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Non-canonical functions of SNAIL drive context-specific cancer progression

SNAIL is a key transcriptional regulator in embryonic development and cancer. Its effects in physiology and disease are believed to be linked to its role as a master regulator of epithelial-to-mesenchymal transition (EMT). Here, we report EMT-independent oncogenic SNAIL functions in cancer. Using ge...

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Autores principales: Paul, Mariel C., Schneeweis, Christian, Falcomatà, Chiara, Shan, Chuan, Rossmeisl, Daniel, Koutsouli, Stella, Klement, Christine, Zukowska, Magdalena, Widholz, Sebastian A., Jesinghaus, Moritz, Heuermann, Konstanze K., Engleitner, Thomas, Seidler, Barbara, Sleiman, Katia, Steiger, Katja, Tschurtschenthaler, Markus, Walter, Benjamin, Weidemann, Sören A., Pietsch, Regina, Schnieke, Angelika, Schmid, Roland M., Robles, Maria S., Andrieux, Geoffroy, Boerries, Melanie, Rad, Roland, Schneider, Günter, Saur, Dieter
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9992512/
https://www.ncbi.nlm.nih.gov/pubmed/36882420
http://dx.doi.org/10.1038/s41467-023-36505-0
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author Paul, Mariel C.
Schneeweis, Christian
Falcomatà, Chiara
Shan, Chuan
Rossmeisl, Daniel
Koutsouli, Stella
Klement, Christine
Zukowska, Magdalena
Widholz, Sebastian A.
Jesinghaus, Moritz
Heuermann, Konstanze K.
Engleitner, Thomas
Seidler, Barbara
Sleiman, Katia
Steiger, Katja
Tschurtschenthaler, Markus
Walter, Benjamin
Weidemann, Sören A.
Pietsch, Regina
Schnieke, Angelika
Schmid, Roland M.
Robles, Maria S.
Andrieux, Geoffroy
Boerries, Melanie
Rad, Roland
Schneider, Günter
Saur, Dieter
author_facet Paul, Mariel C.
Schneeweis, Christian
Falcomatà, Chiara
Shan, Chuan
Rossmeisl, Daniel
Koutsouli, Stella
Klement, Christine
Zukowska, Magdalena
Widholz, Sebastian A.
Jesinghaus, Moritz
Heuermann, Konstanze K.
Engleitner, Thomas
Seidler, Barbara
Sleiman, Katia
Steiger, Katja
Tschurtschenthaler, Markus
Walter, Benjamin
Weidemann, Sören A.
Pietsch, Regina
Schnieke, Angelika
Schmid, Roland M.
Robles, Maria S.
Andrieux, Geoffroy
Boerries, Melanie
Rad, Roland
Schneider, Günter
Saur, Dieter
author_sort Paul, Mariel C.
collection PubMed
description SNAIL is a key transcriptional regulator in embryonic development and cancer. Its effects in physiology and disease are believed to be linked to its role as a master regulator of epithelial-to-mesenchymal transition (EMT). Here, we report EMT-independent oncogenic SNAIL functions in cancer. Using genetic models, we systematically interrogated SNAIL effects in various oncogenic backgrounds and tissue types. SNAIL-related phenotypes displayed remarkable tissue- and genetic context-dependencies, ranging from protective effects as observed in KRAS- or WNT-driven intestinal cancers, to dramatic acceleration of tumorigenesis, as shown in KRAS-induced pancreatic cancer. Unexpectedly, SNAIL-driven oncogenesis was not associated with E-cadherin downregulation or induction of an overt EMT program. Instead, we show that SNAIL induces bypass of senescence and cell cycle progression through p16(INK4A)-independent inactivation of the Retinoblastoma (RB)-restriction checkpoint. Collectively, our work identifies non-canonical EMT-independent functions of SNAIL and unravel its complex context-dependent role in cancer.
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spelling pubmed-99925122023-03-09 Non-canonical functions of SNAIL drive context-specific cancer progression Paul, Mariel C. Schneeweis, Christian Falcomatà, Chiara Shan, Chuan Rossmeisl, Daniel Koutsouli, Stella Klement, Christine Zukowska, Magdalena Widholz, Sebastian A. Jesinghaus, Moritz Heuermann, Konstanze K. Engleitner, Thomas Seidler, Barbara Sleiman, Katia Steiger, Katja Tschurtschenthaler, Markus Walter, Benjamin Weidemann, Sören A. Pietsch, Regina Schnieke, Angelika Schmid, Roland M. Robles, Maria S. Andrieux, Geoffroy Boerries, Melanie Rad, Roland Schneider, Günter Saur, Dieter Nat Commun Article SNAIL is a key transcriptional regulator in embryonic development and cancer. Its effects in physiology and disease are believed to be linked to its role as a master regulator of epithelial-to-mesenchymal transition (EMT). Here, we report EMT-independent oncogenic SNAIL functions in cancer. Using genetic models, we systematically interrogated SNAIL effects in various oncogenic backgrounds and tissue types. SNAIL-related phenotypes displayed remarkable tissue- and genetic context-dependencies, ranging from protective effects as observed in KRAS- or WNT-driven intestinal cancers, to dramatic acceleration of tumorigenesis, as shown in KRAS-induced pancreatic cancer. Unexpectedly, SNAIL-driven oncogenesis was not associated with E-cadherin downregulation or induction of an overt EMT program. Instead, we show that SNAIL induces bypass of senescence and cell cycle progression through p16(INK4A)-independent inactivation of the Retinoblastoma (RB)-restriction checkpoint. Collectively, our work identifies non-canonical EMT-independent functions of SNAIL and unravel its complex context-dependent role in cancer. Nature Publishing Group UK 2023-03-07 /pmc/articles/PMC9992512/ /pubmed/36882420 http://dx.doi.org/10.1038/s41467-023-36505-0 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Paul, Mariel C.
Schneeweis, Christian
Falcomatà, Chiara
Shan, Chuan
Rossmeisl, Daniel
Koutsouli, Stella
Klement, Christine
Zukowska, Magdalena
Widholz, Sebastian A.
Jesinghaus, Moritz
Heuermann, Konstanze K.
Engleitner, Thomas
Seidler, Barbara
Sleiman, Katia
Steiger, Katja
Tschurtschenthaler, Markus
Walter, Benjamin
Weidemann, Sören A.
Pietsch, Regina
Schnieke, Angelika
Schmid, Roland M.
Robles, Maria S.
Andrieux, Geoffroy
Boerries, Melanie
Rad, Roland
Schneider, Günter
Saur, Dieter
Non-canonical functions of SNAIL drive context-specific cancer progression
title Non-canonical functions of SNAIL drive context-specific cancer progression
title_full Non-canonical functions of SNAIL drive context-specific cancer progression
title_fullStr Non-canonical functions of SNAIL drive context-specific cancer progression
title_full_unstemmed Non-canonical functions of SNAIL drive context-specific cancer progression
title_short Non-canonical functions of SNAIL drive context-specific cancer progression
title_sort non-canonical functions of snail drive context-specific cancer progression
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9992512/
https://www.ncbi.nlm.nih.gov/pubmed/36882420
http://dx.doi.org/10.1038/s41467-023-36505-0
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