Foxa2 and Cdx2 cooperate with Nkx2-1 to inhibit lung adenocarcinoma metastasis
Despite the fact that the majority of lung cancer deaths are due to metastasis, the molecular mechanisms driving metastatic progression are poorly understood. Here, we present evidence that loss of Foxa2 and Cdx2 synergizes with loss of Nkx2-1 to fully activate the metastatic program. These three li...
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Other Authors: | |
| Format: | Article |
| Language: | en_US |
| Published: |
Cold Spring Harbor Laboratory Press
2016
|
| Online Access: | http://hdl.handle.net/1721.1/102087 https://orcid.org/0000-0001-6988-4260 https://orcid.org/0000-0001-5785-8911 https://orcid.org/0000-0003-1655-2443 https://orcid.org/0000-0003-3214-4554 https://orcid.org/0000-0002-7799-6454 |
| _version_ | 1826188346986070016 |
|---|---|
| author | Li, Carman Man-Chung Gocheva, Vasilena Wang, Shi Yun Date, Saya R. Ng, Sheng Rong Whittaker, Charles A. Bronson, Roderick T. Snyder, Eric L. Oudin, Madeleine Julie Gertler, Frank Bhutkar, Arjun Jacks, Tyler E |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Li, Carman Man-Chung Gocheva, Vasilena Wang, Shi Yun Date, Saya R. Ng, Sheng Rong Whittaker, Charles A. Bronson, Roderick T. Snyder, Eric L. Oudin, Madeleine Julie Gertler, Frank Bhutkar, Arjun Jacks, Tyler E |
| author_sort | Li, Carman Man-Chung |
| collection | MIT |
| description | Despite the fact that the majority of lung cancer deaths are due to metastasis, the molecular mechanisms driving metastatic progression are poorly understood. Here, we present evidence that loss of Foxa2 and Cdx2 synergizes with loss of Nkx2-1 to fully activate the metastatic program. These three lineage-specific transcription factors are consistently down-regulated in metastatic cells compared with nonmetastatic cells. Knockdown of these three factors acts synergistically and is sufficient to promote the metastatic potential of nonmetastatic cells to that of naturally arising metastatic cells in vivo. Furthermore, silencing of these three transcription factors is sufficient to account for a significant fraction of the gene expression differences between the nonmetastatic and metastatic states in lung adenocarcinoma, including up-regulated expression of the invadopodia component Tks5[subscript long], the embryonal proto-oncogene Hmga2, and the epithelial-to-mesenchymal mediator Snail. Finally, analyses of tumors from a genetically engineered mouse model and patients show that low expression of Nkx2-1, Foxa2, and Cdx2 strongly correlates with more advanced tumors and worse survival. Our findings reveal that a large part of the complex transcriptional network in metastasis can be controlled by a small number of regulatory nodes that function redundantly, and loss of multiple nodes is required to fully activate the metastatic program. |
| first_indexed | 2024-09-23T07:58:16Z |
| format | Article |
| id | mit-1721.1/102087 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T07:58:16Z |
| publishDate | 2016 |
| publisher | Cold Spring Harbor Laboratory Press |
| record_format | dspace |
| spelling | mit-1721.1/1020872022-09-30T01:24:38Z Foxa2 and Cdx2 cooperate with Nkx2-1 to inhibit lung adenocarcinoma metastasis Li, Carman Man-Chung Gocheva, Vasilena Wang, Shi Yun Date, Saya R. Ng, Sheng Rong Whittaker, Charles A. Bronson, Roderick T. Snyder, Eric L. Oudin, Madeleine Julie Gertler, Frank Bhutkar, Arjun Jacks, Tyler E Massachusetts Institute of Technology. Department of Biology Massachusetts Institute of Technology. Department of Mechanical Engineering Koch Institute for Integrative Cancer Research at MIT Li, Carman Man-Chung Gocheva, Vasilena Oudin, Madeleine Julie Bhutkar, Arjun (AJ) Wang, Shi Yun Date, Saya R. Ng, Sheng Rong Whittaker, Charles A. Gertler, Frank Jacks, Tyler E. Despite the fact that the majority of lung cancer deaths are due to metastasis, the molecular mechanisms driving metastatic progression are poorly understood. Here, we present evidence that loss of Foxa2 and Cdx2 synergizes with loss of Nkx2-1 to fully activate the metastatic program. These three lineage-specific transcription factors are consistently down-regulated in metastatic cells compared with nonmetastatic cells. Knockdown of these three factors acts synergistically and is sufficient to promote the metastatic potential of nonmetastatic cells to that of naturally arising metastatic cells in vivo. Furthermore, silencing of these three transcription factors is sufficient to account for a significant fraction of the gene expression differences between the nonmetastatic and metastatic states in lung adenocarcinoma, including up-regulated expression of the invadopodia component Tks5[subscript long], the embryonal proto-oncogene Hmga2, and the epithelial-to-mesenchymal mediator Snail. Finally, analyses of tumors from a genetically engineered mouse model and patients show that low expression of Nkx2-1, Foxa2, and Cdx2 strongly correlates with more advanced tumors and worse survival. Our findings reveal that a large part of the complex transcriptional network in metastasis can be controlled by a small number of regulatory nodes that function redundantly, and loss of multiple nodes is required to fully activate the metastatic program. National Cancer Institute (U.S.) (Cancer Center Support Grant P30-CA14051) Howard Hughes Medical Institute National Institutes of Health (U.S.) (Grant 5-U01-CA84306) United States. Dept. of Defense. Breast Cancer Research Program (U.S.) (Grant W81XWH-12-1-0031) Ludwig Center for Molecular Oncology 2016-04-01T20:58:52Z 2016-04-01T20:58:52Z 2015-09 2015-06 Article http://purl.org/eprint/type/JournalArticle 0890-9369 1549-5477 http://hdl.handle.net/1721.1/102087 Li, Carman Man-Chung, Vasilena Gocheva, Madeleine J. Oudin, Arjun Bhutkar, Shi Yun Wang, Saya R. Date, Sheng Rong Ng, et al. “Foxa2 and Cdx2 Cooperate with Nkx2-1 to Inhibit Lung Adenocarcinoma Metastasis.” Genes Dev. 29, no. 17 (September 1, 2015): 1850–1862. https://orcid.org/0000-0001-6988-4260 https://orcid.org/0000-0001-5785-8911 https://orcid.org/0000-0003-1655-2443 https://orcid.org/0000-0003-3214-4554 https://orcid.org/0000-0002-7799-6454 en_US http://dx.doi.org/10.1101/gad.267393.115 Genes & Development Creative Commons Attribution http://creativecommons.org/licenses/by-nc/4.0/ application/pdf Cold Spring Harbor Laboratory Press Cold Spring Harbor Laboratory Press |
| spellingShingle | Li, Carman Man-Chung Gocheva, Vasilena Wang, Shi Yun Date, Saya R. Ng, Sheng Rong Whittaker, Charles A. Bronson, Roderick T. Snyder, Eric L. Oudin, Madeleine Julie Gertler, Frank Bhutkar, Arjun Jacks, Tyler E Foxa2 and Cdx2 cooperate with Nkx2-1 to inhibit lung adenocarcinoma metastasis |
| title | Foxa2 and Cdx2 cooperate with Nkx2-1 to inhibit lung adenocarcinoma metastasis |
| title_full | Foxa2 and Cdx2 cooperate with Nkx2-1 to inhibit lung adenocarcinoma metastasis |
| title_fullStr | Foxa2 and Cdx2 cooperate with Nkx2-1 to inhibit lung adenocarcinoma metastasis |
| title_full_unstemmed | Foxa2 and Cdx2 cooperate with Nkx2-1 to inhibit lung adenocarcinoma metastasis |
| title_short | Foxa2 and Cdx2 cooperate with Nkx2-1 to inhibit lung adenocarcinoma metastasis |
| title_sort | foxa2 and cdx2 cooperate with nkx2 1 to inhibit lung adenocarcinoma metastasis |
| url | http://hdl.handle.net/1721.1/102087 https://orcid.org/0000-0001-6988-4260 https://orcid.org/0000-0001-5785-8911 https://orcid.org/0000-0003-1655-2443 https://orcid.org/0000-0003-3214-4554 https://orcid.org/0000-0002-7799-6454 |
| work_keys_str_mv | AT licarmanmanchung foxa2andcdx2cooperatewithnkx21toinhibitlungadenocarcinomametastasis AT gochevavasilena foxa2andcdx2cooperatewithnkx21toinhibitlungadenocarcinomametastasis AT wangshiyun foxa2andcdx2cooperatewithnkx21toinhibitlungadenocarcinomametastasis AT datesayar foxa2andcdx2cooperatewithnkx21toinhibitlungadenocarcinomametastasis AT ngshengrong foxa2andcdx2cooperatewithnkx21toinhibitlungadenocarcinomametastasis AT whittakercharlesa foxa2andcdx2cooperatewithnkx21toinhibitlungadenocarcinomametastasis AT bronsonroderickt foxa2andcdx2cooperatewithnkx21toinhibitlungadenocarcinomametastasis AT snyderericl foxa2andcdx2cooperatewithnkx21toinhibitlungadenocarcinomametastasis AT oudinmadeleinejulie foxa2andcdx2cooperatewithnkx21toinhibitlungadenocarcinomametastasis AT gertlerfrank foxa2andcdx2cooperatewithnkx21toinhibitlungadenocarcinomametastasis AT bhutkararjun foxa2andcdx2cooperatewithnkx21toinhibitlungadenocarcinomametastasis AT jackstylere foxa2andcdx2cooperatewithnkx21toinhibitlungadenocarcinomametastasis |