Integrin-β4 identifies cancer stem cell-enriched populations of partially mesenchymal carcinoma cells
Neoplastic cells within individual carcinomas often exhibit considerable phenotypic heterogeneity in their epithelial versus mesenchymal-like cell states. Because carcinoma cells with mesenchymal features are often more resistant to therapy and may serve as a source of relapse, we sought to determin...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
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National Academy of Sciences (U.S.)
2017
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| Online Access: | http://hdl.handle.net/1721.1/112217 https://orcid.org/0000-0002-0895-3557 |
| _version_ | 1811089635013558272 |
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| author | Bierie, Brian Pierce, Sarah E. Kroeger, Cornelia Stover, Daniel G. Pattabiraman, Diwakar R. Thiru, Prathapan Liu Donaher, Joana Reinhardt, Ferenc Chaffer, Christine L. Keckesova, Zuzana Weinberg, Robert A |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Bierie, Brian Pierce, Sarah E. Kroeger, Cornelia Stover, Daniel G. Pattabiraman, Diwakar R. Thiru, Prathapan Liu Donaher, Joana Reinhardt, Ferenc Chaffer, Christine L. Keckesova, Zuzana Weinberg, Robert A |
| author_sort | Bierie, Brian |
| collection | MIT |
| description | Neoplastic cells within individual carcinomas often exhibit considerable phenotypic heterogeneity in their epithelial versus mesenchymal-like cell states. Because carcinoma cells with mesenchymal features are often more resistant to therapy and may serve as a source of relapse, we sought to determine whether such cells could be further stratified into functionally distinct subtypes. Indeed, we find that a basal epithelial marker, integrin- β4 (ITGB4), can be used to enable stratification of mesenchymallike triple-negative breast cancer (TNBC) cells that differ from one another in their relative tumorigenic abilities. Notably, we demonstrate that ITGB4 + cancer stem cell (CSC)-enriched mesenchymal cells reside in an intermediate epithelial/mesenchymal phenotypic state. Among patients with TNBC who received chemotherapy, elevated ITGB4 expression was associated with a worse 5-year probability of relapse-free survival.Mechanistically,we find that the ZEB1 (zinc finger E-box binding homeobox 1) transcription factor activity in highly mesenchymal SUM159 TNBC cells can repress expression of the epithelial transcription factor TAp63α (tumor protein 63 isoform 1), a protein that promotes ITGB4 expression. In addition, we demonstrate that ZEB1 and ITGB4 are important in modulating the histopathological phenotypes of tumors derived from mesenchymal TNBC cells. Hence, mesenchymal carcinoma cell populations are internally heterogeneous, and ITGB4 is a mechanistically driven prognostic biomarker that can be used to identify the more aggressive subtypes of mesenchymal carcinoma cells in TNBC. The ability to rapidly isolate and mechanistically interrogate the CSC-enriched, partially mesenchymal carcinoma cells should further enable identification of novel therapeutic opportunities to improve the prognosis for high-risk patients with TNBC. |
| first_indexed | 2024-09-23T14:22:19Z |
| format | Article |
| id | mit-1721.1/112217 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2024-09-23T14:22:19Z |
| publishDate | 2017 |
| publisher | National Academy of Sciences (U.S.) |
| record_format | dspace |
| spelling | mit-1721.1/1122172022-09-29T09:03:17Z Integrin-β4 identifies cancer stem cell-enriched populations of partially mesenchymal carcinoma cells Bierie, Brian Pierce, Sarah E. Kroeger, Cornelia Stover, Daniel G. Pattabiraman, Diwakar R. Thiru, Prathapan Liu Donaher, Joana Reinhardt, Ferenc Chaffer, Christine L. Keckesova, Zuzana Weinberg, Robert A Massachusetts Institute of Technology. Department of Biology Weinberg, Robert A Neoplastic cells within individual carcinomas often exhibit considerable phenotypic heterogeneity in their epithelial versus mesenchymal-like cell states. Because carcinoma cells with mesenchymal features are often more resistant to therapy and may serve as a source of relapse, we sought to determine whether such cells could be further stratified into functionally distinct subtypes. Indeed, we find that a basal epithelial marker, integrin- β4 (ITGB4), can be used to enable stratification of mesenchymallike triple-negative breast cancer (TNBC) cells that differ from one another in their relative tumorigenic abilities. Notably, we demonstrate that ITGB4 + cancer stem cell (CSC)-enriched mesenchymal cells reside in an intermediate epithelial/mesenchymal phenotypic state. Among patients with TNBC who received chemotherapy, elevated ITGB4 expression was associated with a worse 5-year probability of relapse-free survival.Mechanistically,we find that the ZEB1 (zinc finger E-box binding homeobox 1) transcription factor activity in highly mesenchymal SUM159 TNBC cells can repress expression of the epithelial transcription factor TAp63α (tumor protein 63 isoform 1), a protein that promotes ITGB4 expression. In addition, we demonstrate that ZEB1 and ITGB4 are important in modulating the histopathological phenotypes of tumors derived from mesenchymal TNBC cells. Hence, mesenchymal carcinoma cell populations are internally heterogeneous, and ITGB4 is a mechanistically driven prognostic biomarker that can be used to identify the more aggressive subtypes of mesenchymal carcinoma cells in TNBC. The ability to rapidly isolate and mechanistically interrogate the CSC-enriched, partially mesenchymal carcinoma cells should further enable identification of novel therapeutic opportunities to improve the prognosis for high-risk patients with TNBC. 2017-11-17T14:38:44Z 2017-11-17T14:38:44Z 2017-03 2016-11 2017-10-30T12:17:12Z Article http://purl.org/eprint/type/JournalArticle 0027-8424 1091-6490 http://hdl.handle.net/1721.1/112217 Bierie, Brian et al. “Integrin-Β4 Identifies Cancer Stem Cell-Enriched Populations of Partially Mesenchymal Carcinoma Cells.” Proceedings of the National Academy of Sciences 114, 12 (March 2017): E2337–E2346 © 2017 National Academy of Sciences https://orcid.org/0000-0002-0895-3557 http://dx.doi.org/10.1073/PNAS.1618298114 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 | Bierie, Brian Pierce, Sarah E. Kroeger, Cornelia Stover, Daniel G. Pattabiraman, Diwakar R. Thiru, Prathapan Liu Donaher, Joana Reinhardt, Ferenc Chaffer, Christine L. Keckesova, Zuzana Weinberg, Robert A Integrin-β4 identifies cancer stem cell-enriched populations of partially mesenchymal carcinoma cells |
| title | Integrin-β4 identifies cancer stem cell-enriched populations of partially mesenchymal carcinoma cells |
| title_full | Integrin-β4 identifies cancer stem cell-enriched populations of partially mesenchymal carcinoma cells |
| title_fullStr | Integrin-β4 identifies cancer stem cell-enriched populations of partially mesenchymal carcinoma cells |
| title_full_unstemmed | Integrin-β4 identifies cancer stem cell-enriched populations of partially mesenchymal carcinoma cells |
| title_short | Integrin-β4 identifies cancer stem cell-enriched populations of partially mesenchymal carcinoma cells |
| title_sort | integrin β4 identifies cancer stem cell enriched populations of partially mesenchymal carcinoma cells |
| url | http://hdl.handle.net/1721.1/112217 https://orcid.org/0000-0002-0895-3557 |
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