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; 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

doi:10.1016/j.cell.2016.02.059

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'ArioSara 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^*

^*Corresponding author for this work

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

5 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 language	English
Pages (from-to)	317-330
Number of pages	14
Journal	Cell
Volume	165
Issue number	2
DOIs	https://doi.org/10.1016/j.cell.2016.02.059
Publication status	Published - 7 Apr 2016

Keywords

BRAF-like colon cancer
functional genomics
RANBP2
targeted treatment
vinorelbine

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10.1016/j.cell.2016.02.059

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Vecchione, L., Gambino, V., Raaijmakers, J., Schlicker, A., Fumagalli, A., Russo, M., Villanueva, A., Beerling, E., Bartolini, A., Mollevi, D. G., El-Murr, N., Chiron, M., Calvet, L., Nicolazzi, C., Combeau, C., Henry, C., Simon, I. M., Tian, S., In 'T Veld, S., ... 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

@article{bf14e1a07b814fc4b7606c564df305f7,

title = "A Vulnerability of a Subset of Colon Cancers with Potential Clinical Utility",

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.",

keywords = "BRAF-like colon cancer, functional genomics, RANBP2, targeted treatment, vinorelbine",

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

year = "2016",

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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

TY - JOUR

T1 - A Vulnerability of a Subset of Colon Cancers with Potential Clinical Utility

AU - Vecchione, Loredana

AU - Gambino, Valentina

AU - Raaijmakers, Jonne

AU - Schlicker, Andreas

AU - Fumagalli, Arianna

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

AU - Combeau, Cécile

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.

AU - Lieftink, Cor

AU - Linn, Sabine

AU - Rumpf-Kienzl, Cornelia

AU - Delorenzi, Mauro

AU - Wessels, Lodewyk

AU - Salazar, Ramon

AU - Di Nicolantonio, Federica

AU - Bardelli, Alberto

AU - Van Rheenen, Jacco

AU - Medema, René H.

AU - Tejpar, Sabine

AU - Bernards, René

PY - 2016/4/7

Y1 - 2016/4/7

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.

AB - 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.

KW - BRAF-like colon cancer

KW - functional genomics

KW - RANBP2

KW - targeted treatment

KW - vinorelbine

UR - http://www.scopus.com/inward/record.url?scp=84963994913&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2016.02.059

DO - 10.1016/j.cell.2016.02.059

M3 - Article

C2 - 27058664

AN - SCOPUS:84963994913

SN - 0092-8674

VL - 165

SP - 317

EP - 330

JO - Cell

JF - Cell

IS - 2

ER -

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

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Keywords

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