A Vulnerability of a Subset of Colon Cancers with Potential Clinical Utility

Loredana Vecchione, Valentina Gambino, Jonne Raaijmakers, Andreas Schlicker, Arianna Fumagalli, Mariangela Russo, Alberto Villanueva, Evelyne Beerling, Alice Bartolini, David G. Mollevi, Nizar El-Murr, Marielle Chiron, Loreley Calvet, Céline Nicolazzi, Cécile Combeau, Christophe Henry, Iris M. Simon, Sun Tian, Sjors In 'T Veld, Giovanni D'Ario & 14 others Sara Mainardi, Roderick L. Beijersbergen, Cor Lieftink, Sabine Linn, Cornelia Rumpf-Kienzl, Mauro Delorenzi, Lodewyk Wessels, Ramon Salazar, Federica Di Nicolantonio, Alberto Bardelli, Jacco Van Rheenen, René H. Medema, Sabine Tejpar, René Bernards

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

BRAF(V600E) mutant colon cancers (CCs) have a characteristic gene expression signature that is also found in some tumors lacking this mutation. Collectively, they are referred to as "BRAF-like" tumors and represent some 20% of CCs. We used a shRNA-based genetic screen focused on genes upregulated in BRAF(V600E) CCs to identify vulnerabilities of this tumor subtype that might be exploited therapeutically. Here, we identify RANBP2 (also known as NUP358) as essential for survival of BRAF-like, but not for non-BRAF-like, CC cells. Suppression of RANBP2 results in mitotic defects only in BRAF-like CC cells, leading to cell death. Mechanistically, RANBP2 silencing reduces microtubule outgrowth from the kinetochores, thereby inducing spindle perturbations, providing an explanation for the observed mitotic defects. We find that BRAF-like CCs display far greater sensitivity to the microtubule poison vinorelbine both in vitro and in vivo, suggesting that vinorelbine is a potential tailored treatment for BRAF-like CCs.

Original languageEnglish
Pages (from-to)317-330
Number of pages14
JournalCell
Volume165
Issue number2
DOIs
Publication statusPublished - Apr 7 2016

Fingerprint

Colonic Neoplasms
Tumors
Defects
Poisons
Cell death
Gene expression
Small Interfering RNA
Microtubules
Genes
Display devices
Kinetochores
Neoplasms
ran-binding protein 2
Transcriptome
Cell Death
vinorelbine
Mutation

Keywords

  • BRAF-like colon cancer
  • functional genomics
  • RANBP2
  • targeted treatment
  • vinorelbine

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Vecchione, L., Gambino, V., Raaijmakers, J., Schlicker, A., Fumagalli, A., Russo, M., ... Bernards, R. (2016). A Vulnerability of a Subset of Colon Cancers with Potential Clinical Utility. Cell, 165(2), 317-330. https://doi.org/10.1016/j.cell.2016.02.059

A Vulnerability of a Subset of Colon Cancers with Potential Clinical Utility. / Vecchione, Loredana; Gambino, Valentina; Raaijmakers, Jonne; Schlicker, Andreas; Fumagalli, Arianna; Russo, Mariangela; Villanueva, Alberto; Beerling, Evelyne; Bartolini, Alice; Mollevi, David G.; El-Murr, Nizar; Chiron, Marielle; Calvet, Loreley; Nicolazzi, Céline; Combeau, Cécile; Henry, Christophe; Simon, Iris M.; Tian, Sun; In 'T Veld, Sjors; D'Ario, Giovanni; Mainardi, Sara; Beijersbergen, Roderick L.; Lieftink, Cor; Linn, Sabine; Rumpf-Kienzl, Cornelia; Delorenzi, Mauro; Wessels, Lodewyk; Salazar, Ramon; Di Nicolantonio, Federica; Bardelli, Alberto; Van Rheenen, Jacco; Medema, René H.; Tejpar, Sabine; Bernards, René.

In: Cell, Vol. 165, No. 2, 07.04.2016, p. 317-330.

Research output: Contribution to journalArticle

Vecchione, L, Gambino, V, Raaijmakers, J, Schlicker, A, Fumagalli, A, Russo, M, Villanueva, A, Beerling, E, Bartolini, A, Mollevi, DG, El-Murr, N, Chiron, M, Calvet, L, Nicolazzi, C, Combeau, C, Henry, C, Simon, IM, Tian, S, In 'T Veld, S, D'Ario, G, Mainardi, S, Beijersbergen, RL, Lieftink, C, Linn, S, Rumpf-Kienzl, C, Delorenzi, M, Wessels, L, Salazar, R, Di Nicolantonio, F, Bardelli, A, Van Rheenen, J, Medema, RH, Tejpar, S & Bernards, R 2016, 'A Vulnerability of a Subset of Colon Cancers with Potential Clinical Utility', Cell, vol. 165, no. 2, pp. 317-330. https://doi.org/10.1016/j.cell.2016.02.059
Vecchione L, Gambino V, Raaijmakers J, Schlicker A, Fumagalli A, Russo M et al. A Vulnerability of a Subset of Colon Cancers with Potential Clinical Utility. Cell. 2016 Apr 7;165(2):317-330. https://doi.org/10.1016/j.cell.2016.02.059
Vecchione, Loredana ; Gambino, Valentina ; Raaijmakers, Jonne ; Schlicker, Andreas ; Fumagalli, Arianna ; Russo, Mariangela ; Villanueva, Alberto ; Beerling, Evelyne ; Bartolini, Alice ; Mollevi, David G. ; El-Murr, Nizar ; Chiron, Marielle ; Calvet, Loreley ; Nicolazzi, Céline ; Combeau, Cécile ; Henry, Christophe ; Simon, Iris M. ; Tian, Sun ; In 'T Veld, Sjors ; D'Ario, Giovanni ; Mainardi, Sara ; Beijersbergen, Roderick L. ; Lieftink, Cor ; Linn, Sabine ; Rumpf-Kienzl, Cornelia ; Delorenzi, Mauro ; Wessels, Lodewyk ; Salazar, Ramon ; Di Nicolantonio, Federica ; Bardelli, Alberto ; Van Rheenen, Jacco ; Medema, René H. ; Tejpar, Sabine ; Bernards, René. / A Vulnerability of a Subset of Colon Cancers with Potential Clinical Utility. In: Cell. 2016 ; Vol. 165, No. 2. pp. 317-330.
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abstract = "BRAF(V600E) mutant colon cancers (CCs) have a characteristic gene expression signature that is also found in some tumors lacking this mutation. Collectively, they are referred to as {"}BRAF-like{"} tumors and represent some 20{\%} of CCs. We used a shRNA-based genetic screen focused on genes upregulated in BRAF(V600E) CCs to identify vulnerabilities of this tumor subtype that might be exploited therapeutically. Here, we identify RANBP2 (also known as NUP358) as essential for survival of BRAF-like, but not for non-BRAF-like, CC cells. Suppression of RANBP2 results in mitotic defects only in BRAF-like CC cells, leading to cell death. Mechanistically, RANBP2 silencing reduces microtubule outgrowth from the kinetochores, thereby inducing spindle perturbations, providing an explanation for the observed mitotic defects. We find that BRAF-like CCs display far greater sensitivity to the microtubule poison vinorelbine both in vitro and in vivo, suggesting that vinorelbine is a potential tailored treatment for BRAF-like CCs.",
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AU - Russo, Mariangela

AU - Villanueva, Alberto

AU - Beerling, Evelyne

AU - Bartolini, Alice

AU - Mollevi, David G.

AU - El-Murr, Nizar

AU - Chiron, Marielle

AU - Calvet, Loreley

AU - Nicolazzi, Céline

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AU - Henry, Christophe

AU - Simon, Iris M.

AU - Tian, Sun

AU - In 'T Veld, Sjors

AU - D'Ario, Giovanni

AU - Mainardi, Sara

AU - Beijersbergen, Roderick L.

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AU - Linn, Sabine

AU - Rumpf-Kienzl, Cornelia

AU - Delorenzi, Mauro

AU - Wessels, Lodewyk

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AU - Di Nicolantonio, Federica

AU - Bardelli, Alberto

AU - Van Rheenen, Jacco

AU - Medema, René H.

AU - Tejpar, Sabine

AU - Bernards, René

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N2 - BRAF(V600E) mutant colon cancers (CCs) have a characteristic gene expression signature that is also found in some tumors lacking this mutation. Collectively, they are referred to as "BRAF-like" tumors and represent some 20% of CCs. We used a shRNA-based genetic screen focused on genes upregulated in BRAF(V600E) CCs to identify vulnerabilities of this tumor subtype that might be exploited therapeutically. Here, we identify RANBP2 (also known as NUP358) as essential for survival of BRAF-like, but not for non-BRAF-like, CC cells. Suppression of RANBP2 results in mitotic defects only in BRAF-like CC cells, leading to cell death. Mechanistically, RANBP2 silencing reduces microtubule outgrowth from the kinetochores, thereby inducing spindle perturbations, providing an explanation for the observed mitotic defects. We find that BRAF-like CCs display far greater sensitivity to the microtubule poison vinorelbine both in vitro and in vivo, suggesting that vinorelbine is a potential tailored treatment for BRAF-like CCs.

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