Regulation of Cellular Heterogeneity and Rates of Symmetric and Asymmetric Divisions in Triple-Negative Breast Cancer
Differentiation events contribute to phenotypic cellular heterogeneity within tumors and influence disease progression and response to therapy. Here, we dissect mechanisms controlling intratumoral heterogeneity within triple-negative basal-like breast cancers. Tumor cells expressing the cytokeratin...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
|---|---|
| Other Authors: | |
| Format: | Article |
| Published: |
Elsevier
2018
|
| Online Access: | http://hdl.handle.net/1721.1/118749 https://orcid.org/0000-0001-5024-9718 https://orcid.org/0000-0001-8567-2049 |
| _version_ | 1826208877535821824 |
|---|---|
| author | Granit, Roy Z. Masury, Hadas Condiotti, Reba Fixler, Yaakov Gabai, Yael Glikman, Tzofia Winter, Eitan Nevo, Yuval Carmon, Einat Sella, Tamar Sonnenblick, Amir Peretz, Tamar Lehmann, Ulrich Paz, Keren Piccioni, Federica Ben-Porath, Ittai Dalin, Simona Regev, Aviv Root, David |
| author2 | Massachusetts Institute of Technology. Department of Biological Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Biological Engineering Granit, Roy Z. Masury, Hadas Condiotti, Reba Fixler, Yaakov Gabai, Yael Glikman, Tzofia Winter, Eitan Nevo, Yuval Carmon, Einat Sella, Tamar Sonnenblick, Amir Peretz, Tamar Lehmann, Ulrich Paz, Keren Piccioni, Federica Ben-Porath, Ittai Dalin, Simona Regev, Aviv Root, David |
| author_sort | Granit, Roy Z. |
| collection | MIT |
| description | Differentiation events contribute to phenotypic cellular heterogeneity within tumors and influence disease progression and response to therapy. Here, we dissect mechanisms controlling intratumoral heterogeneity within triple-negative basal-like breast cancers. Tumor cells expressing the cytokeratin K14 possess a differentiation state that is associated with that of normal luminal progenitors, and K14-negative cells are in a state closer to that of mature luminal cells. We show that cells can transition between these states through asymmetric divisions, which produce one K14+and one K14−daughter cell, and that these asymmetric divisions contribute to the generation of cellular heterogeneity. We identified several regulators that control the proportion of K14+cells in the population. EZH2 and Notch increase the numbers of K14+cells and their rates of symmetric divisions, and FOXA1 has an opposing effect. Our findings demonstrate that asymmetric divisions generate differentiation transitions and heterogeneity, and identify pathways that control breast cancer cellular composition. |
| first_indexed | 2024-09-23T14:14:04Z |
| format | Article |
| id | mit-1721.1/118749 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2024-09-23T14:14:04Z |
| publishDate | 2018 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | mit-1721.1/1187492022-10-01T19:57:57Z Regulation of Cellular Heterogeneity and Rates of Symmetric and Asymmetric Divisions in Triple-Negative Breast Cancer Granit, Roy Z. Masury, Hadas Condiotti, Reba Fixler, Yaakov Gabai, Yael Glikman, Tzofia Winter, Eitan Nevo, Yuval Carmon, Einat Sella, Tamar Sonnenblick, Amir Peretz, Tamar Lehmann, Ulrich Paz, Keren Piccioni, Federica Ben-Porath, Ittai Dalin, Simona Regev, Aviv Root, David Massachusetts Institute of Technology. Department of Biological Engineering Massachusetts Institute of Technology. Department of Biology Dalin, Simona Regev, Aviv Root, David Differentiation events contribute to phenotypic cellular heterogeneity within tumors and influence disease progression and response to therapy. Here, we dissect mechanisms controlling intratumoral heterogeneity within triple-negative basal-like breast cancers. Tumor cells expressing the cytokeratin K14 possess a differentiation state that is associated with that of normal luminal progenitors, and K14-negative cells are in a state closer to that of mature luminal cells. We show that cells can transition between these states through asymmetric divisions, which produce one K14+and one K14−daughter cell, and that these asymmetric divisions contribute to the generation of cellular heterogeneity. We identified several regulators that control the proportion of K14+cells in the population. EZH2 and Notch increase the numbers of K14+cells and their rates of symmetric divisions, and FOXA1 has an opposing effect. Our findings demonstrate that asymmetric divisions generate differentiation transitions and heterogeneity, and identify pathways that control breast cancer cellular composition. 2018-10-23T12:28:35Z 2018-10-23T12:28:35Z 2018-09 2018-07 2018-10-22T17:00:45Z Article http://purl.org/eprint/type/JournalArticle 22111247 http://hdl.handle.net/1721.1/118749 Granit, Roy Z., Hadas Masury, Reba Condiotti, Yaakov Fixler, Yael Gabai, Tzofia Glikman, Simona Dalin, et al. “Regulation of Cellular Heterogeneity and Rates of Symmetric and Asymmetric Divisions in Triple-Negative Breast Cancer.” Cell Reports 24, no. 12 (September 2018): 3237–3250. https://orcid.org/0000-0001-5024-9718 https://orcid.org/0000-0001-8567-2049 http://dx.doi.org/10.1016/j.celrep.2018.08.053 Cell Reports Creative Commons Attribution-NonCommercial-NoDerivs License http://creativecommons.org/licenses/by-nc-nd/4.0/ application/pdf Elsevier Elsevier |
| spellingShingle | Granit, Roy Z. Masury, Hadas Condiotti, Reba Fixler, Yaakov Gabai, Yael Glikman, Tzofia Winter, Eitan Nevo, Yuval Carmon, Einat Sella, Tamar Sonnenblick, Amir Peretz, Tamar Lehmann, Ulrich Paz, Keren Piccioni, Federica Ben-Porath, Ittai Dalin, Simona Regev, Aviv Root, David Regulation of Cellular Heterogeneity and Rates of Symmetric and Asymmetric Divisions in Triple-Negative Breast Cancer |
| title | Regulation of Cellular Heterogeneity and Rates of Symmetric and Asymmetric Divisions in Triple-Negative Breast Cancer |
| title_full | Regulation of Cellular Heterogeneity and Rates of Symmetric and Asymmetric Divisions in Triple-Negative Breast Cancer |
| title_fullStr | Regulation of Cellular Heterogeneity and Rates of Symmetric and Asymmetric Divisions in Triple-Negative Breast Cancer |
| title_full_unstemmed | Regulation of Cellular Heterogeneity and Rates of Symmetric and Asymmetric Divisions in Triple-Negative Breast Cancer |
| title_short | Regulation of Cellular Heterogeneity and Rates of Symmetric and Asymmetric Divisions in Triple-Negative Breast Cancer |
| title_sort | regulation of cellular heterogeneity and rates of symmetric and asymmetric divisions in triple negative breast cancer |
| url | http://hdl.handle.net/1721.1/118749 https://orcid.org/0000-0001-5024-9718 https://orcid.org/0000-0001-8567-2049 |
| work_keys_str_mv | AT granitroyz regulationofcellularheterogeneityandratesofsymmetricandasymmetricdivisionsintriplenegativebreastcancer AT masuryhadas regulationofcellularheterogeneityandratesofsymmetricandasymmetricdivisionsintriplenegativebreastcancer AT condiottireba regulationofcellularheterogeneityandratesofsymmetricandasymmetricdivisionsintriplenegativebreastcancer AT fixleryaakov regulationofcellularheterogeneityandratesofsymmetricandasymmetricdivisionsintriplenegativebreastcancer AT gabaiyael regulationofcellularheterogeneityandratesofsymmetricandasymmetricdivisionsintriplenegativebreastcancer AT glikmantzofia regulationofcellularheterogeneityandratesofsymmetricandasymmetricdivisionsintriplenegativebreastcancer AT wintereitan regulationofcellularheterogeneityandratesofsymmetricandasymmetricdivisionsintriplenegativebreastcancer AT nevoyuval regulationofcellularheterogeneityandratesofsymmetricandasymmetricdivisionsintriplenegativebreastcancer AT carmoneinat regulationofcellularheterogeneityandratesofsymmetricandasymmetricdivisionsintriplenegativebreastcancer AT sellatamar regulationofcellularheterogeneityandratesofsymmetricandasymmetricdivisionsintriplenegativebreastcancer AT sonnenblickamir regulationofcellularheterogeneityandratesofsymmetricandasymmetricdivisionsintriplenegativebreastcancer AT peretztamar regulationofcellularheterogeneityandratesofsymmetricandasymmetricdivisionsintriplenegativebreastcancer AT lehmannulrich regulationofcellularheterogeneityandratesofsymmetricandasymmetricdivisionsintriplenegativebreastcancer AT pazkeren regulationofcellularheterogeneityandratesofsymmetricandasymmetricdivisionsintriplenegativebreastcancer AT piccionifederica regulationofcellularheterogeneityandratesofsymmetricandasymmetricdivisionsintriplenegativebreastcancer AT benporathittai regulationofcellularheterogeneityandratesofsymmetricandasymmetricdivisionsintriplenegativebreastcancer AT dalinsimona regulationofcellularheterogeneityandratesofsymmetricandasymmetricdivisionsintriplenegativebreastcancer AT regevaviv regulationofcellularheterogeneityandratesofsymmetricandasymmetricdivisionsintriplenegativebreastcancer AT rootdavid regulationofcellularheterogeneityandratesofsymmetricandasymmetricdivisionsintriplenegativebreastcancer |