CFTR is a tumor suppressor gene in murine and human intestinal cancer

B. L. N. Than; J. F. Linnekamp; T. K. Starr; D. A. Largaespada; A. Rod; Y. Zhang; V. Bruner; J. Abrahante; A. Schumann; T. Luczak; A. Niemczyk; M. G. O'Sullivan; J. P. Medema; R. J. A. Fijneman; G. A. Meijer; E. van den Broek; C. A. Hodges; P. M. Scott; L. Vermeulen; R. T. Cormier

doi:https://doi.org/10.1038/onc.2015.483

CFTR is a tumor suppressor gene in murine and human intestinal cancer

B. L. N. Than, J. F. Linnekamp, T. K. Starr, D. A. Largaespada, A. Rod, Y. Zhang, V. Bruner, J. Abrahante, A. Schumann, T. Luczak, A. Niemczyk, M. G. O'Sullivan, J. P. Medema, R. J. A. Fijneman, G. A. Meijer, E. van den Broek, C. A. Hodges, P. M. Scott, L. Vermeulen, R. T. Cormier

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

124 Citations (Scopus)

Abstract

CFTR, the cystic fibrosis (CF) gene, encodes for the CFTR protein that plays an essential role in anion regulation and tissue homeostasis of various epithelia. In the gastrointestinal (GI) tract CFTR promotes chloride and bicarbonate secretion, playing an essential role in ion and acid-base homeostasis. Cftr has been identified as a candidate driver gene for colorectal cancer (CRC) in several Sleeping Beauty DNA transposon-based forward genetic screens in mice. Further, recent epidemiological and clinical studies indicate that CF patients are at high risk for developing tumors in the colon. To investigate the effects of CFTR dysregulation on GI cancer, we generated Apc(Min) mice that carried an intestinal-specific knockout of Cftr. Our results indicate that Cftr is a tumor suppressor gene in the intestinal tract as Cftr mutant mice developed significantly more tumors in the colon and the entire small intestine. In Apc(+/+) mice aged to ~1 year, Cftr deficiency alone caused the development of intestinal tumors in >60% of mice. Colon organoid formation was significantly increased in organoids created from Cftr mutant mice compared with wild-type controls, suggesting a potential role of Cftr in regulating the intestinal stem cell compartment. Microarray data from the Cftr-deficient colon and the small intestine identified dysregulated genes that belong to groups of immune response, ion channel, intestinal stem cell and other growth signaling regulators. These associated clusters of genes were confirmed by pathway analysis using Ingenuity Pathway Analysis and gene set enrichment analysis (GSEA). We also conducted RNA Seq analysis of tumors from Apc(+/+) Cftr knockout mice and identified sets of genes dysregulated in tumors including altered Wnt β-catenin target genes. Finally we analyzed expression of CFTR in early stage human CRC patients stratified by risk of recurrence and found that loss of expression of CFTR was significantly associated with poor disease-free survival

Original language	English
Pages (from-to)	4179-4187
Journal	Oncogene
Volume	35
Issue number	32
DOIs	https://doi.org/10.1038/onc.2015.483
Publication status	Published - Aug 2016

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https://doi.org/10.1038/onc.2015.483

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Than, B. L. N., Linnekamp, J. F., Starr, T. K., Largaespada, D. A., Rod, A., Zhang, Y., Bruner, V., Abrahante, J., Schumann, A., Luczak, T., Niemczyk, A., O'Sullivan, M. G., Medema, J. P., Fijneman, R. J. A., Meijer, G. A., van den Broek, E., Hodges, C. A., Scott, P. M., Vermeulen, L., & Cormier, R. T. (2016). CFTR is a tumor suppressor gene in murine and human intestinal cancer. Oncogene, 35(32), 4179-4187. https://doi.org/10.1038/onc.2015.483

@article{8e4d4fcb5e1244f19d6b7613245c7e5c,

title = "CFTR is a tumor suppressor gene in murine and human intestinal cancer",

abstract = "CFTR, the cystic fibrosis (CF) gene, encodes for the CFTR protein that plays an essential role in anion regulation and tissue homeostasis of various epithelia. In the gastrointestinal (GI) tract CFTR promotes chloride and bicarbonate secretion, playing an essential role in ion and acid-base homeostasis. Cftr has been identified as a candidate driver gene for colorectal cancer (CRC) in several Sleeping Beauty DNA transposon-based forward genetic screens in mice. Further, recent epidemiological and clinical studies indicate that CF patients are at high risk for developing tumors in the colon. To investigate the effects of CFTR dysregulation on GI cancer, we generated Apc(Min) mice that carried an intestinal-specific knockout of Cftr. Our results indicate that Cftr is a tumor suppressor gene in the intestinal tract as Cftr mutant mice developed significantly more tumors in the colon and the entire small intestine. In Apc(+/+) mice aged to ~1 year, Cftr deficiency alone caused the development of intestinal tumors in >60% of mice. Colon organoid formation was significantly increased in organoids created from Cftr mutant mice compared with wild-type controls, suggesting a potential role of Cftr in regulating the intestinal stem cell compartment. Microarray data from the Cftr-deficient colon and the small intestine identified dysregulated genes that belong to groups of immune response, ion channel, intestinal stem cell and other growth signaling regulators. These associated clusters of genes were confirmed by pathway analysis using Ingenuity Pathway Analysis and gene set enrichment analysis (GSEA). We also conducted RNA Seq analysis of tumors from Apc(+/+) Cftr knockout mice and identified sets of genes dysregulated in tumors including altered Wnt β-catenin target genes. Finally we analyzed expression of CFTR in early stage human CRC patients stratified by risk of recurrence and found that loss of expression of CFTR was significantly associated with poor disease-free survival",

author = "Than, {B. L. N.} and Linnekamp, {J. F.} and Starr, {T. K.} and Largaespada, {D. A.} and A. Rod and Y. Zhang and V. Bruner and J. Abrahante and A. Schumann and T. Luczak and A. Niemczyk and O'Sullivan, {M. G.} and Medema, {J. P.} and Fijneman, {R. J. A.} and Meijer, {G. A.} and {van den Broek}, E. and Hodges, {C. A.} and Scott, {P. M.} and L. Vermeulen and Cormier, {R. T.}",

year = "2016",

month = aug,

doi = "https://doi.org/10.1038/onc.2015.483",

language = "English",

volume = "35",

pages = "4179--4187",

journal = "Oncogene",

issn = "0950-9232",

publisher = "Nature Publishing Group",

number = "32",

}

Than, BLN, Linnekamp, JF, Starr, TK, Largaespada, DA, Rod, A, Zhang, Y, Bruner, V, Abrahante, J, Schumann, A, Luczak, T, Niemczyk, A, O'Sullivan, MG, Medema, JP, Fijneman, RJA, Meijer, GA, van den Broek, E, Hodges, CA, Scott, PM, Vermeulen, L & Cormier, RT 2016, 'CFTR is a tumor suppressor gene in murine and human intestinal cancer', Oncogene, vol. 35, no. 32, pp. 4179-4187. https://doi.org/10.1038/onc.2015.483

TY - JOUR

T1 - CFTR is a tumor suppressor gene in murine and human intestinal cancer

AU - Than, B. L. N.

AU - Linnekamp, J. F.

AU - Starr, T. K.

AU - Largaespada, D. A.

AU - Rod, A.

AU - Zhang, Y.

AU - Bruner, V.

AU - Abrahante, J.

AU - Schumann, A.

AU - Luczak, T.

AU - Niemczyk, A.

AU - O'Sullivan, M. G.

AU - Medema, J. P.

AU - Fijneman, R. J. A.

AU - Meijer, G. A.

AU - van den Broek, E.

AU - Hodges, C. A.

AU - Scott, P. M.

AU - Vermeulen, L.

AU - Cormier, R. T.

PY - 2016/8

Y1 - 2016/8

N2 - CFTR, the cystic fibrosis (CF) gene, encodes for the CFTR protein that plays an essential role in anion regulation and tissue homeostasis of various epithelia. In the gastrointestinal (GI) tract CFTR promotes chloride and bicarbonate secretion, playing an essential role in ion and acid-base homeostasis. Cftr has been identified as a candidate driver gene for colorectal cancer (CRC) in several Sleeping Beauty DNA transposon-based forward genetic screens in mice. Further, recent epidemiological and clinical studies indicate that CF patients are at high risk for developing tumors in the colon. To investigate the effects of CFTR dysregulation on GI cancer, we generated Apc(Min) mice that carried an intestinal-specific knockout of Cftr. Our results indicate that Cftr is a tumor suppressor gene in the intestinal tract as Cftr mutant mice developed significantly more tumors in the colon and the entire small intestine. In Apc(+/+) mice aged to ~1 year, Cftr deficiency alone caused the development of intestinal tumors in >60% of mice. Colon organoid formation was significantly increased in organoids created from Cftr mutant mice compared with wild-type controls, suggesting a potential role of Cftr in regulating the intestinal stem cell compartment. Microarray data from the Cftr-deficient colon and the small intestine identified dysregulated genes that belong to groups of immune response, ion channel, intestinal stem cell and other growth signaling regulators. These associated clusters of genes were confirmed by pathway analysis using Ingenuity Pathway Analysis and gene set enrichment analysis (GSEA). We also conducted RNA Seq analysis of tumors from Apc(+/+) Cftr knockout mice and identified sets of genes dysregulated in tumors including altered Wnt β-catenin target genes. Finally we analyzed expression of CFTR in early stage human CRC patients stratified by risk of recurrence and found that loss of expression of CFTR was significantly associated with poor disease-free survival

AB - CFTR, the cystic fibrosis (CF) gene, encodes for the CFTR protein that plays an essential role in anion regulation and tissue homeostasis of various epithelia. In the gastrointestinal (GI) tract CFTR promotes chloride and bicarbonate secretion, playing an essential role in ion and acid-base homeostasis. Cftr has been identified as a candidate driver gene for colorectal cancer (CRC) in several Sleeping Beauty DNA transposon-based forward genetic screens in mice. Further, recent epidemiological and clinical studies indicate that CF patients are at high risk for developing tumors in the colon. To investigate the effects of CFTR dysregulation on GI cancer, we generated Apc(Min) mice that carried an intestinal-specific knockout of Cftr. Our results indicate that Cftr is a tumor suppressor gene in the intestinal tract as Cftr mutant mice developed significantly more tumors in the colon and the entire small intestine. In Apc(+/+) mice aged to ~1 year, Cftr deficiency alone caused the development of intestinal tumors in >60% of mice. Colon organoid formation was significantly increased in organoids created from Cftr mutant mice compared with wild-type controls, suggesting a potential role of Cftr in regulating the intestinal stem cell compartment. Microarray data from the Cftr-deficient colon and the small intestine identified dysregulated genes that belong to groups of immune response, ion channel, intestinal stem cell and other growth signaling regulators. These associated clusters of genes were confirmed by pathway analysis using Ingenuity Pathway Analysis and gene set enrichment analysis (GSEA). We also conducted RNA Seq analysis of tumors from Apc(+/+) Cftr knockout mice and identified sets of genes dysregulated in tumors including altered Wnt β-catenin target genes. Finally we analyzed expression of CFTR in early stage human CRC patients stratified by risk of recurrence and found that loss of expression of CFTR was significantly associated with poor disease-free survival

U2 - https://doi.org/10.1038/onc.2015.483

DO - https://doi.org/10.1038/onc.2015.483

M3 - Article

C2 - 26751771

SN - 0950-9232

VL - 35

SP - 4179

EP - 4187

JO - Oncogene

JF - Oncogene

IS - 32

ER -