SOX9 triggers different epithelial to mesenchymal transition states to promote pancreatic cancer progression

Carrasco-Garcia, E. (Estefania)|||/items/ba45a153-c596-454a-9ed5-a85db319c200; Lopez-Serra, L. (Lidia)|||/items/68c2b4fa-baba-41c0-8c42-d7ca93647d40; Moncho-Amor, V. (Veronica)|||/items/a6a9757a-0135-4ffe-8b9b-c4af8b7bddcb; Carazo-Melo, F.(Fernando)|||/items/23abbe07-938d-434d-9483-864ef915f6b5; Aldaz, P. (Paula)|||/items/b9c0f230-0f8e-46a0-94e8-b85079ff62d9; Collado, M. (Manuel)|||/items/162d4146-4fa1-4f12-b63d-d4cd694a53ac; Bell, D. (Donald)|||/items/962fa51f-6f79-4ff9-a611-8585c695b9df; Gaafar, A. (Ayman)|||/items/8f807755-ad47-46f9-84b3-62d8ea4923f4; Karamitopoulou, E. (Eva)|||/items/209982f5-e411-4379-9574-1b31a27eaaa6; Tzankov, A. (Alexandar)|||/items/ceb514e7-d807-42da-a3de-52ae27771b52; Hidalgo, M. (Manuel)|||/items/82c25e37-ac17-42a8-89b6-9314a92a4b74; Rubio-Díaz-Cordovés, A. (Ángel)|||/items/7d740e1e-38db-46ea-9834-8c61aa6eedee; Serrano, M. (Manuel)|||/items/eab5ede4-df61-4fcb-ac7f-4c22d34c4030; Lawrie, C.H. (Charles H.)|||/items/30e8e5fb-0147-456d-8aa0-5bd189b30229; Lovell-Badge, R. (Robin)|||/items/c0ce18f2-245e-4e49-9835-0785934bce20; Matheu, A. (Ander)|||/items/79d399df-1789-495b-af31-49af2b5ea9e0

SOX9 triggers different epithelial to mesenchymal transition states to promote pancreatic cancer progression

Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers mainly due to spatial obstacles to complete resection, early metastasis and therapy resistance. The molecular events accompanying PDAC progression remain poorly understood. SOX9 is required for maintaining the panc...

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Autores:	Carrasco-Garcia, E. (Estefania)\|\|\|/items/ba45a153-c596-454a-9ed5-a85db319c200, Lopez-Serra, L. (Lidia)\|\|\|/items/68c2b4fa-baba-41c0-8c42-d7ca93647d40, Moncho-Amor, V. (Veronica)\|\|\|/items/a6a9757a-0135-4ffe-8b9b-c4af8b7bddcb, Carazo-Melo, F.(Fernando)\|\|\|/items/23abbe07-938d-434d-9483-864ef915f6b5, Aldaz, P. (Paula)\|\|\|/items/b9c0f230-0f8e-46a0-94e8-b85079ff62d9, Collado, M. (Manuel)\|\|\|/items/162d4146-4fa1-4f12-b63d-d4cd694a53ac, Bell, D. (Donald)\|\|\|/items/962fa51f-6f79-4ff9-a611-8585c695b9df, Gaafar, A. (Ayman)\|\|\|/items/8f807755-ad47-46f9-84b3-62d8ea4923f4, Karamitopoulou, E. (Eva)\|\|\|/items/209982f5-e411-4379-9574-1b31a27eaaa6, Tzankov, A. (Alexandar)\|\|\|/items/ceb514e7-d807-42da-a3de-52ae27771b52, Hidalgo, M. (Manuel)\|\|\|/items/82c25e37-ac17-42a8-89b6-9314a92a4b74, Rubio-Díaz-Cordovés, A. (Ángel)\|\|\|/items/7d740e1e-38db-46ea-9834-8c61aa6eedee, Serrano, M. (Manuel)\|\|\|/items/eab5ede4-df61-4fcb-ac7f-4c22d34c4030, Lawrie, C.H. (Charles H.)\|\|\|/items/30e8e5fb-0147-456d-8aa0-5bd189b30229, Lovell-Badge, R. (Robin)\|\|\|/items/c0ce18f2-245e-4e49-9835-0785934bce20, Matheu, A. (Ander)\|\|\|/items/79d399df-1789-495b-af31-49af2b5ea9e0
Tipo de recurso:	artículo
Fecha de publicación:	2022
País:	España
Institución:	Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:	Dadun. Depósito Académico Digital de la Universidad de Navarra
Idioma:	inglés
OAI Identifier:	oai:dadun.unav.edu:10171/123732
Acceso en línea:	https://hdl.handle.net/10171/123732
Access Level:	acceso abierto
Palabra clave:	EMT SOX9 Chemoresistance Metastasis Pancreatic cancer Plasticity

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repository_id_str
spelling	SOX9 triggers different epithelial to mesenchymal transition states to promote pancreatic cancer progressionCarrasco-Garcia, E. (Estefania)\|\|\|/items/ba45a153-c596-454a-9ed5-a85db319c200Lopez-Serra, L. (Lidia)\|\|\|/items/68c2b4fa-baba-41c0-8c42-d7ca93647d40Moncho-Amor, V. (Veronica)\|\|\|/items/a6a9757a-0135-4ffe-8b9b-c4af8b7bddcbCarazo-Melo, F.(Fernando)\|\|\|/items/23abbe07-938d-434d-9483-864ef915f6b5Aldaz, P. (Paula)\|\|\|/items/b9c0f230-0f8e-46a0-94e8-b85079ff62d9Collado, M. (Manuel)\|\|\|/items/162d4146-4fa1-4f12-b63d-d4cd694a53acBell, D. (Donald)\|\|\|/items/962fa51f-6f79-4ff9-a611-8585c695b9dfGaafar, A. (Ayman)\|\|\|/items/8f807755-ad47-46f9-84b3-62d8ea4923f4Karamitopoulou, E. (Eva)\|\|\|/items/209982f5-e411-4379-9574-1b31a27eaaa6Tzankov, A. (Alexandar)\|\|\|/items/ceb514e7-d807-42da-a3de-52ae27771b52Hidalgo, M. (Manuel)\|\|\|/items/82c25e37-ac17-42a8-89b6-9314a92a4b74Rubio-Díaz-Cordovés, A. (Ángel)\|\|\|/items/7d740e1e-38db-46ea-9834-8c61aa6eedeeSerrano, M. (Manuel)\|\|\|/items/eab5ede4-df61-4fcb-ac7f-4c22d34c4030Lawrie, C.H. (Charles H.)\|\|\|/items/30e8e5fb-0147-456d-8aa0-5bd189b30229Lovell-Badge, R. (Robin)\|\|\|/items/c0ce18f2-245e-4e49-9835-0785934bce20Matheu, A. (Ander)\|\|\|/items/79d399df-1789-495b-af31-49af2b5ea9e0EMTSOX9ChemoresistanceMetastasisPancreatic cancerPlasticityBackground: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers mainly due to spatial obstacles to complete resection, early metastasis and therapy resistance. The molecular events accompanying PDAC progression remain poorly understood. SOX9 is required for maintaining the pancreatic ductal identity and it is involved in the initiation of pancreatic cancer. In addition, SOX9 is a transcription factor linked to stem cell activity and is commonly overexpressed in solid cancers. It cooperates with Snail/Slug to induce epithelial-mesenchymal transition (EMT) during neural development and in diseases such as organ fibrosis or different types of cancer. Methods: We investigated the roles of SOX9 in pancreatic tumor cell plasticity, metastatic dissemination and chemoresistance using pancreatic cancer cell lines as well as mouse embryo fibroblasts. In addition, we characterized the clinical relevance of SOX9 in pancreatic cancer using human biopsies. Results: Gain- and loss-of-function of SOX9 in PDAC cells revealed that high levels of SOX9 increased migration and invasion, and promoted EMT and metastatic dissemination, whilst SOX9 silencing resulted in metastasis inhibition, along with a phenotypic reversion to epithelial features and loss of stemness potential. In both contexts, EMT factors were not altered. Moreover, high levels of SOX9 promoted resistance to gemcitabine. In contrast, overexpression of SOX9 was sufficient to promote metastatic potential in K-Ras transformed MEFs, triggering EMT associated with Snail/Slug activity. In clinical samples, SOX9 expression was analyzed in 198 PDAC cases by immunohistochemistry and in 53 patient derived xenografts (PDXs). SOX9 was overexpressed in primary adenocarcinomas and particularly in metastases. Notably, SOX9 expression correlated with high vimentin and low E-cadherin expression. Conclusions: Our results indicate that SOX9 facilitates PDAC progression and metastasis by triggering stemness and EMT.MDPIDadun. Depósito Académico Digital Universidad de Navarra20222022-01-0120222022-01-01journal articlehttp://purl.org/coar/resource_type/c_6501info:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/10171/123732reponame:Dadun. Depósito Académico Digital de la Universidad de Navarrainstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglésengopen accesshttp://purl.org/coar/access_right/c_abf2info:eu-repo/semantics/openAccessoai:dadun.unav.edu:10171/1237322026-06-21T12:47:57Z
dc.title.none.fl_str_mv	SOX9 triggers different epithelial to mesenchymal transition states to promote pancreatic cancer progression
title	SOX9 triggers different epithelial to mesenchymal transition states to promote pancreatic cancer progression
spellingShingle	SOX9 triggers different epithelial to mesenchymal transition states to promote pancreatic cancer progression Carrasco-Garcia, E. (Estefania)\|\|\|/items/ba45a153-c596-454a-9ed5-a85db319c200 EMT SOX9 Chemoresistance Metastasis Pancreatic cancer Plasticity
title_short	SOX9 triggers different epithelial to mesenchymal transition states to promote pancreatic cancer progression
title_full	SOX9 triggers different epithelial to mesenchymal transition states to promote pancreatic cancer progression
title_fullStr	SOX9 triggers different epithelial to mesenchymal transition states to promote pancreatic cancer progression
title_full_unstemmed	SOX9 triggers different epithelial to mesenchymal transition states to promote pancreatic cancer progression
title_sort	SOX9 triggers different epithelial to mesenchymal transition states to promote pancreatic cancer progression
dc.creator.none.fl_str_mv	Carrasco-Garcia, E. (Estefania)\|\|\|/items/ba45a153-c596-454a-9ed5-a85db319c200 Lopez-Serra, L. (Lidia)\|\|\|/items/68c2b4fa-baba-41c0-8c42-d7ca93647d40 Moncho-Amor, V. (Veronica)\|\|\|/items/a6a9757a-0135-4ffe-8b9b-c4af8b7bddcb Carazo-Melo, F.(Fernando)\|\|\|/items/23abbe07-938d-434d-9483-864ef915f6b5 Aldaz, P. (Paula)\|\|\|/items/b9c0f230-0f8e-46a0-94e8-b85079ff62d9 Collado, M. (Manuel)\|\|\|/items/162d4146-4fa1-4f12-b63d-d4cd694a53ac Bell, D. (Donald)\|\|\|/items/962fa51f-6f79-4ff9-a611-8585c695b9df Gaafar, A. (Ayman)\|\|\|/items/8f807755-ad47-46f9-84b3-62d8ea4923f4 Karamitopoulou, E. (Eva)\|\|\|/items/209982f5-e411-4379-9574-1b31a27eaaa6 Tzankov, A. (Alexandar)\|\|\|/items/ceb514e7-d807-42da-a3de-52ae27771b52 Hidalgo, M. (Manuel)\|\|\|/items/82c25e37-ac17-42a8-89b6-9314a92a4b74 Rubio-Díaz-Cordovés, A. (Ángel)\|\|\|/items/7d740e1e-38db-46ea-9834-8c61aa6eedee Serrano, M. (Manuel)\|\|\|/items/eab5ede4-df61-4fcb-ac7f-4c22d34c4030 Lawrie, C.H. (Charles H.)\|\|\|/items/30e8e5fb-0147-456d-8aa0-5bd189b30229 Lovell-Badge, R. (Robin)\|\|\|/items/c0ce18f2-245e-4e49-9835-0785934bce20 Matheu, A. (Ander)\|\|\|/items/79d399df-1789-495b-af31-49af2b5ea9e0
author	Carrasco-Garcia, E. (Estefania)\|\|\|/items/ba45a153-c596-454a-9ed5-a85db319c200
author_facet	Carrasco-Garcia, E. (Estefania)\|\|\|/items/ba45a153-c596-454a-9ed5-a85db319c200 Lopez-Serra, L. (Lidia)\|\|\|/items/68c2b4fa-baba-41c0-8c42-d7ca93647d40 Moncho-Amor, V. (Veronica)\|\|\|/items/a6a9757a-0135-4ffe-8b9b-c4af8b7bddcb Carazo-Melo, F.(Fernando)\|\|\|/items/23abbe07-938d-434d-9483-864ef915f6b5 Aldaz, P. (Paula)\|\|\|/items/b9c0f230-0f8e-46a0-94e8-b85079ff62d9 Collado, M. (Manuel)\|\|\|/items/162d4146-4fa1-4f12-b63d-d4cd694a53ac Bell, D. (Donald)\|\|\|/items/962fa51f-6f79-4ff9-a611-8585c695b9df Gaafar, A. (Ayman)\|\|\|/items/8f807755-ad47-46f9-84b3-62d8ea4923f4 Karamitopoulou, E. (Eva)\|\|\|/items/209982f5-e411-4379-9574-1b31a27eaaa6 Tzankov, A. (Alexandar)\|\|\|/items/ceb514e7-d807-42da-a3de-52ae27771b52 Hidalgo, M. (Manuel)\|\|\|/items/82c25e37-ac17-42a8-89b6-9314a92a4b74 Rubio-Díaz-Cordovés, A. (Ángel)\|\|\|/items/7d740e1e-38db-46ea-9834-8c61aa6eedee Serrano, M. (Manuel)\|\|\|/items/eab5ede4-df61-4fcb-ac7f-4c22d34c4030 Lawrie, C.H. (Charles H.)\|\|\|/items/30e8e5fb-0147-456d-8aa0-5bd189b30229 Lovell-Badge, R. (Robin)\|\|\|/items/c0ce18f2-245e-4e49-9835-0785934bce20 Matheu, A. (Ander)\|\|\|/items/79d399df-1789-495b-af31-49af2b5ea9e0
author_role	author
author2	Lopez-Serra, L. (Lidia)\|\|\|/items/68c2b4fa-baba-41c0-8c42-d7ca93647d40 Moncho-Amor, V. (Veronica)\|\|\|/items/a6a9757a-0135-4ffe-8b9b-c4af8b7bddcb Carazo-Melo, F.(Fernando)\|\|\|/items/23abbe07-938d-434d-9483-864ef915f6b5 Aldaz, P. (Paula)\|\|\|/items/b9c0f230-0f8e-46a0-94e8-b85079ff62d9 Collado, M. (Manuel)\|\|\|/items/162d4146-4fa1-4f12-b63d-d4cd694a53ac Bell, D. (Donald)\|\|\|/items/962fa51f-6f79-4ff9-a611-8585c695b9df Gaafar, A. (Ayman)\|\|\|/items/8f807755-ad47-46f9-84b3-62d8ea4923f4 Karamitopoulou, E. (Eva)\|\|\|/items/209982f5-e411-4379-9574-1b31a27eaaa6 Tzankov, A. (Alexandar)\|\|\|/items/ceb514e7-d807-42da-a3de-52ae27771b52 Hidalgo, M. (Manuel)\|\|\|/items/82c25e37-ac17-42a8-89b6-9314a92a4b74 Rubio-Díaz-Cordovés, A. (Ángel)\|\|\|/items/7d740e1e-38db-46ea-9834-8c61aa6eedee Serrano, M. (Manuel)\|\|\|/items/eab5ede4-df61-4fcb-ac7f-4c22d34c4030 Lawrie, C.H. (Charles H.)\|\|\|/items/30e8e5fb-0147-456d-8aa0-5bd189b30229 Lovell-Badge, R. (Robin)\|\|\|/items/c0ce18f2-245e-4e49-9835-0785934bce20 Matheu, A. (Ander)\|\|\|/items/79d399df-1789-495b-af31-49af2b5ea9e0
author2_role	author author author author author author author author author author author author author author author
dc.contributor.none.fl_str_mv	Dadun. Depósito Académico Digital Universidad de Navarra
dc.subject.none.fl_str_mv	EMT SOX9 Chemoresistance Metastasis Pancreatic cancer Plasticity
topic	EMT SOX9 Chemoresistance Metastasis Pancreatic cancer Plasticity
description	Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers mainly due to spatial obstacles to complete resection, early metastasis and therapy resistance. The molecular events accompanying PDAC progression remain poorly understood. SOX9 is required for maintaining the pancreatic ductal identity and it is involved in the initiation of pancreatic cancer. In addition, SOX9 is a transcription factor linked to stem cell activity and is commonly overexpressed in solid cancers. It cooperates with Snail/Slug to induce epithelial-mesenchymal transition (EMT) during neural development and in diseases such as organ fibrosis or different types of cancer. Methods: We investigated the roles of SOX9 in pancreatic tumor cell plasticity, metastatic dissemination and chemoresistance using pancreatic cancer cell lines as well as mouse embryo fibroblasts. In addition, we characterized the clinical relevance of SOX9 in pancreatic cancer using human biopsies. Results: Gain- and loss-of-function of SOX9 in PDAC cells revealed that high levels of SOX9 increased migration and invasion, and promoted EMT and metastatic dissemination, whilst SOX9 silencing resulted in metastasis inhibition, along with a phenotypic reversion to epithelial features and loss of stemness potential. In both contexts, EMT factors were not altered. Moreover, high levels of SOX9 promoted resistance to gemcitabine. In contrast, overexpression of SOX9 was sufficient to promote metastatic potential in K-Ras transformed MEFs, triggering EMT associated with Snail/Slug activity. In clinical samples, SOX9 expression was analyzed in 198 PDAC cases by immunohistochemistry and in 53 patient derived xenografts (PDXs). SOX9 was overexpressed in primary adenocarcinomas and particularly in metastases. Notably, SOX9 expression correlated with high vimentin and low E-cadherin expression. Conclusions: Our results indicate that SOX9 facilitates PDAC progression and metastasis by triggering stemness and EMT.
publishDate	2022
dc.date.none.fl_str_mv	2022 2022-01-01 2022 2022-01-01
dc.type.none.fl_str_mv	journal article http://purl.org/coar/resource_type/c_6501
dc.type.openaire.fl_str_mv	info:eu-repo/semantics/article
format	article
dc.identifier.none.fl_str_mv	https://hdl.handle.net/10171/123732
url	https://hdl.handle.net/10171/123732
dc.language.none.fl_str_mv	Inglés eng
language_invalid_str_mv	Inglés
language	eng
dc.rights.none.fl_str_mv	open access http://purl.org/coar/access_right/c_abf2
dc.rights.openaire.fl_str_mv	info:eu-repo/semantics/openAccess
rights_invalid_str_mv	open access http://purl.org/coar/access_right/c_abf2
eu_rights_str_mv	openAccess
dc.format.none.fl_str_mv	application/pdf
dc.publisher.none.fl_str_mv	MDPI
publisher.none.fl_str_mv	MDPI
dc.source.none.fl_str_mv	reponame:Dadun. Depósito Académico Digital de la Universidad de Navarra instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str	Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str	Dadun. Depósito Académico Digital de la Universidad de Navarra
collection	Dadun. Depósito Académico Digital de la Universidad de Navarra
repository.name.fl_str_mv
repository.mail.fl_str_mv
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SOX9 triggers different epithelial to mesenchymal transition states to promote pancreatic cancer progression

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