familial adenomatous polyposis patients, which contributes to EMT and cancer stem cell inhibition.ConclusionsWe provide evidence of phenotypic biomarkers of response to aspirin with an increased epithelial and reduced stem-like state mediated by an increase in Dickkopf-1. This highlights a novel mechanism of aspirin-mediated Wnt inhibition and potential phenotypic and molecular biomarkers for trials.

KW - Epithelial-mesenchymal transition

KW - Stem cells

KW - Organoids

KW - Migration

KW - Invasion

U2 - 10.1016/j.jcmgh.2020.09.010

DO - 10.1016/j.jcmgh.2020.09.010

M3 - Article

SN - 2352-345X

VL - 11

SP - 465

EP - 489

JO - Cellular and Molecular Gastroenterology and Hepatology

JF - Cellular and Molecular Gastroenterology and Hepatology

IS - 2

ER -

Aspirin rescues Wnt-driven stem-like phenotype in human intestinal organoids and increases the Wnt antagonist Dickkopf-1

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Asta Valanciute

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