Regulation of Cellular Heterogeneity and Rates of Symmetric and Asymmetric Divisions in Triple-Negative Breast Cancer
Summary: 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 cyt...
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| Format: | Article |
| Language: | English |
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Elsevier
2018-09-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124718313391 |
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doaj-17fd09a8613d4560b76a4fa0d578df12 |
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Article |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Roy Z. Granit Hadas Masury Reba Condiotti Yaakov Fixler Yael Gabai Tzofia Glikman Simona Dalin Eitan Winter Yuval Nevo Einat Carmon Tamar Sella Amir Sonnenblick Tamar Peretz Ulrich Lehmann Keren Paz Federica Piccioni Aviv Regev David E. Root Ittai Ben-Porath |
| spellingShingle |
Roy Z. Granit Hadas Masury Reba Condiotti Yaakov Fixler Yael Gabai Tzofia Glikman Simona Dalin Eitan Winter Yuval Nevo Einat Carmon Tamar Sella Amir Sonnenblick Tamar Peretz Ulrich Lehmann Keren Paz Federica Piccioni Aviv Regev David E. Root Ittai Ben-Porath Regulation of Cellular Heterogeneity and Rates of Symmetric and Asymmetric Divisions in Triple-Negative Breast Cancer Cell Reports |
| author_facet |
Roy Z. Granit Hadas Masury Reba Condiotti Yaakov Fixler Yael Gabai Tzofia Glikman Simona Dalin Eitan Winter Yuval Nevo Einat Carmon Tamar Sella Amir Sonnenblick Tamar Peretz Ulrich Lehmann Keren Paz Federica Piccioni Aviv Regev David E. Root Ittai Ben-Porath |
| author_sort |
Roy Z. Granit |
| title |
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_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_sort |
regulation of cellular heterogeneity and rates of symmetric and asymmetric divisions in triple-negative breast cancer |
| publisher |
Elsevier |
| series |
Cell Reports |
| issn |
2211-1247 |
| publishDate |
2018-09-01 |
| description |
Summary: 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. : Granit et al. study the sources of phenotypic cellular heterogeneity in triple-negative breast cancers. They find that cancer cells can undergo asymmetric divisions that produce K14+ and K14− daughters and thereby generate heterogeneity. K14+ cells possess a progenitor-associated, tumorigenic phenotype, and the authors identify regulators that control their relative numbers. Keywords: triple-negative breast cancer, basal-like breast cancer, tumor heterogeneity, asymmetric divisions, mammary progenitor cells, EZH2, Notch, FOXA1, NFIB, KLF5 |
| url |
http://www.sciencedirect.com/science/article/pii/S2211124718313391 |
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doaj-17fd09a8613d4560b76a4fa0d578df122020-11-25T01:31:30ZengElsevierCell Reports2211-12472018-09-01241232373250Regulation of Cellular Heterogeneity and Rates of Symmetric and Asymmetric Divisions in Triple-Negative Breast CancerRoy Z. Granit0Hadas Masury1Reba Condiotti2Yaakov Fixler3Yael Gabai4Tzofia Glikman5Simona Dalin6Eitan Winter7Yuval Nevo8Einat Carmon9Tamar Sella10Amir Sonnenblick11Tamar Peretz12Ulrich Lehmann13Keren Paz14Federica Piccioni15Aviv Regev16David E. Root17Ittai Ben-Porath18Department of Developmental Biology and Cancer Research, Institute for Medical Research–Israel-Canada, The Hebrew University–Hadassah Medical School, Jerusalem 91120, IsraelDepartment of Developmental Biology and Cancer Research, Institute for Medical Research–Israel-Canada, The Hebrew University–Hadassah Medical School, Jerusalem 91120, IsraelDepartment of Developmental Biology and Cancer Research, Institute for Medical Research–Israel-Canada, The Hebrew University–Hadassah Medical School, Jerusalem 91120, IsraelDepartment of Developmental Biology and Cancer Research, Institute for Medical Research–Israel-Canada, The Hebrew University–Hadassah Medical School, Jerusalem 91120, IsraelDepartment of Developmental Biology and Cancer Research, Institute for Medical Research–Israel-Canada, The Hebrew University–Hadassah Medical School, Jerusalem 91120, IsraelDepartment of Developmental Biology and Cancer Research, Institute for Medical Research–Israel-Canada, The Hebrew University–Hadassah Medical School, Jerusalem 91120, IsraelDepartment of Developmental Biology and Cancer Research, Institute for Medical Research–Israel-Canada, The Hebrew University–Hadassah Medical School, Jerusalem 91120, IsraelInfo-CORE, Bioinformatics Unit of the I-CORE Computation Center at The Hebrew University and Hadassah, Jerusalem 91120, IsraelInfo-CORE, Bioinformatics Unit of the I-CORE Computation Center at The Hebrew University and Hadassah, Jerusalem 91120, IsraelDepartment of Surgery, Hadassah–Hebrew University Medical Center, Jerusalem 91120, IsraelDepartment of Radiology, Hadassah–Hebrew University Medical Center, Jerusalem 91120, IsraelSharett Institute of Oncology, Hadassah–Hebrew University Medical Center, Jerusalem 91120, IsraelSharett Institute of Oncology, Hadassah–Hebrew University Medical Center, Jerusalem 91120, IsraelInstitute of Pathology, Medizinische Hochschule Hannover, 30625 Hannover, GermanyChampions Oncology, Inc., Baltimore, MD 21205, USABroad Institute of MIT and Harvard, Cambridge, MA 02142, USABroad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Howard Hughes Medical Institute and David H. Koch Institute of Integrative Cancer Biology, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USABroad Institute of MIT and Harvard, Cambridge, MA 02142, USADepartment of Developmental Biology and Cancer Research, Institute for Medical Research–Israel-Canada, The Hebrew University–Hadassah Medical School, Jerusalem 91120, Israel; Corresponding authorSummary: 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. : Granit et al. study the sources of phenotypic cellular heterogeneity in triple-negative breast cancers. They find that cancer cells can undergo asymmetric divisions that produce K14+ and K14− daughters and thereby generate heterogeneity. K14+ cells possess a progenitor-associated, tumorigenic phenotype, and the authors identify regulators that control their relative numbers. Keywords: triple-negative breast cancer, basal-like breast cancer, tumor heterogeneity, asymmetric divisions, mammary progenitor cells, EZH2, Notch, FOXA1, NFIB, KLF5http://www.sciencedirect.com/science/article/pii/S2211124718313391 |