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Extracellular serine controls epidermal stem cell fate and tumor initiation
Tissue stem cells are the cell of origin for many malignancies. Metabolites regulate the balance between self-renewal and differentiation, but whether endogenous metabolic pathways or nutrient availability predispose stem cells to transformation remains unknown. Here, we address this question in epi...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7343604/ https://www.ncbi.nlm.nih.gov/pubmed/32451440 http://dx.doi.org/10.1038/s41556-020-0525-9 |
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author | Baksh, Sanjeethan C Todorova, Pavlina K Gur-Cohen, Shiri Hurwitz, Brian Ge, Yejing Novak, Jesse S S Tierney, Matthew T Racelis, June Fuchs, Elaine Finley, Lydia W S |
author_facet | Baksh, Sanjeethan C Todorova, Pavlina K Gur-Cohen, Shiri Hurwitz, Brian Ge, Yejing Novak, Jesse S S Tierney, Matthew T Racelis, June Fuchs, Elaine Finley, Lydia W S |
author_sort | Baksh, Sanjeethan C |
collection | PubMed |
description | Tissue stem cells are the cell of origin for many malignancies. Metabolites regulate the balance between self-renewal and differentiation, but whether endogenous metabolic pathways or nutrient availability predispose stem cells to transformation remains unknown. Here, we address this question in epidermal stem cells (EpdSCs), a cell of origin for squamous cell carcinoma (SCC). We find that oncogenic EpdSCs are serine auxotrophs whose growth and self-renewal requires abundant exogenous serine. When extracellular serine is limiting, EpdSCs activate de novo serine synthesis, which in turn stimulates αKG-dependent dioxygenases that remove the repressive histone modification H3K27me3 and activate differentiation programs. Accordingly, serine starvation or enforced α-ketoglutarate production antagonizes SCC growth. Conversely, blocking serine synthesis or repressing α-ketoglutarate driven demethylation facilitates malignant progression. Together, these findings reveal that extracellular serine is a critical determinant of EpdSC fate and provide insight into how nutrient availability is integrated with stem cell fate decisions during tumor initiation. |
format | Online Article Text |
id | pubmed-7343604 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
record_format | MEDLINE/PubMed |
spelling | pubmed-73436042020-11-25 Extracellular serine controls epidermal stem cell fate and tumor initiation Baksh, Sanjeethan C Todorova, Pavlina K Gur-Cohen, Shiri Hurwitz, Brian Ge, Yejing Novak, Jesse S S Tierney, Matthew T Racelis, June Fuchs, Elaine Finley, Lydia W S Nat Cell Biol Article Tissue stem cells are the cell of origin for many malignancies. Metabolites regulate the balance between self-renewal and differentiation, but whether endogenous metabolic pathways or nutrient availability predispose stem cells to transformation remains unknown. Here, we address this question in epidermal stem cells (EpdSCs), a cell of origin for squamous cell carcinoma (SCC). We find that oncogenic EpdSCs are serine auxotrophs whose growth and self-renewal requires abundant exogenous serine. When extracellular serine is limiting, EpdSCs activate de novo serine synthesis, which in turn stimulates αKG-dependent dioxygenases that remove the repressive histone modification H3K27me3 and activate differentiation programs. Accordingly, serine starvation or enforced α-ketoglutarate production antagonizes SCC growth. Conversely, blocking serine synthesis or repressing α-ketoglutarate driven demethylation facilitates malignant progression. Together, these findings reveal that extracellular serine is a critical determinant of EpdSC fate and provide insight into how nutrient availability is integrated with stem cell fate decisions during tumor initiation. 2020-05-25 2020-07 /pmc/articles/PMC7343604/ /pubmed/32451440 http://dx.doi.org/10.1038/s41556-020-0525-9 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms |
spellingShingle | Article Baksh, Sanjeethan C Todorova, Pavlina K Gur-Cohen, Shiri Hurwitz, Brian Ge, Yejing Novak, Jesse S S Tierney, Matthew T Racelis, June Fuchs, Elaine Finley, Lydia W S Extracellular serine controls epidermal stem cell fate and tumor initiation |
title | Extracellular serine controls epidermal stem cell fate and tumor initiation |
title_full | Extracellular serine controls epidermal stem cell fate and tumor initiation |
title_fullStr | Extracellular serine controls epidermal stem cell fate and tumor initiation |
title_full_unstemmed | Extracellular serine controls epidermal stem cell fate and tumor initiation |
title_short | Extracellular serine controls epidermal stem cell fate and tumor initiation |
title_sort | extracellular serine controls epidermal stem cell fate and tumor initiation |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7343604/ https://www.ncbi.nlm.nih.gov/pubmed/32451440 http://dx.doi.org/10.1038/s41556-020-0525-9 |
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