Stromal gene expression defines poor-prognosis subtypes in colorectal cancer

Alexandre Calon; Enza Lonardo; Antonio Berenguer-Llergo; Elisa Espinet; Xavier Hernando-Momblona; Mar Iglesias; Marta Sevillano; Sergio Palomo-Ponce; Daniele V.F. Tauriello; Daniel Byrom; Carme Cortina; Clara Morral; Carles Barceló; Sebastien Tosi; Antoni Riera; Camille Stephan Otto Attolini; David Rossell; Elena Sancho; Eduard Batlle

doi:10.1038/ng.3225

Stromal gene expression defines poor-prognosis subtypes in colorectal cancer

Alexandre Calon, Enza Lonardo, Antonio Berenguer-Llergo, Elisa Espinet, Xavier Hernando-Momblona, Mar Iglesias, Marta Sevillano, Sergio Palomo-Ponce, Daniele V.F. Tauriello, Daniel Byrom, Carme Cortina, Clara Morral, Carles Barceló, Sebastien Tosi, Antoni Riera, Camille Stephan Otto Attolini, David Rossell, Elena Sancho, Eduard Batlle^*

^*Corresponding author for this work

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

826 Citations (Scopus)

Abstract

Recent molecular classifications of colorectal cancer (CRC) based on global gene expression profiles have defined subtypes displaying resistance to therapy and poor prognosis. Upon evaluation of these classification systems, we discovered that their predictive power arises from genes expressed by stromal cells rather than epithelial tumor cells. Bioinformatic and immunohistochemical analyses identify stromal markers that associate robustly with disease relapse across the various classifications. Functional studies indicate that cancer-associated fibroblasts (CAFs) increase the frequency of tumor-initiating cells, an effect that is dramatically enhanced by transforming growth factor (TGF)-β signaling. Likewise, we find that all poor-prognosis CRC subtypes share a gene program induced by TGF-β in tumor stromal cells. Using patient-derived tumor organoids and xenografts, we show that the use of TGF-β signaling inhibitors to block the cross-talk between cancer cells and the microenvironment halts disease progression.

Original language	English
Pages (from-to)	320-329
Number of pages	10
Journal	Nature Genetics
Volume	47
Issue number	4
DOIs	https://doi.org/10.1038/ng.3225
Publication status	Published - Apr 2015
Externally published	Yes

Bibliographical note

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© 2015 Nature America, Inc. All rights reserved.

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Calon, A., Lonardo, E., Berenguer-Llergo, A., Espinet, E., Hernando-Momblona, X., Iglesias, M., Sevillano, M., Palomo-Ponce, S., Tauriello, D. V. F., Byrom, D., Cortina, C., Morral, C., Barceló, C., Tosi, S., Riera, A., Attolini, C. S. O., Rossell, D., Sancho, E., & Batlle, E. (2015). Stromal gene expression defines poor-prognosis subtypes in colorectal cancer. Nature Genetics, 47(4), 320-329. https://doi.org/10.1038/ng.3225

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title = "Stromal gene expression defines poor-prognosis subtypes in colorectal cancer",

abstract = "Recent molecular classifications of colorectal cancer (CRC) based on global gene expression profiles have defined subtypes displaying resistance to therapy and poor prognosis. Upon evaluation of these classification systems, we discovered that their predictive power arises from genes expressed by stromal cells rather than epithelial tumor cells. Bioinformatic and immunohistochemical analyses identify stromal markers that associate robustly with disease relapse across the various classifications. Functional studies indicate that cancer-associated fibroblasts (CAFs) increase the frequency of tumor-initiating cells, an effect that is dramatically enhanced by transforming growth factor (TGF)-β signaling. Likewise, we find that all poor-prognosis CRC subtypes share a gene program induced by TGF-β in tumor stromal cells. Using patient-derived tumor organoids and xenografts, we show that the use of TGF-β signaling inhibitors to block the cross-talk between cancer cells and the microenvironment halts disease progression.",

author = "Alexandre Calon and Enza Lonardo and Antonio Berenguer-Llergo and Elisa Espinet and Xavier Hernando-Momblona and Mar Iglesias and Marta Sevillano and Sergio Palomo-Ponce and Tauriello, {Daniele V.F.} and Daniel Byrom and Carme Cortina and Clara Morral and Carles Barcel{\'o} and Sebastien Tosi and Antoni Riera and Attolini, {Camille Stephan Otto} and David Rossell and Elena Sancho and Eduard Batlle",

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doi = "10.1038/ng.3225",

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Calon, A, Lonardo, E, Berenguer-Llergo, A, Espinet, E, Hernando-Momblona, X, Iglesias, M, Sevillano, M, Palomo-Ponce, S, Tauriello, DVF, Byrom, D, Cortina, C, Morral, C, Barceló, C, Tosi, S, Riera, A, Attolini, CSO, Rossell, D, Sancho, E & Batlle, E 2015, 'Stromal gene expression defines poor-prognosis subtypes in colorectal cancer', Nature Genetics, vol. 47, no. 4, pp. 320-329. https://doi.org/10.1038/ng.3225

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AU - Calon, Alexandre

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AU - Hernando-Momblona, Xavier

AU - Iglesias, Mar

AU - Sevillano, Marta

AU - Palomo-Ponce, Sergio

AU - Tauriello, Daniele V.F.

AU - Byrom, Daniel

AU - Cortina, Carme

AU - Morral, Clara

AU - Barceló, Carles

AU - Tosi, Sebastien

AU - Riera, Antoni

AU - Attolini, Camille Stephan Otto

AU - Rossell, David

AU - Sancho, Elena

AU - Batlle, Eduard

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AB - Recent molecular classifications of colorectal cancer (CRC) based on global gene expression profiles have defined subtypes displaying resistance to therapy and poor prognosis. Upon evaluation of these classification systems, we discovered that their predictive power arises from genes expressed by stromal cells rather than epithelial tumor cells. Bioinformatic and immunohistochemical analyses identify stromal markers that associate robustly with disease relapse across the various classifications. Functional studies indicate that cancer-associated fibroblasts (CAFs) increase the frequency of tumor-initiating cells, an effect that is dramatically enhanced by transforming growth factor (TGF)-β signaling. Likewise, we find that all poor-prognosis CRC subtypes share a gene program induced by TGF-β in tumor stromal cells. Using patient-derived tumor organoids and xenografts, we show that the use of TGF-β signaling inhibitors to block the cross-talk between cancer cells and the microenvironment halts disease progression.

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Stromal gene expression defines poor-prognosis subtypes in colorectal cancer

Abstract

Bibliographical note

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