Inhibiting NR5A2 targets stemness in pancreatic cancer by disrupting SOX2/MYC signaling and restoring chemosensitivity

Zheng, Quan; Tang, Jiajia; Aicher, Alexandra; Bou Kheir, Tony; Sabanovic, Berina; Ananthanarayanan, Preeta; Reina, Chiara; Chen, Minchun; Gu, Jian-Min; He, Bin; Alcalá, Sonia; Behrens, Diana; Lawlor, Rita T.; Scarpa, Aldo; Hidalgo, Manuel; Sainz, Bruno Jr.; Sancho, Patricia; Heeschen, Christopher

Inhibiting NR5A2 targets stemness in pancreatic cancer by disrupting SOX2/MYC signaling and restoring chemosensitivity

[Background]; Pancreatic ductal adenocarcinoma (PDAC) is a profoundly aggressive and fatal cancer. One of the key factors defining its aggressiveness and resilience against chemotherapy is the existence of cancer stem cells (CSCs). The important task of discovering upstream regulators of stemness th...

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Autores:	Zheng, Quan, Tang, Jiajia, Aicher, Alexandra, Bou Kheir, Tony, Sabanovic, Berina, Ananthanarayanan, Preeta, Reina, Chiara, Chen, Minchun, Gu, Jian-Min, He, Bin, Alcalá, Sonia, Behrens, Diana, Lawlor, Rita T., Scarpa, Aldo, Hidalgo, Manuel, Sainz, Bruno Jr., Sancho, Patricia, Heeschen, Christopher
Tipo de recurso:	artículo
Estado:	Versión publicada
Fecha de publicación:	2023
País:	España
Institución:	Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:	DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:	oai:digital.csic.es:10261/349714
Acceso en línea:	http://hdl.handle.net/10261/349714
Access Level:	acceso abierto
Palabra clave:	Pancreatic ductal adenocarcinoma Cancer stem cells Metabolism SOX2 MYC

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oai_identifier_str	oai:digital.csic.es:10261/349714
network_acronym_str	ES
network_name_str	España
repository_id_str
dc.title.none.fl_str_mv	Inhibiting NR5A2 targets stemness in pancreatic cancer by disrupting SOX2/MYC signaling and restoring chemosensitivity
title	Inhibiting NR5A2 targets stemness in pancreatic cancer by disrupting SOX2/MYC signaling and restoring chemosensitivity
spellingShingle	Inhibiting NR5A2 targets stemness in pancreatic cancer by disrupting SOX2/MYC signaling and restoring chemosensitivity Zheng, Quan Pancreatic ductal adenocarcinoma Cancer stem cells Metabolism SOX2 MYC
title_short	Inhibiting NR5A2 targets stemness in pancreatic cancer by disrupting SOX2/MYC signaling and restoring chemosensitivity
title_full	Inhibiting NR5A2 targets stemness in pancreatic cancer by disrupting SOX2/MYC signaling and restoring chemosensitivity
title_fullStr	Inhibiting NR5A2 targets stemness in pancreatic cancer by disrupting SOX2/MYC signaling and restoring chemosensitivity
title_full_unstemmed	Inhibiting NR5A2 targets stemness in pancreatic cancer by disrupting SOX2/MYC signaling and restoring chemosensitivity
title_sort	Inhibiting NR5A2 targets stemness in pancreatic cancer by disrupting SOX2/MYC signaling and restoring chemosensitivity
dc.creator.none.fl_str_mv	Zheng, Quan Tang, Jiajia Aicher, Alexandra Bou Kheir, Tony Sabanovic, Berina Ananthanarayanan, Preeta Reina, Chiara Chen, Minchun Gu, Jian-Min He, Bin Alcalá, Sonia Behrens, Diana Lawlor, Rita T. Scarpa, Aldo Hidalgo, Manuel Sainz, Bruno Jr. Sancho, Patricia Heeschen, Christopher
author	Zheng, Quan
author_facet	Zheng, Quan Tang, Jiajia Aicher, Alexandra Bou Kheir, Tony Sabanovic, Berina Ananthanarayanan, Preeta Reina, Chiara Chen, Minchun Gu, Jian-Min He, Bin Alcalá, Sonia Behrens, Diana Lawlor, Rita T. Scarpa, Aldo Hidalgo, Manuel Sainz, Bruno Jr. Sancho, Patricia Heeschen, Christopher
author_role	author
author2	Tang, Jiajia Aicher, Alexandra Bou Kheir, Tony Sabanovic, Berina Ananthanarayanan, Preeta Reina, Chiara Chen, Minchun Gu, Jian-Min He, Bin Alcalá, Sonia Behrens, Diana Lawlor, Rita T. Scarpa, Aldo Hidalgo, Manuel Sainz, Bruno Jr. Sancho, Patricia Heeschen, Christopher
author2_role	author author author author author author author author author author author author author author author author author
dc.contributor.none.fl_str_mv	European Research Council European Commission Regione Piemonte Shanghai Municipal Education Commission National Natural Science Foundation of China Ministry of Science and Technology (Taiwan) Associazione Italiana per la Ricerca sul Cancro Ministero della Salute Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv	Pancreatic ductal adenocarcinoma Cancer stem cells Metabolism SOX2 MYC
topic	Pancreatic ductal adenocarcinoma Cancer stem cells Metabolism SOX2 MYC
description	[Background]; Pancreatic ductal adenocarcinoma (PDAC) is a profoundly aggressive and fatal cancer. One of the key factors defining its aggressiveness and resilience against chemotherapy is the existence of cancer stem cells (CSCs). The important task of discovering upstream regulators of stemness that are amenable for targeting in PDAC is essential for the advancement of more potent therapeutic approaches. In this study, we sought to elucidate the function of the nuclear receptor subfamily 5, group A, member 2 (NR5A2) in the context of pancreatic CSCs.
publishDate	2023
dc.date.none.fl_str_mv	2023 2024 2024
dc.type.none.fl_str_mv	info:eu-repo/semantics/article http://purl.org/coar/resource_type/c_6501 Publisher's version info:eu-repo/semantics/publishedVersion
format	article
status_str	publishedVersion
dc.identifier.none.fl_str_mv	http://hdl.handle.net/10261/349714
url	http://hdl.handle.net/10261/349714
dc.language.none.fl_str_mv	Gallego
language_invalid_str_mv	Gallego
dc.relation.none.fl_str_mv	#PLACEHOLDER_PARENT_METADATA_VALUE# info:eu-repo/grantAgreement/EC/FP7/602783 Zheng, Quan; Tang, Jiajia; Aicher, Alexandra; Bou Kheir, Tony; Sabanovic, Berina; Ananthanarayanan, Preeta; Reina, Chiara; Chen, Minchun; Gu, Jian-Min; He, Bin; Alcalá, Sonia; Behrens, Diana; Lawlo, Rita T.; Scarpa, Aldo; Hidalgo, Manuel; Sainz, Bruno Jr.; Sancho, Patricia; Heeschen, Christopher; 2023; Additional file 1 of Inhibiting NR5A2 targets stemness in pancreatic cancer by disrupting SOX2/MYC signaling and restoring chemosensitivity [Dataset]; FIgshare; https://doi.org/10.6084/m9.figshare.24647258.v1 https://doi.org/10.1186/s13046-023-02883-y Sí
dc.rights.none.fl_str_mv	info:eu-repo/semantics/openAccess
eu_rights_str_mv	openAccess
dc.format.none.fl_str_mv	application/pdf
dc.publisher.none.fl_str_mv	BioMed Central
publisher.none.fl_str_mv	BioMed Central
dc.source.none.fl_str_mv	reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str	Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str	DIGITAL.CSIC. Repositorio Institucional del CSIC
collection	DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_	1869423092608008192
spelling	Inhibiting NR5A2 targets stemness in pancreatic cancer by disrupting SOX2/MYC signaling and restoring chemosensitivityZheng, QuanTang, JiajiaAicher, AlexandraBou Kheir, TonySabanovic, BerinaAnanthanarayanan, PreetaReina, ChiaraChen, MinchunGu, Jian-MinHe, BinAlcalá, SoniaBehrens, DianaLawlor, Rita T.Scarpa, AldoHidalgo, ManuelSainz, Bruno Jr.Sancho, PatriciaHeeschen, ChristopherPancreatic ductal adenocarcinomaCancer stem cellsMetabolismSOX2MYC[Background]; Pancreatic ductal adenocarcinoma (PDAC) is a profoundly aggressive and fatal cancer. One of the key factors defining its aggressiveness and resilience against chemotherapy is the existence of cancer stem cells (CSCs). The important task of discovering upstream regulators of stemness that are amenable for targeting in PDAC is essential for the advancement of more potent therapeutic approaches. In this study, we sought to elucidate the function of the nuclear receptor subfamily 5, group A, member 2 (NR5A2) in the context of pancreatic CSCs.[Methods]: We modeled human PDAC using primary PDAC cells and CSC-enriched sphere cultures. NR5A2 was genetically silenced or inhibited with Cpd3. Assays included RNA-seq, sphere/colony formation, cell viability/toxicity, real-time PCR, western blot, immunofluorescence, ChIP, CUT&Tag, XF Analysis, lactate production, and in vivo tumorigenicity assays. PDAC models from 18 patients were treated with Cpd3-loaded nanocarriers.[Results]: Our findings demonstrate that NR5A2 plays a dual role in PDAC. In differentiated cancer cells, NR5A2 promotes cell proliferation by inhibiting CDKN1A. On the other hand, in the CSC population, NR5A2 enhances stemness by upregulating SOX2 through direct binding to its promotor/enhancer region. Additionally, NR5A2 suppresses MYC, leading to the activation of the mitochondrial biogenesis factor PPARGC1A and a shift in metabolism towards oxidative phosphorylation, which is a crucial feature of stemness in PDAC. Importantly, our study shows that the specific NR5A2 inhibitor, Cpd3, sensitizes a significant fraction of PDAC models derived from 18 patients to standard chemotherapy. This treatment approach results in durable remissions and long-term survival. Furthermore, we demonstrate that the expression levels of NR5A2/SOX2 can predict the response to treatment.[Conclusions]: The findings of our study highlight the cell context-dependent effects of NR5A2 in PDAC. We have identified a novel pharmacological strategy to modulate SOX2 and MYC levels, which disrupts stemness and prevents relapse in this deadly disease. These insights provide valuable information for the development of targeted therapies for PDAC, offering new hope for improved patient outcomes.This work was supported by the ERC Advanced Investigator Grant (Pa-CSC 233460, to CH), the European Community's Seventh Framework Programme (FP7) under grant agreement n° 602783 (CAM-PaC, to CH), the Fondazione del Piemonte per l’Oncologia – IRCCS (PTCRC-Intra-2021 to CH), the Shanghai Municipal Education Commission (2021–01-07–00-02-E00090, to CH), the National Natural Science Foundation of China (82130074 and 82250710179 to CH; 81902673, to QZ), the Ministry of Science and Technology, Taiwan (Grant number MOST 111–2314-B-039–056, to AA), Shanghai Pujiang Program (21PJ1408900, to JT), Associazione Italiana Ricerca Cancro IG n. 26343 (A.S.), and Fondazione Italiana Malattie Pancreas – Ministero Salute FIMP_CUP J37G22000230001 (RTL).Peer reviewedBioMed CentralEuropean Research CouncilEuropean CommissionRegione PiemonteShanghai Municipal Education CommissionNational Natural Science Foundation of ChinaMinistry of Science and Technology (Taiwan)Associazione Italiana per la Ricerca sul CancroMinistero della SaluteConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202420242023info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://hdl.handle.net/10261/349714reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Gallego#PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/EC/FP7/602783Zheng, Quan; Tang, Jiajia; Aicher, Alexandra; Bou Kheir, Tony; Sabanovic, Berina; Ananthanarayanan, Preeta; Reina, Chiara; Chen, Minchun; Gu, Jian-Min; He, Bin; Alcalá, Sonia; Behrens, Diana; Lawlo, Rita T.; Scarpa, Aldo; Hidalgo, Manuel; Sainz, Bruno Jr.; Sancho, Patricia; Heeschen, Christopher; 2023; Additional file 1 of Inhibiting NR5A2 targets stemness in pancreatic cancer by disrupting SOX2/MYC signaling and restoring chemosensitivity [Dataset]; FIgshare; https://doi.org/10.6084/m9.figshare.24647258.v1https://doi.org/10.1186/s13046-023-02883-ySíinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/3497142026-05-22T06:33:51Z
score	15,811543

Inhibiting NR5A2 targets stemness in pancreatic cancer by disrupting SOX2/MYC signaling and restoring chemosensitivity

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