Cell-State Transitions Regulated by SLUG Are Critical for Tissue Regeneration and Tumor Initiation
Perturbations in stem cell activity and differentiation can lead to developmental defects and cancer. We use an approach involving a quantitative model of cell-state transitions in vitro to gain insights into how SLUG/SNAI2, a key developmental transcription factor, modulates mammary epithelial stem...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | en_US |
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Elsevier
2015
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| Online Access: | http://hdl.handle.net/1721.1/96452 https://orcid.org/0000-0002-9703-1780 |
| _version_ | 1826205554764152832 |
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| author | Phillips, Sarah Prat, Aleix Sedic, Maja Proia, Theresa Wronski, Ania Mazumdar, Sohini Skibinski, Adam Shirley, Stephanie H. Perou, Charles M. Gill, Grace Kuperwasser, Charlotte Gupta, Piyush |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Phillips, Sarah Prat, Aleix Sedic, Maja Proia, Theresa Wronski, Ania Mazumdar, Sohini Skibinski, Adam Shirley, Stephanie H. Perou, Charles M. Gill, Grace Kuperwasser, Charlotte Gupta, Piyush |
| author_sort | Phillips, Sarah |
| collection | MIT |
| description | Perturbations in stem cell activity and differentiation can lead to developmental defects and cancer. We use an approach involving a quantitative model of cell-state transitions in vitro to gain insights into how SLUG/SNAI2, a key developmental transcription factor, modulates mammary epithelial stem cell activity and differentiation in vivo. In the absence of SLUG, stem cells fail to transition into basal progenitor cells, while existing basal progenitor cells undergo luminal differentiation; together, these changes result in abnormal mammary architecture and defects in tissue function. Furthermore, we show that in the absence of SLUG, mammary stem cell activity necessary for tissue regeneration and cancer initiation is lost. Mechanistically, SLUG regulates differentiation and cellular plasticity by recruiting the chromatin modifier lysine-specific demethylase 1 (LSD1) to promoters of lineage-specific genes to repress transcription. Together, these results demonstrate that SLUG plays a dual role in repressing luminal epithelial differentiation while unlocking stem cell transitions necessary for tumorigenesis. |
| first_indexed | 2024-09-23T13:15:18Z |
| format | Article |
| id | mit-1721.1/96452 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T13:15:18Z |
| publishDate | 2015 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | mit-1721.1/964522022-10-01T13:59:46Z Cell-State Transitions Regulated by SLUG Are Critical for Tissue Regeneration and Tumor Initiation Phillips, Sarah Prat, Aleix Sedic, Maja Proia, Theresa Wronski, Ania Mazumdar, Sohini Skibinski, Adam Shirley, Stephanie H. Perou, Charles M. Gill, Grace Kuperwasser, Charlotte Gupta, Piyush Massachusetts Institute of Technology. Department of Biology Whitehead Institute for Biomedical Research Gupta, Piyush Perturbations in stem cell activity and differentiation can lead to developmental defects and cancer. We use an approach involving a quantitative model of cell-state transitions in vitro to gain insights into how SLUG/SNAI2, a key developmental transcription factor, modulates mammary epithelial stem cell activity and differentiation in vivo. In the absence of SLUG, stem cells fail to transition into basal progenitor cells, while existing basal progenitor cells undergo luminal differentiation; together, these changes result in abnormal mammary architecture and defects in tissue function. Furthermore, we show that in the absence of SLUG, mammary stem cell activity necessary for tissue regeneration and cancer initiation is lost. Mechanistically, SLUG regulates differentiation and cellular plasticity by recruiting the chromatin modifier lysine-specific demethylase 1 (LSD1) to promoters of lineage-specific genes to repress transcription. Together, these results demonstrate that SLUG plays a dual role in repressing luminal epithelial differentiation while unlocking stem cell transitions necessary for tumorigenesis. Breast Cancer Research Foundation Eunice Kennedy Shriver National Institute of Child Health and Human Development (U.S.) (R01HD073035) National Cancer Institute (U.S.). Breast SPORE Program (P50-CA58223-09A1) National Cancer Institute (U.S.) (Grant R01-CA148761) National Cancer Institute (U.S.) (R01CA125554) National Center for Research Resources (U.S.) (Grant UL1 RR025752) National Center for Advancing Translational Sciences (U.S.) (Grant UL1 TR000073) 2015-04-08T18:01:53Z 2015-04-08T18:01:53Z 2014-04 2014-03 Article http://purl.org/eprint/type/JournalArticle 22136711 http://hdl.handle.net/1721.1/96452 Phillips, Sarah, Aleix Prat, Maja Sedic, Theresa Proia, Ania Wronski, Sohini Mazumdar, Adam Skibinski, et al. “Cell-State Transitions Regulated by SLUG Are Critical for Tissue Regeneration and Tumor Initiation.” Stem Cell Reports 2, no. 5 (May 2014): 633–647. https://orcid.org/0000-0002-9703-1780 en_US http://dx.doi.org/10.1016/j.stemcr.2014.03.008 Stem Cell Reports Creative Commons Attribution-NonCommercial-NoDerivatives http://creativecommons.org/licenses/by-nc-nd/3.0/ application/pdf Elsevier Elsevier |
| spellingShingle | Phillips, Sarah Prat, Aleix Sedic, Maja Proia, Theresa Wronski, Ania Mazumdar, Sohini Skibinski, Adam Shirley, Stephanie H. Perou, Charles M. Gill, Grace Kuperwasser, Charlotte Gupta, Piyush Cell-State Transitions Regulated by SLUG Are Critical for Tissue Regeneration and Tumor Initiation |
| title | Cell-State Transitions Regulated by SLUG Are Critical for Tissue Regeneration and Tumor Initiation |
| title_full | Cell-State Transitions Regulated by SLUG Are Critical for Tissue Regeneration and Tumor Initiation |
| title_fullStr | Cell-State Transitions Regulated by SLUG Are Critical for Tissue Regeneration and Tumor Initiation |
| title_full_unstemmed | Cell-State Transitions Regulated by SLUG Are Critical for Tissue Regeneration and Tumor Initiation |
| title_short | Cell-State Transitions Regulated by SLUG Are Critical for Tissue Regeneration and Tumor Initiation |
| title_sort | cell state transitions regulated by slug are critical for tissue regeneration and tumor initiation |
| url | http://hdl.handle.net/1721.1/96452 https://orcid.org/0000-0002-9703-1780 |
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