TGFβ signaling directs serrated adenomas to the mesenchymal colorectal cancer subtype

Evelyn Fessler; Jarno Drost; Sander R. van Hooff; Janneke F. Linnekamp; Xin Wang; Marnix Jansen; Felipe De Sousa E Melo; Pramudita R. Prasetyanti; Joep E.G. Ijspeert; Marek Franitza; Peter Nürnberg; Carel J.M. van Noesel; Evelien Dekker; Louis Vermeulen; Hans Clevers; Jan Paul Medema

doi:10.15252/emmm.201606184

TGFβ signaling directs serrated adenomas to the mesenchymal colorectal cancer subtype

Evelyn Fessler, Jarno Drost, Sander R. van Hooff, Janneke F. Linnekamp, Xin Wang, Marnix Jansen, Felipe De Sousa E Melo, Pramudita R. Prasetyanti, Joep E.G. Ijspeert, Marek Franitza, Peter Nürnberg, Carel J.M. van Noesel, Evelien Dekker, Louis Vermeulen, Hans Clevers, Jan Paul Medema^*

^*Corresponding author for this work

Department of Biomedical Sciences

Research output: Journal Publications and Reviews › RGC 21 - Publication in refereed journal › peer-review

139 Citations (Scopus)

47 Downloads (CityUHK Scholars)

Abstract

The heterogeneous nature of colorectal cancer (CRC) complicates prognosis and is suggested to be a determining factor in the efficacy of adjuvant therapy for individual patients. Based on gene expression profiling, CRC is currently classified into four consensus molecular subtypes (CMSs), characterized by specific biological programs, thus suggesting the existence of unifying developmental drivers for each CMS. Using human organoid cultures, we investigated the role of such developmental drivers at the premalignant stage of distinct CRC subtypes and found that TGFβ plays an important role in the development of the mesenchymal CMS4, which is of special interest due to its association with dismal prognosis. We show that in tubular adenomas (TAs), which progress to classical CRCs, the dominating response to TGFβ is death by apoptosis. By contrast, induction of a mesenchymal phenotype upon TGFβ treatment prevails in a genetically engineered organoid culture carrying a BRAF^V ^600E mutation, constituting a model system for sessile serrated adenomas (SSAs). Our data indicate that TGFβ signaling is already active in SSA precursor lesions and that TGFβ is a critical cue for directing SSAs to the mesenchymal, poor-prognosis CMS4 of CRC.

Original language	English
Pages (from-to)	745-760
Journal	EMBO Molecular Medicine
Volume	8
Issue number	7
DOIs	https://doi.org/10.15252/emmm.201606184
Publication status	Published - 1 Jul 2016

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Research Keywords

cancer subtypes
colorectal cancer
epithelial–mesenchymal transition
sessile serrated adenoma
transforming growth factor beta (TGFβ)

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This full text is made available under CC-BY 4.0. https://creativecommons.org/licenses/by/4.0/

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Fessler, E., Drost, J., van Hooff, S. R., Linnekamp, J. F., Wang, X., Jansen, M., De Sousa E Melo, F., Prasetyanti, P. R., Ijspeert, J. E. G., Franitza, M., Nürnberg, P., van Noesel, C. J. M., Dekker, E., Vermeulen, L., Clevers, H., & Medema, J. P. (2016). TGFβ signaling directs serrated adenomas to the mesenchymal colorectal cancer subtype. EMBO Molecular Medicine, 8(7), 745-760. https://doi.org/10.15252/emmm.201606184

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title = "TGFβ signaling directs serrated adenomas to the mesenchymal colorectal cancer subtype",

abstract = "The heterogeneous nature of colorectal cancer (CRC) complicates prognosis and is suggested to be a determining factor in the efficacy of adjuvant therapy for individual patients. Based on gene expression profiling, CRC is currently classified into four consensus molecular subtypes (CMSs), characterized by specific biological programs, thus suggesting the existence of unifying developmental drivers for each CMS. Using human organoid cultures, we investigated the role of such developmental drivers at the premalignant stage of distinct CRC subtypes and found that TGFβ plays an important role in the development of the mesenchymal CMS4, which is of special interest due to its association with dismal prognosis. We show that in tubular adenomas (TAs), which progress to classical CRCs, the dominating response to TGFβ is death by apoptosis. By contrast, induction of a mesenchymal phenotype upon TGFβ treatment prevails in a genetically engineered organoid culture carrying a BRAFV 600E mutation, constituting a model system for sessile serrated adenomas (SSAs). Our data indicate that TGFβ signaling is already active in SSA precursor lesions and that TGFβ is a critical cue for directing SSAs to the mesenchymal, poor-prognosis CMS4 of CRC.",

keywords = "cancer subtypes, colorectal cancer, epithelial–mesenchymal transition, sessile serrated adenoma, transforming growth factor beta (TGFβ)",

author = "Evelyn Fessler and Jarno Drost and {van Hooff}, {Sander R.} and Linnekamp, {Janneke F.} and Xin Wang and Marnix Jansen and {De Sousa E Melo}, Felipe and Prasetyanti, {Pramudita R.} and Ijspeert, {Joep E.G.} and Marek Franitza and Peter N{\"u}rnberg and {van Noesel}, {Carel J.M.} and Evelien Dekker and Louis Vermeulen and Hans Clevers and Medema, {Jan Paul}",

year = "2016",

month = jul,

day = "1",

doi = "10.15252/emmm.201606184",

language = "English",

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pages = "745--760",

journal = "EMBO Molecular Medicine",

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Fessler, E, Drost, J, van Hooff, SR, Linnekamp, JF, Wang, X, Jansen, M, De Sousa E Melo, F, Prasetyanti, PR, Ijspeert, JEG, Franitza, M, Nürnberg, P, van Noesel, CJM, Dekker, E, Vermeulen, L, Clevers, H & Medema, JP 2016, 'TGFβ signaling directs serrated adenomas to the mesenchymal colorectal cancer subtype', EMBO Molecular Medicine, vol. 8, no. 7, pp. 745-760. https://doi.org/10.15252/emmm.201606184

TY - JOUR

T1 - TGFβ signaling directs serrated adenomas to the mesenchymal colorectal cancer subtype

AU - Fessler, Evelyn

AU - Drost, Jarno

AU - van Hooff, Sander R.

AU - Linnekamp, Janneke F.

AU - Wang, Xin

AU - Jansen, Marnix

AU - De Sousa E Melo, Felipe

AU - Prasetyanti, Pramudita R.

AU - Ijspeert, Joep E.G.

AU - Franitza, Marek

AU - Nürnberg, Peter

AU - van Noesel, Carel J.M.

AU - Dekker, Evelien

AU - Vermeulen, Louis

AU - Clevers, Hans

AU - Medema, Jan Paul

PY - 2016/7/1

Y1 - 2016/7/1

N2 - The heterogeneous nature of colorectal cancer (CRC) complicates prognosis and is suggested to be a determining factor in the efficacy of adjuvant therapy for individual patients. Based on gene expression profiling, CRC is currently classified into four consensus molecular subtypes (CMSs), characterized by specific biological programs, thus suggesting the existence of unifying developmental drivers for each CMS. Using human organoid cultures, we investigated the role of such developmental drivers at the premalignant stage of distinct CRC subtypes and found that TGFβ plays an important role in the development of the mesenchymal CMS4, which is of special interest due to its association with dismal prognosis. We show that in tubular adenomas (TAs), which progress to classical CRCs, the dominating response to TGFβ is death by apoptosis. By contrast, induction of a mesenchymal phenotype upon TGFβ treatment prevails in a genetically engineered organoid culture carrying a BRAFV 600E mutation, constituting a model system for sessile serrated adenomas (SSAs). Our data indicate that TGFβ signaling is already active in SSA precursor lesions and that TGFβ is a critical cue for directing SSAs to the mesenchymal, poor-prognosis CMS4 of CRC.

AB - The heterogeneous nature of colorectal cancer (CRC) complicates prognosis and is suggested to be a determining factor in the efficacy of adjuvant therapy for individual patients. Based on gene expression profiling, CRC is currently classified into four consensus molecular subtypes (CMSs), characterized by specific biological programs, thus suggesting the existence of unifying developmental drivers for each CMS. Using human organoid cultures, we investigated the role of such developmental drivers at the premalignant stage of distinct CRC subtypes and found that TGFβ plays an important role in the development of the mesenchymal CMS4, which is of special interest due to its association with dismal prognosis. We show that in tubular adenomas (TAs), which progress to classical CRCs, the dominating response to TGFβ is death by apoptosis. By contrast, induction of a mesenchymal phenotype upon TGFβ treatment prevails in a genetically engineered organoid culture carrying a BRAFV 600E mutation, constituting a model system for sessile serrated adenomas (SSAs). Our data indicate that TGFβ signaling is already active in SSA precursor lesions and that TGFβ is a critical cue for directing SSAs to the mesenchymal, poor-prognosis CMS4 of CRC.

KW - cancer subtypes

KW - colorectal cancer

KW - epithelial–mesenchymal transition

KW - sessile serrated adenoma

KW - transforming growth factor beta (TGFβ)

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U2 - 10.15252/emmm.201606184

DO - 10.15252/emmm.201606184

M3 - RGC 21 - Publication in refereed journal

C2 - 27221051

SN - 1757-4676

VL - 8

SP - 745

EP - 760

JO - EMBO Molecular Medicine

JF - EMBO Molecular Medicine

IS - 7

ER -

TGFβ signaling directs serrated adenomas to the mesenchymal colorectal cancer subtype

Abstract

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Research Keywords

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