BCL9/9L-β-catenin Signaling is Associated With Poor Outcome in Colorectal Cancer

Andreas E. Moor, Pascale Anderle, Claudio Cantù, Patrick Rodriguez, Norbert Wiedemann, Frédérique Baruthio, Jürgen Deka, Sylvie André, Tomas Valenta, Matthias B. Moor, B. Györffy, David Barras, Mauro Delorenzi, Konrad Basler, Michel Aguet

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

BCL9/9L proteins enhance the transcriptional output of the β-catenin/TCF transcriptional complex and contribute critically to upholding the high WNT signaling level required for stemness maintenance in the intestinal epithelium. Here we show that a BCL9/9L-dependent gene signature derived from independent mouse colorectal cancer (CRC) models unprecedentedly separates patient subgroups with regard to progression free and overall survival. We found that this effect was by and large attributable to stemness related gene sets. Remarkably, this signature proved associated with recently described poor prognosis CRC subtypes exhibiting high stemness and/or epithelial-to-mesenchymal transition (EMT) traits. Consistent with the notion that high WNT signaling is required for stemness maintenance, ablating Bcl9/9l-β-catenin in murine oncogenic intestinal organoids provoked their differentiation and completely abrogated their tumorigenicity, while not affecting their proliferation. Therapeutic strategies aimed at targeting WNT responses may be limited by intestinal toxicity. Our findings suggest that attenuating WNT signaling to an extent that affects stemness maintenance without disturbing intestinal renewal might be well tolerated and prove sufficient to reduce CRC recurrence and dramatically improve disease outcome.

Original languageEnglish
Pages (from-to)1932-1943
Number of pages12
JournalEBioMedicine
Volume2
Issue number12
DOIs
Publication statusPublished - Dec 1 2015

Fingerprint

Catenins
Colorectal Neoplasms
Maintenance
Genes
Organoids
Epithelial-Mesenchymal Transition
Intestinal Mucosa
Disease-Free Survival
Toxicity
Recurrence
Proteins
Therapeutics

Keywords

  • BCL9/9L-β-catenin
  • Cancer stem cells
  • Colorectal cancer subtypes
  • Patient outcome
  • WNT signaling

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Moor, A. E., Anderle, P., Cantù, C., Rodriguez, P., Wiedemann, N., Baruthio, F., ... Aguet, M. (2015). BCL9/9L-β-catenin Signaling is Associated With Poor Outcome in Colorectal Cancer. EBioMedicine, 2(12), 1932-1943. https://doi.org/10.1016/j.ebiom.2015.10.030

BCL9/9L-β-catenin Signaling is Associated With Poor Outcome in Colorectal Cancer. / Moor, Andreas E.; Anderle, Pascale; Cantù, Claudio; Rodriguez, Patrick; Wiedemann, Norbert; Baruthio, Frédérique; Deka, Jürgen; André, Sylvie; Valenta, Tomas; Moor, Matthias B.; Györffy, B.; Barras, David; Delorenzi, Mauro; Basler, Konrad; Aguet, Michel.

In: EBioMedicine, Vol. 2, No. 12, 01.12.2015, p. 1932-1943.

Research output: Contribution to journalArticle

Moor, AE, Anderle, P, Cantù, C, Rodriguez, P, Wiedemann, N, Baruthio, F, Deka, J, André, S, Valenta, T, Moor, MB, Györffy, B, Barras, D, Delorenzi, M, Basler, K & Aguet, M 2015, 'BCL9/9L-β-catenin Signaling is Associated With Poor Outcome in Colorectal Cancer', EBioMedicine, vol. 2, no. 12, pp. 1932-1943. https://doi.org/10.1016/j.ebiom.2015.10.030
Moor AE, Anderle P, Cantù C, Rodriguez P, Wiedemann N, Baruthio F et al. BCL9/9L-β-catenin Signaling is Associated With Poor Outcome in Colorectal Cancer. EBioMedicine. 2015 Dec 1;2(12):1932-1943. https://doi.org/10.1016/j.ebiom.2015.10.030
Moor, Andreas E. ; Anderle, Pascale ; Cantù, Claudio ; Rodriguez, Patrick ; Wiedemann, Norbert ; Baruthio, Frédérique ; Deka, Jürgen ; André, Sylvie ; Valenta, Tomas ; Moor, Matthias B. ; Györffy, B. ; Barras, David ; Delorenzi, Mauro ; Basler, Konrad ; Aguet, Michel. / BCL9/9L-β-catenin Signaling is Associated With Poor Outcome in Colorectal Cancer. In: EBioMedicine. 2015 ; Vol. 2, No. 12. pp. 1932-1943.
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