p53 constrains progression to anaplastic thyroid carcinoma in a Braf-mutant mouse model of papillary thyroid cancer
Anaplastic thyroid carcinoma (ATC) has among the worst prognoses of any solid malignancy. The low incidence of the disease has in part precluded systematic clinical trials and tissue collection, and there has been little progress in developing effective therapies. v-raf murine sarcoma viral oncogene...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | en_US |
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National Academy of Sciences (U.S.)
2014
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| Online Access: | http://hdl.handle.net/1721.1/91529 https://orcid.org/0000-0001-5785-8911 https://orcid.org/0000-0003-4336-2135 |
| _version_ | 1826213300483915776 |
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| author | McFadden, David Glenn Vernon, Amanda Santiago, Philip M. Martinez-McFaline, Raul Crowley, Denise M. McMahon, Martin Sadow, Peter M. Bhutkar, Arjun Jacks, Tyler E |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology McFadden, David Glenn Vernon, Amanda Santiago, Philip M. Martinez-McFaline, Raul Crowley, Denise M. McMahon, Martin Sadow, Peter M. Bhutkar, Arjun Jacks, Tyler E |
| author_sort | McFadden, David Glenn |
| collection | MIT |
| description | Anaplastic thyroid carcinoma (ATC) has among the worst prognoses of any solid malignancy. The low incidence of the disease has in part precluded systematic clinical trials and tissue collection, and there has been little progress in developing effective therapies. v-raf murine sarcoma viral oncogene homolog B (BRAF) and tumor protein p53 (TP53) mutations cooccur in a high proportion of ATCs, particularly those associated with a precursor papillary thyroid carcinoma (PTC). To develop an adult-onset model of BRAF-mutant ATC, we generated a thyroid-specific CreER transgenic mouse. We used a Cre-regulated Braf[superscript V600E] mouse and a conditional Trp53 allelic series to demonstrate that p53 constrains progression from PTC to ATC. Gene expression and immunohistochemical analyses of murine tumors identified the cardinal features of human ATC including loss of differentiation, local invasion, distant metastasis, and rapid lethality. We used small-animal ultrasound imaging to monitor autochthonous tumors and showed that treatment with the selective BRAF inhibitor PLX4720 improved survival but did not lead to tumor regression or suppress signaling through the MAPK pathway. The combination of PLX4720 and the mapk/Erk kinase (MEK) inhibitor PD0325901 more completely suppressed MAPK pathway activation in mouse and human ATC cell lines and improved the structural response and survival of ATC-bearing animals. This model expands the limited repertoire of autochthonous models of clinically aggressive thyroid cancer, and these data suggest that small-molecule MAPK pathway inhibitors hold clinical promise in the treatment of advanced thyroid carcinoma. |
| first_indexed | 2024-09-23T15:46:53Z |
| format | Article |
| id | mit-1721.1/91529 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T15:46:53Z |
| publishDate | 2014 |
| publisher | National Academy of Sciences (U.S.) |
| record_format | dspace |
| spelling | mit-1721.1/915292022-09-29T16:04:52Z p53 constrains progression to anaplastic thyroid carcinoma in a Braf-mutant mouse model of papillary thyroid cancer McFadden, David Glenn Vernon, Amanda Santiago, Philip M. Martinez-McFaline, Raul Crowley, Denise M. McMahon, Martin Sadow, Peter M. Bhutkar, Arjun Jacks, Tyler E Massachusetts Institute of Technology. Department of Biology Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences Koch Institute for Integrative Cancer Research at MIT McFadden, David Glenn Vernon, Amanda Santiago, Philip M. Martinez-McFaline, Raul Bhutkar, Arjun (AJ) Crowley, Denise M. Jacks, Tyler E. Anaplastic thyroid carcinoma (ATC) has among the worst prognoses of any solid malignancy. The low incidence of the disease has in part precluded systematic clinical trials and tissue collection, and there has been little progress in developing effective therapies. v-raf murine sarcoma viral oncogene homolog B (BRAF) and tumor protein p53 (TP53) mutations cooccur in a high proportion of ATCs, particularly those associated with a precursor papillary thyroid carcinoma (PTC). To develop an adult-onset model of BRAF-mutant ATC, we generated a thyroid-specific CreER transgenic mouse. We used a Cre-regulated Braf[superscript V600E] mouse and a conditional Trp53 allelic series to demonstrate that p53 constrains progression from PTC to ATC. Gene expression and immunohistochemical analyses of murine tumors identified the cardinal features of human ATC including loss of differentiation, local invasion, distant metastasis, and rapid lethality. We used small-animal ultrasound imaging to monitor autochthonous tumors and showed that treatment with the selective BRAF inhibitor PLX4720 improved survival but did not lead to tumor regression or suppress signaling through the MAPK pathway. The combination of PLX4720 and the mapk/Erk kinase (MEK) inhibitor PD0325901 more completely suppressed MAPK pathway activation in mouse and human ATC cell lines and improved the structural response and survival of ATC-bearing animals. This model expands the limited repertoire of autochthonous models of clinically aggressive thyroid cancer, and these data suggest that small-molecule MAPK pathway inhibitors hold clinical promise in the treatment of advanced thyroid carcinoma. Howard Hughes Medical Institute National Cancer Institute (U.S.) (Career Development Award K08CA160658) American Thyroid Association (Research Award) 2014-11-12T13:56:33Z 2014-11-12T13:56:33Z 2014-04 2013-12 Article http://purl.org/eprint/type/JournalArticle 0027-8424 1091-6490 http://hdl.handle.net/1721.1/91529 McFadden, D. G., A. Vernon, P. M. Santiago, R. Martinez-McFaline, A. Bhutkar, D. M. Crowley, M. McMahon, P. M. Sadow, and T. Jacks. “P53 Constrains Progression to Anaplastic Thyroid Carcinoma in a Braf-Mutant Mouse Model of Papillary Thyroid Cancer.” Proceedings of the National Academy of Sciences 111, no. 16 (April 7, 2014): E1600–E1609. https://orcid.org/0000-0001-5785-8911 https://orcid.org/0000-0003-4336-2135 en_US http://dx.doi.org/10.1073/pnas.1404357111 Proceedings of the National Academy of Sciences Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf National Academy of Sciences (U.S.) PNAS |
| spellingShingle | McFadden, David Glenn Vernon, Amanda Santiago, Philip M. Martinez-McFaline, Raul Crowley, Denise M. McMahon, Martin Sadow, Peter M. Bhutkar, Arjun Jacks, Tyler E p53 constrains progression to anaplastic thyroid carcinoma in a Braf-mutant mouse model of papillary thyroid cancer |
| title | p53 constrains progression to anaplastic thyroid carcinoma in a Braf-mutant mouse model of papillary thyroid cancer |
| title_full | p53 constrains progression to anaplastic thyroid carcinoma in a Braf-mutant mouse model of papillary thyroid cancer |
| title_fullStr | p53 constrains progression to anaplastic thyroid carcinoma in a Braf-mutant mouse model of papillary thyroid cancer |
| title_full_unstemmed | p53 constrains progression to anaplastic thyroid carcinoma in a Braf-mutant mouse model of papillary thyroid cancer |
| title_short | p53 constrains progression to anaplastic thyroid carcinoma in a Braf-mutant mouse model of papillary thyroid cancer |
| title_sort | p53 constrains progression to anaplastic thyroid carcinoma in a braf mutant mouse model of papillary thyroid cancer |
| url | http://hdl.handle.net/1721.1/91529 https://orcid.org/0000-0001-5785-8911 https://orcid.org/0000-0003-4336-2135 |
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