Inactivation of Capicua drives cancer metastasis

Ross A. Okimoto; Frank Breitenbuecher; Victor R. Olivas; Wei Wu; Beatrice Gini; Matan Hofree; Saurabh Asthana; Gorjan Hrustanovic; Jennifer Flanagan; Asmin Tulpule; Collin M. Blakely; Henry J. Haringsma; Andrew D. Simmons; Kyle Gowen; James Suh; Vincent A. Miller; Siraj Ali; Martin Schuler; Trever G. Bivona

doi:10.1038/ng.3728

Inactivation of Capicua drives cancer metastasis

Ross A. Okimoto, Frank Breitenbuecher, Victor R. Olivas, Wei Wu, Beatrice Gini, Matan Hofree, Saurabh Asthana, Gorjan Hrustanovic, Jennifer Flanagan, Asmin Tulpule, Collin M. Blakely, Henry J. Haringsma, Andrew D. Simmons, Kyle Gowen, James Suh, Vincent A. Miller, Siraj Ali, Martin Schuler, Trever G. Bivona

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

Abstract

Metastasis is the leading cause of death in people with lung cancer, yet the molecular effectors underlying tumor dissemination remain poorly defined. Through the development of an in vivo spontaneous lung cancer metastasis model, we show that the developmentally regulated transcriptional repressor Capicua (CIC) suppresses invasion and metastasis. Inactivation of CIC relieves repression of its effector ETV4, driving ETV4-mediated upregulation of MMP24, which is necessary and sufficient for metastasis. Loss of CIC, or an increase in levels of its effectors ETV4 and MMP24, is a biomarker of tumor progression and worse outcomes in people with lung and/or gastric cancer. Our findings reveal CIC as a conserved metastasis suppressor, highlighting new anti-metastatic strategies that could potentially improve patient outcomes.

Original language	English
Pages (from-to)	87-96
Number of pages	10
Journal	Nature Genetics
Volume	49
Issue number	1
DOIs	https://doi.org/10.1038/ng.3728
State	Published - 1 Jan 2017
Externally published	Yes

UN SDGs

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

SDG 3 Good Health and Well-being

All Science Journal Classification (ASJC) codes

Genetics

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10.1038/ng.3728

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Okimoto, R. A., Breitenbuecher, F., Olivas, V. R., Wu, W., Gini, B., Hofree, M., Asthana, S., Hrustanovic, G., Flanagan, J., Tulpule, A., Blakely, C. M., Haringsma, H. J., Simmons, A. D., Gowen, K., Suh, J., Miller, V. A., Ali, S., Schuler, M., & Bivona, T. G. (2017). Inactivation of Capicua drives cancer metastasis. Nature Genetics, 49(1), 87-96. https://doi.org/10.1038/ng.3728

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title = "Inactivation of Capicua drives cancer metastasis",

abstract = "Metastasis is the leading cause of death in people with lung cancer, yet the molecular effectors underlying tumor dissemination remain poorly defined. Through the development of an in vivo spontaneous lung cancer metastasis model, we show that the developmentally regulated transcriptional repressor Capicua (CIC) suppresses invasion and metastasis. Inactivation of CIC relieves repression of its effector ETV4, driving ETV4-mediated upregulation of MMP24, which is necessary and sufficient for metastasis. Loss of CIC, or an increase in levels of its effectors ETV4 and MMP24, is a biomarker of tumor progression and worse outcomes in people with lung and/or gastric cancer. Our findings reveal CIC as a conserved metastasis suppressor, highlighting new anti-metastatic strategies that could potentially improve patient outcomes.",

author = "Okimoto, \{Ross A.\} and Frank Breitenbuecher and Olivas, \{Victor R.\} and Wei Wu and Beatrice Gini and Matan Hofree and Saurabh Asthana and Gorjan Hrustanovic and Jennifer Flanagan and Asmin Tulpule and Blakely, \{Collin M.\} and Haringsma, \{Henry J.\} and Simmons, \{Andrew D.\} and Kyle Gowen and James Suh and Miller, \{Vincent A.\} and Siraj Ali and Martin Schuler and Bivona, \{Trever G.\}",

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doi = "10.1038/ng.3728",

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AU - Okimoto, Ross A.

AU - Breitenbuecher, Frank

AU - Olivas, Victor R.

AU - Wu, Wei

AU - Gini, Beatrice

AU - Hofree, Matan

AU - Asthana, Saurabh

AU - Hrustanovic, Gorjan

AU - Flanagan, Jennifer

AU - Tulpule, Asmin

AU - Blakely, Collin M.

AU - Haringsma, Henry J.

AU - Simmons, Andrew D.

AU - Gowen, Kyle

AU - Suh, James

AU - Miller, Vincent A.

AU - Ali, Siraj

AU - Schuler, Martin

AU - Bivona, Trever G.

PY - 2017/1/1

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N2 - Metastasis is the leading cause of death in people with lung cancer, yet the molecular effectors underlying tumor dissemination remain poorly defined. Through the development of an in vivo spontaneous lung cancer metastasis model, we show that the developmentally regulated transcriptional repressor Capicua (CIC) suppresses invasion and metastasis. Inactivation of CIC relieves repression of its effector ETV4, driving ETV4-mediated upregulation of MMP24, which is necessary and sufficient for metastasis. Loss of CIC, or an increase in levels of its effectors ETV4 and MMP24, is a biomarker of tumor progression and worse outcomes in people with lung and/or gastric cancer. Our findings reveal CIC as a conserved metastasis suppressor, highlighting new anti-metastatic strategies that could potentially improve patient outcomes.

AB - Metastasis is the leading cause of death in people with lung cancer, yet the molecular effectors underlying tumor dissemination remain poorly defined. Through the development of an in vivo spontaneous lung cancer metastasis model, we show that the developmentally regulated transcriptional repressor Capicua (CIC) suppresses invasion and metastasis. Inactivation of CIC relieves repression of its effector ETV4, driving ETV4-mediated upregulation of MMP24, which is necessary and sufficient for metastasis. Loss of CIC, or an increase in levels of its effectors ETV4 and MMP24, is a biomarker of tumor progression and worse outcomes in people with lung and/or gastric cancer. Our findings reveal CIC as a conserved metastasis suppressor, highlighting new anti-metastatic strategies that could potentially improve patient outcomes.

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DO - 10.1038/ng.3728

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SN - 1061-4036

VL - 49

SP - 87

EP - 96

JO - Nature Genetics

JF - Nature Genetics

IS - 1

ER -

Inactivation of Capicua drives cancer metastasis

Abstract

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All Science Journal Classification (ASJC) codes

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