ROS production and NF-κB activation triggered by RAC1 facilitate WNT-driven intestinal stem cell proliferation and colorectal cancer initiation

Kevin B. Myant, Patrizia Cammereri, Ewan J. McGhee, Rachel A. Ridgway, David J. Huels, Julia B. Cordero, Sarah Schwitalla, Gabriela Kalna, Erin-Lee Ogg, Dimitros Athineos, Paul Timpson, Marcos Vidal, Graeme I. Murray, Florian R. Greten, Kurt I. Anderson, Owen J. Sansom

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Abstract

The Adenomatous Polyposis Coli (APC) gene is mutated in the majority of colorectal cancers (CRCs). Loss of APC leads to constitutively active WNT signaling, hyperproliferation, and tumorigenesis. Identification of pathways that facilitate tumorigenesis after APC loss is important for therapeutic development. Here, we show that RAC1 is a critical mediator of tumorigenesis after APC loss. We find that RAC1 is required for expansion of the LGR5 intestinal stem cell (ISC) signature, progenitor hyperproliferation, and transformation. Mechanistically, RAC1-driven ROS and NF-κB signaling mediate these processes. Together, these data highlight that ROS production and NF-κB activation triggered by RAC1 are critical events in CRC initiation.
Original languageEnglish
Pages (from-to)761-773
Number of pages13
JournalCell Stem Cell
Volume12
Issue number6
DOIs
Publication statusPublished - 6 Jun 2013

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Adenomatous Polyposis Coli
Colorectal Neoplasms
Carcinogenesis
Stem Cells
Cell Proliferation
APC Genes
Therapeutics

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Myant, K. B., Cammereri, P., McGhee, E. J., Ridgway, R. A., Huels, D. J., Cordero, J. B., ... Sansom, O. J. (2013). ROS production and NF-κB activation triggered by RAC1 facilitate WNT-driven intestinal stem cell proliferation and colorectal cancer initiation. Cell Stem Cell, 12(6), 761-773. https://doi.org/10.1016/j.stem.2013.04.006

ROS production and NF-κB activation triggered by RAC1 facilitate WNT-driven intestinal stem cell proliferation and colorectal cancer initiation. / Myant, Kevin B.; Cammereri, Patrizia; McGhee, Ewan J.; Ridgway, Rachel A.; Huels, David J.; Cordero, Julia B.; Schwitalla, Sarah; Kalna, Gabriela; Ogg, Erin-Lee; Athineos, Dimitros; Timpson, Paul; Vidal, Marcos; Murray, Graeme I.; Greten, Florian R.; Anderson, Kurt I.; Sansom, Owen J.

In: Cell Stem Cell, Vol. 12, No. 6, 06.06.2013, p. 761-773.

Research output: Contribution to journalArticle

Myant, KB, Cammereri, P, McGhee, EJ, Ridgway, RA, Huels, DJ, Cordero, JB, Schwitalla, S, Kalna, G, Ogg, E-L, Athineos, D, Timpson, P, Vidal, M, Murray, GI, Greten, FR, Anderson, KI & Sansom, OJ 2013, 'ROS production and NF-κB activation triggered by RAC1 facilitate WNT-driven intestinal stem cell proliferation and colorectal cancer initiation', Cell Stem Cell, vol. 12, no. 6, pp. 761-773. https://doi.org/10.1016/j.stem.2013.04.006
Myant, Kevin B. ; Cammereri, Patrizia ; McGhee, Ewan J. ; Ridgway, Rachel A. ; Huels, David J. ; Cordero, Julia B. ; Schwitalla, Sarah ; Kalna, Gabriela ; Ogg, Erin-Lee ; Athineos, Dimitros ; Timpson, Paul ; Vidal, Marcos ; Murray, Graeme I. ; Greten, Florian R. ; Anderson, Kurt I. ; Sansom, Owen J. / ROS production and NF-κB activation triggered by RAC1 facilitate WNT-driven intestinal stem cell proliferation and colorectal cancer initiation. In: Cell Stem Cell. 2013 ; Vol. 12, No. 6. pp. 761-773.
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